Research ArticleClinical Studies

Hypothyroidism as a Predictive Clinical Marker of Better Treatment Response to Sunitinib Therapy

DAVOR KUST, MARIN PRPIĆ, JURE MURGIĆ, MARIJANA JAZVIĆ, BLANKA JAKŠIĆ, DRAŽENA KRILIĆ, ANTE BOLANČA and ZVONKO KUSIĆ
Anticancer Research June 2014, 34 (6) 3177-3184;

Abstract

Background: Tyrosine kinase inhibitors are standard treatment in patients with metastatic renal cell carcinoma (mRCC). Several studies have indicated that side-effects including hypothyroidism may serve as potential predictive biomarkers of treatment efficacy. Patients and Methods: All patients with clear cell mRCC treated with sunitinib in the first-line setting in our Center between November 2008 and October 2013 were included. Thyroid function was assessed after every 2 cycles. Prognostic factors were tested using Cox proportional hazards model for univariate analysis. Results: During treatment, 29.3% developed hypothyroidism, with a median of peak TSH values of 34.4 mIU/L. Patients who had both TSH >4 mIU/L and were receiving substitution therapy with levothyroxine had prolonged PFS compared to all other patients (25.3 months vs. 9.0 months; p=0.042). Conclusion: The rate of hypothyroidism as a side-effect of sunitinib in patients with mRCC is significant. Patients with symptomatic hypothyroidism experienced significantly longer PFS, but without difference in OS.

Renal cell carcinoma (RCC) is the most frequent type of kidney cancer (2-3% of all cancers), with increasing incidence worldwide (1). Tyrosine kinase inhibitors (TKIs), especially sunitinib and sorafenib are nowadays a standard treatment option in patients with metastatic renal cell carcinoma (mRCC) (2). Underlying mechanism of action of sunitinib is complex and not entirely understood. It inhibits cellular signaling by targeting multiple receptor tyrosine kinases (RTKs), including all receptors for platelet-derived growth factor and vascular endothelial growth factor receptors, as well as some others, until now still not enough investigated receptors (3). By inhibiting these RTKs, sunitinib leads to reduction of tumor mass, both directly (cancer cell death) and indirectly by reduced vascularisation of tumor, as a consequence of inhibited angiogenesis.

Although generally well-tolerated and associated with low incidence of toxicities grade 3 or 4, sunitinib exhibits a distinct pattern of side-effects that require monitoring and management. The most common ones are hypertension, hand-foot syndrome, diarrhea, fatigue, stomatitis and hypothyroidism (4). Several studies have indicated that some side-effects, such as hypertension, hypothyroidism and hand-foot syndrome may serve as potential predictive biomarkers of treatment efficacy, but results are still controversial, with some studies confirming, and other rejecting these hypotheses (5-8). The mechanism of hypothyroidism development in patients receiving sunitinib therapy is not yet clearly understood, but it has been shown that sunitinib regulates growth and function in both normal and neoplastic thyroid cells. Sunitinib-induced hypothyroidism is usually mild, and can be easily treated with thyroid hormone replacement therapy (only patients with hypothyroidism grade 2 or higher require treatment) (9).

Assessment of thyroid function with thyroid hormone levels measurement is a standard procedure in our Institution for patients treated with TKIs. This study was undertaken to establish optimal diagnostic and treatment procedures in patients with sunitinib-induced hypothyroidism, with stress on determining possible predictive value of hypothyroidism that occurs during treatment.

