Review
Acquired Hypothyroidism as a Predictive Marker of Outcome in Patients With Metastatic Renal Cell Carcinoma Treated With Tyrosine Kinase Inhibitors: A Literature-Based Meta-Analysis Andreas Nearchou,1,2 Antonis Valachis,2,3 Pehr Lind,1,2 Olof Akre,4 Per Sandström1 Abstract Hypothyroidism in patients with metastatic renal cell carcinoma (mRCC) during treatment with the tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib is a well-established side effect. Furthermore, the potential role of hypothyroidism as predictive marker of outcome has been studied but with conflicting results. The aim of the present metaanalysis was to assess the predictive value of hypothyroidism for progression-free (PFS) and overall survival (OS) in patients with mRCC during TKI therapy. We searched PubMed and the electronic abstract databases of the major international congresses’ proceedings to identify all eligible studies that reported a correlation between the development of hypothyroidism during TKI treatment and outcome in patients with mRCC. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS and OS were obtained from these publications and pooled in a meta-analysis. Eleven studies with a total of 500 patients fulfilled the inclusion criteria. We found no statistical significant difference in PFS between patients who developed hypothyroidism during sunitinib therapy and unaffected patients (HR, 0.82; 95% CI, 0.59-1.13; P ¼ .22; 6 studies; 250 patients). The HR for OS was 0.52 (95% CI, 0.31-0.87; P ¼ .01) for patients who developed hypothyroidism during sunitinib therapy compared with patients who did not (4 studies; 147 patients). The development of hypothyroidism during TKI therapy is not clearly shown to be predictive of efficacy in patients with mRCC. The observed advantage in OS for the patients with acquired hypothyroidism should be interpreted with caution. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: mRCC, sorafenib, sunitinib, thyroid function, TKI
Introduction Renal cell carcinoma (RCC) accounts for approximately 90% of all renal malignancies.1 Approximately 20% to 30% of all new RCC patients are diagnosed with metastatic disease. In addition, another 40% of surgically treated patients will have a relapse and develop metastatic RCC (mRCC) during follow-up.2 Historically, the prognosis of patients with mRCC was extremely poor and the therapeutic options limited. However, presently 7 1
Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden Centre for Clinical Research Sörmland, Uppsala University, Uppsala, Sweden 3 Department of Radiology, Oncology and Radiation Science, University of Uppsala, Uppsala, Sweden 4 Department of Medicine, Karolinska Institute, Stockholm, Sweden 2
Submitted: Jul 20, 2014; Revised: Oct 1, 2014; Accepted: Oct 20, 2014 Address for correspondence: Andreas Nearchou, MD, Z1:00, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2014.10.002
different molecular targeted therapies (either targeting the Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor or the mammalian target of rapamycin [mTOR] pathway) have been approved for the treatment of mRCC.3-8 In this new era of targeted therapies, the median survival for patients with mRCC has been extended to 30 to 36 months.9-11 The oncologists are facing a challenge in treatment decision-making for patients with mRCC because there are 4 alternatives as first-line treatment and 3 more that serve as second- or third-line therapies. During the past years, many investigators have therefore tried to find predictive factors that could help the treating physicians choose the most ideal sequence of targeted therapies for each individual.12-18 Currently there is, however, no clear consensus about the sequence of targeted therapies and the efforts to identify factors that predict outcome for each treatment option continue. The tyrosine kinase inhibitors (TKIs) are designed to selectively inhibit the enzymes that are responsible for the signal transduction
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Acquired Hypothyroidism in Metastatic Renal Cancer cascades. In addition to their beneficial antitumor activity, clinical toxicities have also been observed. These might be caused by multiple so-called “off-target” effects and downstream signaling pathways of target kinases.19 A potential side effect of TKIs, the pathophysiological mechanism of which has not yet been completely explained, is the development of hypothyroidism. Specifically, sunitinib and sorafenib have been associated with the development of hypothyroidism.20 Several studies have found that some drug-specific toxicities of targeted therapies might serve as predictive factors for treatment efficacy.21 A similar hypothesis that the development of hypothyroidism during the treatment of mRCC with sunitinib or sorafenib could predict treatment efficacy has been proposed. Several investigators have studied this hypothesis but their results are conflicting. Because of the large spectrum of treatment alternatives and the increasing need for predictive markers, we conducted a metaanalysis of relevant studies to determine whether acquired hypothyroidism during TKI therapy can serve as a predictive marker of efficacy in patients with mRCC.
Materials and Methods Search Strategy Two independent investigators (AN and AV) searched the PubMed and the electronic abstract databases of the major international congresses’ proceedings (the American Society of Clinical Oncology [ASCO] Annual Meeting, the ASCO Genitourinary Cancers Symposium, and the European Society for Medical Oncology [ESMO] congresses) using the following searching algorithm: (sunitinib OR sorafenib OR pazopanib OR axitinib) AND renal cancer AND hypothyroidism. There were no restrictions on the language or the year of publication and the search was updated in June 2014. Furthermore, all reference lists of eligible studies and relevant reviews were also scrutinized to identify relevant articles missed by the electronic searches. When more than 1 publication was identified from the same study, we used the report with the longest follow-up or with the largest cohort to avoid duplication of results.
Selection Criteria The studies were considered eligible if they included patients with mRCC who were treated with TKIs and reported rates of acquired hypothyroidism and efficacy data. We excluded studies that included patients with different types of cancer and studies that did not provide any efficacy data on patients with euthyroidism versus hypothyroidism. We also excluded case reports.