Patients and Methods

Patients. All patients with clear-cell mRCC treated with sunitinib in the first-line setting in our Center between November 2008 and October 2013 were included. To receive sunitinib, patients had to meet following criteria: Absence of brain metastases, alanine and aspartate transaminase serume levels less than 5-times above the upper limit normal (ULN). Patients who received other therapy in the first-line setting, such as sorafenib and temsirolimus, were excluded from the study. Basic characteristics of patients are shown in Table I. Patients are predominantly classified as intermediate prognostic-group according to Memorial Sloan-Kettering Cancer Center (MSKCC) index, and all except one patient (inoperable disease due to locally advanced tumor) underwent nephrectomy prior to sunitinib therapy. Median age at diagnosis of RCC was 59 years, and median age at the initiation of sunitinib therapy was 60 years. Treatment efficacy assessment included computed tomography (CT) scan, bone scintigraphy, and other imaging techniques according to clinical indication, and was done after every 2 cycles of sunitinib therapy. Objective response to treatment was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1. Complete blood count (CBC) and biochemistry were assessed every 2 weeks at the beginning of therapy (first several months, depending on frequency and severity of side-effects), and later once monthly.

Hypothyroidism is defined as TSH level above ULN, combined with corresponding clinical symptoms (the one most commonly observed was fatigue). Thyroid function was assessed prior to introduction of therapy by evaluating the presence of symptoms and checking medical history, to identify possible pre-existing hormone imbalance. If hypothyroidism was suspected, additional tests; TSH, free thyroxine (FT4)/thyroxine (T4), and free triiodothyronine (FT3)/triiodothyronine (T3), were performed. Hormonal status was assessed after every 2 cycles of therapy, during the 2-weeks off period (time when patients do not take sunitinib). Reference ranges in our laboratory are as follows: TSH from 0.4 to 4 mIU/L, FT3 from 2.76 to 6.45 ng/mL, FT4 from 11.5 to 22.7 ng/mL. Sub-clinical hypothyroidism is defined as elevated TSH levels, but with normal FT4/T4 and FT3/T3 serum levels. In patients with TSH >4 mIU/L and evident symptoms of hypothyroidism (grade 2 or higher), substitution therapy with levothyroxine was introduced. An informed consent for thyroid hormone evaluation was not required, since it is a routine test at our Department.

The total number of patients with metastatic kidney cancer who were treated with sunitinib was 45. For the purpose of this analysis, only patients who received ≥2 cycles of sunitinib treatment and had available thyroid function data were included. All forty-five patients received at least two cycles of sunitinib. After excluding 4 patients who had no available thyroid function data, 41 patients remained eligible for final prognostic factor analysis.

Statistical methods. Progression-free survival (PFS) was calculated from the date of initiation of sunitinib treatment to disease progression or death. Overall survival (OS) was calculated from the date of initiation of sunitinib treatment to date of death. Patients who survived to the end of observation were censored. No patient was lost to follow-up. Both PFS and OS were estimated using the Kaplan-Meier method, and the difference between survival curves was assessed by the log-rank test. Prognostic factors were tested using Cox proportional hazards model for univariate analysis. p-Value less than 0.05 was considered statistically significant. Cut-off date for survival analysis was October 1st 2013.

Results

Patients' characteristics. All patients were treated with upfront sunitinib (50 mg daily), as recommended (4 weeks-On/2 weeks-Off schedule). In 7 patients (17%) sunitinib dose was reduced to 37.5 mg. None of the patients required additional dose reductions. In 4 patients (9.8%), modification of standard treatment schedule (2 weeks-On/1 week-Off) was introduced, but with no changes of sunitinib dose. Treatment with sunitinib was permanently discontinued in 2 patients (4.9%), in both due to extensive deterioration of renal function (rise of serum creatinine level). Median patient age at the beginning of sunitinib therapy was 60 years, and 80.5% were younger than 70 years. The majority of them (68.3%) had an Eastern Cooperative Oncology Group (ECOG) performance status 0, and almost all (97.6%) had underwent previous nephrectomy. The majority of them (73.2%) developed metastases in period less than one year from initial diagnosis, and 68.3% were classified with intermediate-risk disease according to the MSKCC prognostic index. Almost half of the patients (43.9%) had two sites of metastasis, and most common sites of metastasis were lung (65.9%), bone (34.1%) and lymph nodes (29.3%).

View this table:
Table I.

Patients' characteristics (N=41).

Thyroid function prior the sunitinib treatment. Baseline TSH levels were not available for patients included in the analysis. However, only patients with no history of thyroid impairment or disease, and with no symptoms of hypothyroidism were included in the analysis.

Thyroid function during treatment with sunitinib. During treatment, 12 patients (29.3%) developed hypothyroidism, with median peak TSH values of 34.4 mIU/L (range 4.3-92.5 mIU/L). Median time-to-diagnosis of hypothyroidism was 4.35 months (range 2.4-25.4 months). In 8 of these 12 patients (66.7%), TSH values >10mIU/L were found. Hormone replacement therapy with levothyroxine was initiated in 7 patients (17.1%). Two patients with TSH >10 mIU/L died too early to receive levothyroxine therapy, and one patient received therapy due to symptomatic hypothyroidism, although TSH levels were below 10 mIU/L. Median time-to-initiation of therapy with levothyroxine was 11.3 months, and median peak levothyroxine dose was 100 μg daily.

In one patient, hyperthyroidism was registered at the beginning of sunitinib treatment, with a TSH level of 0.077 mIU/L, and thiamazole antithyroid therapy was introduced. In the course of treatment, after approximately 6 months he converted to hypothyroidism, with a maximum TSH level of 56.6 mIU/L (Figure 1). The patient started to receive levothyroxine, in the beginning 50 μg per day, and later dose was raised up to 100 μg per day. This patient is a long-term survivor, and is on sunitinib therapy for 28 months, still without any signs of disease progression.

Thyroid function data are presented in Table II. The median follow-up period after initiation of sunitinib treatment was 40 months (range 5-48 months). A median of 6 cycles (range 2-32) were administered. Four patients (9.8%) had durable responses consisting of either partial response or stable disease measured at the last follow-up, while the other 37 patients (90.2%) experienced disease progression. Out of 4 patients who had long-term response, 3 patients had TSH level more than 4 mIU/L (75%), and two patients had experienced grade 2 hypothyroidism (50%).

Progression-free survival analysis. Univariate analysis of PFS is shown in Table III. The median PFS for all patient cohort was 10.1 months (95% confidence interval [CI] 6.5-13.3 months). Patients who had peak TSH value (TSHmax) >4 mIU/L had prolonged PFS compared to those who had TSHmax <4 mIU/L (14.2 months vs. 10.1 months; hazard ratio [HR] 0.50; 95%CI 0.26-0.97; p=0.059). Furthermore, patients who had both TSH >4 mIU/L and were taking substitution therapy with levothyroxine (grade 2 hypothyroidism) had prolonged PFS compared to those who had either TSH >4 mIU/L and were not taking levothyroxine replacement therapy, and those who had TSH <4 mIU/L – in other words patients who developed grade 2 hypothyroidism vs. all other patients (25.3 months vs. 9.0 months; hazard ratio [HR] 0.40; 95%CI 0.20-0.83; p=0.042). The association between grade 2 hypothyroidism and PFS is shown in Figure 2.

Overall survival. Univariate analysis of OS is shown in Table IV. The median OS was 25.0 months for the entire patient cohort (95%CI 13.2-40.3 months). Patients who had TSHmax >4 mIU/L had longer OS compared to those who had TSHmax <4 mIU/L (33.0 months vs. 22.1 months; hazard ratio [HR] 0.61; 95%CI 0.27-1.36; p=0.2353). Furthermore, patients who had both TSH >4 mIU/L and were receiving substitution therapy with levothyroxine (grade 2 hypothyroidism) had prolonged OS compared to those who had either TSH >4 mIU/L and were not taking levothyroxine replacement therapy and those who had TSH <4 mIU/L – in other words, patients who developed grade 2 hypothyroidism vs. all other patients (46.0 months vs. 22.1 months; HR 0.54; 95%CI 0.22-1.30; p=0.2052).

Figure 1.
Figure 1.

Alteration of TSH levels during sunitinib therapy. The patient had hyperthyroidism at the start of treatment, and hypothyroidism developed later on during therapy. Introduction of thiamazole and levothyroxine, as well as levothyroxine doses are shown. Thyroid function was assessed regularly, after every 2 cycles of sunitinib. 1: Introduction of thiamazole; 2: thiamazole withdrawal, introduction of levothyroxine 50 μg daily; 3: introduction of levothyroxine 75 μg daily; 4: introduction of levothyroxine 100 μg daily; 5: levothyroxine reduced to 87.5 μg daily; 6: re-introduction of levothyroxine 100 μg daily. Darker area represents TSH <4 mIU/L.

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Table II.

Thyroid function data in female and male patients.

Predictor factor analysis for PFS and OS. Besides TSHmax level (>4 mIU/L vs. <4 mIU/L), and presence of grade 2 hypothyroidism (grade 2 vs. grade 1 hypothyroidism or euthyreosis), other potential factors that might influence PFS and OS were analyzed. These included patient age (older than 70 years vs. younger than 70 years), time from diagnosis to metastases (≤1 year vs. >1 year), number of metastatic sites (1 vs. 2 vs. ≥3), ECOG performance status (0 vs. ≥1), and MSKCC risk group (1 vs. 2 vs. 3). On univariate analysis, a statistically significant association was found between grade 2 hypothyroidism and PFS. Patients who developed grade 2 hypothyroidism had longer PFS (p=0.042). In univariate predictor factor analysis for OS, ECOG performance status 0 was found to be significant for improved OS (p=0.0066). Association between ECOG performance status 0 and OS is shown in Figure 3. Since only one factor was found to be statistically significant for both PFS and OS (grade 2 hypothyroidism, and ECOG performance status, respectively), multivariate analysis wasn't performed.

Figure 2.
Figure 2.

Association between grade 2 hypothyroidism and PFS.

Discussion

Correlation of side-effects with success of sunitinib therapy is a topic of many discussions. Hypertension is the most well-known side-effect associated with positive outcome of therapy. Hypothyroidism is also suspected to be able to serve as a predictive factor for outcome of therapy, although conclusions are still not uniform (5-9). Guidelines for the treatment of these conditions in patients taking sunitinib are population because of the lack of experimental data in this setting, although they might require for specific approach. Therefore, it is a very actual and relevant topic, and a subject of on-going research, but still bears many unanswered questions.

Figure 3.
Figure 3.

Association between ECOG performance status and OS.

The incidence of hypothyroidism in patients treated with sunitinib varies from 14 to 70% (10, 11). In the largest study, where reported incidence of hypothyroidism was 14%, evaluation and follow-up of thyroid function was not performed on a regular basis (10), so it can be assumed that true incidence could be higher. The incidence itself depends on the length of follow-up of patients on sunitinib therapy (higher in patients who received therapy for a longer period of time), and on the threshold TSH level for hypothyroidism diagnosis, which varies between studies. Elevated TSH level incidence of 70% after following sunitinib treatment seems high (11) – after a long follow-up period, our observed hypothyroidism rate is 29%, and is comparable with some previously published studies (6).

According to our results, female patients taking sunitinib are more likely to develop hypothyroidism (in 57.1% female patients) than male patients (23.5%). Median patient age is 60 years, and it is well-known that in the elderly population (sub)clinical hypothyroidism is more frequent (12). What is the contribution of age and sex on the underlying occurrence of hypothyroidism in patients on sunitinib is difficult to say. It is possible that high thyroid dysfunction rate of 57% in our female patients is partly a reflection of higher predilection in women, although it is a small sample – study included more men than women (34 male and 7 female patients). Also, ULN for TSH slightly differs amongst studies on sunitinib-induced hypothyroidism, and it is ranges around 4 mIU/L (3.77 mIU/L–4.31 mIU/L) (6, 13, 14). Our definition of ULN for TSH (4.00 mIU/L) is within that range, however, TSH level above 4 mIU/L itself is not sufficient for the diagnosis of hypothyroidism, without additional clinical criteria. Given that longer duration of treatment carries a higher risk of developing hypothyroidism (it usually occurs 12-50 weeks after the introduction of sunitinib), it is necessary to regularly monitor the patient during therapy (15). One finding of elevated TSH level is not sufficient for the diagnosis, because certain reversible disorders of thyroid function may occur in up to 85% of patients (11).

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Table III.

Univariate analysis of PFS.

The mechanisms underlying the development of hypothyroidism during sunitinib therapy are not completely understood, and are the subject of ongoing research. In the beginning of treatment with sunitinib, transient disorder of thyroid function with changes in TSH levels often occurs only while taking the drug (during the 4 weeks ON period), while in the OFF period (2 weeks) TSH levels often come back within the normal range. Subclinical hypothyroidism can be diagnosed when TSH levels are elevated also in the OFF period. Fluctuations of thyroid hormone levels during the ON period complicate the diagnosis and monitoring, as well as implementation and calibration of levothyroxine therapy. Therefore, it is reasonable to assess thyroid function during the OFF period (16, 17). Furthermore, the question of monitoring and treatment of hypothyroidism that develops with implementation of alternative treatment schedules (e.g. continuous intake of 37.5 mg, or scheme 2 weeks-On /1 week-Off) is not yet explained, and requires further research. Interval of TSH levels measurement should be frequent enough to enable timely detection of thyroid disorders, and on the other hand rare enough to be applicable. Our Department has an extensive experience in thyroid disorders, and thyroid function was assessed after every two cycles (every three months) in the Off-period during sunitinib therapy, as a routine procedure. It has to be noted that dynamics of thyroid hormone levels is very important for further treatment in patients with registered disorders of thyroid function. Our study group supports mentioned TSH evaluation period as a rational approach.

There are still some concerns regarding timing of levothyroxine therapy initiation in hypothyroid patients, since sunitinib-induced hypothyroidism is etiologically-specific, and may require an individual therapeutic approach. General agreement is that hypothyroidism with TSH levels above 10 mIU/L should be treated with thyroid hormone substitution therapy (18). Patients with TSH values below 4 mIU/L do not need treatment, but the area between 4 and 10 mIU/L is a “no mans land”. In our study, levothyroxine therapy was introduced only in patients with symptomatic hypothyroidism, which demands careful evaluation of symptoms, since some of them may overlap (e.g. fatigue can be a symptom of hypothyroidism, but can also occur as a side-effect of treatment with sunitinib). In recent years, issues regarding possible over–diagnosis and over–treatment of hypothyroidism have emerged. A large community-based study by Taylor et al. analyzed TSH levels at which levothyroxine therapy was introduced (19). They noticed a decline in the threshold of TSH for the initiation of treatment (from 8.7 mIU/L in year 2001 to 7.9 mIU/L in 2009), as well as rise of percentage of patients with TSH levels less than 0.1 mIU/L (from 2.7% to 5.8 %). Furthermore, questions regarding a starting dose of levothyroxine and target TSH levels when on levothyroxine therapy (under 4 mIU/L, or slightly above 4 mIU/L) remain unanswered. Some authors suggest introduction of levothyroxine in all patients with hypothyroidism (8). Our stance is that levothyroxine therapy should be introduced with a lower dose, to minimize the risk for thyroid suppression. For the same reason, thyroid function should be assessed often enough, since prolonged period of treatment with sunitinib and levothyroxine increase the possibility of suppression. A large proportion of patients with mRCC (30%) have metastatic disease in the bones, so any additional risk to the skeletal system should be eliminated (20).

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Table IV.

Univariate Analysis of OS.

Since sunitinib itself may cause cardiac toxicity, levothyroxine should be used with caution in patients with known heart disorders (e.g. high blood pressure and rhythm disorders. One of the most common side-effect of sunitinib treatment is hypertension, while other, such as arrhythmia, including bradycardia and prolongation of the PR and QT intervals may be less frequent (<1%), but can be fatal and are often underestimated (4, 21). Unnecessary introduction of levothyroxine and consequent suppression can lead to occurrence of cardiac symptoms (22). In patients with the history of cardiac events or who are at increased risk for developing cardiac disorders (e.g. acute coronary syndrome, congestive heart failure, pulmonary embolism, stroke), left ventricle ejection fraction should be evaluated at the baseline and periodically during treatment with sunitinib (4). It is also necessary to monitor the patients for clinical signs and symptoms of congestive heart failure. In present study, 9 of 12 patients who developed hypothyroidism, also developed hypertension. In 4 of these 9 patients hypertension was grade 3-4, and in them extra caution was required. There were no other disorders of cardiac function in patients taking levothyroxine. Conclusion might be that the risk of developing severe cardiac and/or bone disorders in patients taking both sunitinib and levothyroxine is relatively low, but still should not be ignored.

Severe hypothyroidism is not a common finding in patients on therapy with sunitinib, as it was not in our study as well. None of the patients exhibited grade 3 (severe symptoms requiring hospitalization) or 4 (life threatening) hypothyroidism. In our study, the group of patients who developed clinically significant hypothyroidism (in our case grade 2, since we had no patients who developed grade 3 or 4), and thus needed levothyroxine substitution therapy, had significantly longer PFS than other groups of patients (euthyroid and with grade 1 hypothyroidism), but the difference in OS between these groups was not significant. For OS, only ECOG performance status was shown to be statistically significant factor – patients with ECOG status 0 had longer OS than those with EGOG status ≥1. This should not be an outstanding finding. ECOG performance status has been recognized for decades as a landmark prognostic factor of survival in many different cancers (23).

This study has several limitations. The first one is due to its retrospective design. As noted earlier, it is possible that in some patients in whom levothyroxine therapy was introduced because of severe fatigue, fatigue itself was a side-effect of sunitinib therapy (or it occurred for other possible reasons) and was not a symptom of hypothyroidism, despite the fact that they also exhibited elevation of TSH levels below normal range. Maybe some of these patients would be classified as grade 1 hypothyroid patients, if it was possible to differentiate the cause of fatigue (grade 1 does not require levothyroxine therapy). Secondly, we had no available baseline TSH levels for our patient cohort. But, as we previously said, only patients who had no previous thyroid impairment were enrolled for this analysis.

In conclusion, the rate of hypothyroidism as a side-effect of sunitinib in patients with mRCC is significant – more than one third of patients developed it at some point during treatment. Patients with symptomatic hypothyroidism (which requires levothyroxine therapy) experienced significantly longer PFS, but without difference in OS. The only statistically significant factor which prolonged OS was ECOG performance status 0. It is necessary to regularly monitor thyroid function, and to carefully assess potential risks and benefits of levothyroxine therapy in these patients, to avoid unnecessary prescription, as well as possible thyroid suppression.

Acknowledgements

Financial Support: None.

Footnotes

  • Conflicts of Interest

    The Authors report no conflicts of interest.

  • Received February 19, 2014.
  • Revision received March 30, 2014.
  • Accepted April 1, 2014.

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Hypothyroidism as a Predictive Clinical Marker of Better Treatment Response to Sunitinib Therapy
DAVOR KUST, MARIN PRPIĆ, JURE MURGIĆ, MARIJANA JAZVIĆ, BLANKA JAKŠIĆ, DRAŽENA KRILIĆ, ANTE BOLANČA, ZVONKO KUSIĆ
Anticancer Research Jun 2014, 34 (6) 3177-3184;
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