Data Extraction
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Two independent authors (AN and AV) extracted the data from the studies and consensus was achieved in all the cases. From each study we extracted the following information (in a prespecified form): author names, year and journal of publication, country of origin, type of study (prospective or retrospective), the definition of hypothyroidism as stated by the authors; type of TKIs given, previous treatment, treatment setting; number of eligible and analyzed patients, sex, age; median follow-up; number of patients with acquired hypothyroidism and time to development of hypothyroidism; outcome measures (as described herein); type of analysis used
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in each outcome (bivariate or multivariate), and variables in multivariate analysis. In case of lack of data, we contacted the primary investigators of each study to provide us with supplementary data.
Risk of Bias and Publication Bias Two authors (AN and AV) independently assessed the risk of bias in each eligible study using the NewcastleeOttawa (NOS) quality assessment scale for cohort studies. The NOS ranges between 0 and 9 stars, with the highest quality studies awarded with a maximum of 9 stars. Publication bias was assessed using the construction of contourenhanced funnel plots.
Outcome Measures The primary outcome of the meta-analysis was the progressionfree survival (PFS) difference between patients who developed hypothyroidism during TKI therapy versus euthyroid patients. The definition of PFS was equal among studies and defined as time from initiation of TKI therapy to disease progression or death (except from 1; Shinohara et al22). The secondary end point was difference in overall survival (OS; defined as time from initiation of TKI therapy to death from any cause).
Statistical Analysis Meta-analyses were performed only if more than 2 studies presented adequate data for the outcome of interest. For the time to event outcomes (PFS and OS), we performed a meta-analysis first by transforming the hazard ratio (HR) and their errors into their log counterparts, and then by using the inverse of variance method and then transformed back into the HR scale. In case of inadequate data (lack of HR with confidence intervals [CIs]) we calculated the HR by using the KaplaneMeier curves or logrank P values and the number of events and total number of patients according to the method described by Tierney et al.23 We assessed the presence of statistical heterogeneity among the studies using the Q statistic and the magnitude of heterogeneity by using the I2 statistic. We considered P < .10 or an I2 > 50% as indicative of substantial heterogeneity. In case of substantial heterogeneity, the pooled odds ratio was calculated based on the random-effects model by DerSimonian and Laird.24 Otherwise, the fixed-effects model with the ManteleHaenszel method was used. Subgroup analyses were performed based on type of study (prospective vs. retrospective), type of treatment used (sunitinib, sorafenib, and sunitinib or sorafenib). All data used in the metaanalyses were derived from bivariate analyses because of the lack of data from multivariate analyses. All reported P values are 2-sided, with significance set at P < .05. All statistical analyses were performed using the Review Manager software (version 5.0; The Nordic Cochrane Centre, The Cochrane Collaboration).
Results Study Selection Our initial search identified a total of 67 potentially relevant studies in PubMed and 5 relevant trials in the ASCO and ESMO online databases. Of these, 46 were excluded leading to 26
Andreas Nearchou et al potentially eligible studies. After scrutiny, a total of 11 studies were considered eligible for the meta-analysis. The selection process and reasons for exclusion of studies from the meta-analysis are shown in Figure 1.
Study Quality The NOS quality assessment scale was performed for all cohort studies for the purpose of quality stratification. Of the 11 trials, 3 were landmark analyses. Furthermore, 5 studies were prospective and 6 retrospective. Trial Characteristics and Study Quality. A total of 500 patients were analyzed in 11 eligible studies. Two studies (Shinohara et al,22 Sella et al25) were excluded for the calculations of meta-analysis because of lack of adequate data for about our primary and secondary end points, despite our effort to retrieve this information from the primary investigators. Besides this, both studies were retrospective and included a limited number of patients. Of the remaining 9 studies that were included in the meta-analytical calculations, 5 were prospective and 4 retrospective. Six studies used the definition of the American Thyroid Association and the American Association of Clinical Endocrinologists to categorize the patients with hypothyroidism and 3 studies defined hypothyroidism with different criteria (ie, Pinto et al26 give no definition of hypothyroidism; Pinto et al27 define hypothyroidism as thyroid-stimulating hormone [TSH] concentration > 5 mU/L and Papazisis et al28 define that as TSH > 4.0 mU/L). The number of stars in the NOS that reflects the quality of eligible studies ranged between 5 and 7. The characteristics of eligible studies are shown in Table 1.22,25-34 Primary Outcome. Six studies reported data on PFS in patients treated with sunitinib (260 patients). No statistically significant
difference in PFS between patients with acquired hypothyroidism during sunitinib treatment and those without hypothyroidism was observed (HR, 0.82; 95% CI, 0.59-1.13; P ¼ .220; Figure 2). For studies that included patients treated with either sunitinib or sorafenib (3 studies; 205 patients), the difference in PFS was statistically significant (HR, 0.59; 95% CI, 0.42-0.84; P ¼ .003) in favor of patients with acquired hypothyroidism (Figure 3). No separate meta-analysis for studies including patients treated only with sorafenib could be performed because there was only 1 study with adequate data on this category (Schmidinger et al33). Secondary Outcome. Four studies, including 147 patients reported data on OS (Schmidinger et al,33 Wolter,34 Pinto et al,26,27). The HR for OS was 0.52 (95% CI, 0.31-0.87; P ¼ .01), which indicates a statistically significant survival benefit for patients who developed hypothyroidism during sunitinib therapy compared with patients who did not (Figure 4). We were unable to perform a meta-analysis of OS in patients treated with sorafenib because of the lack of a sufficient number of studies. Publication Bias Assessment. All meta-analyses funnel plots were symmetrical, indicating that publication bias was unlikely to have had a major influence in the analyses (not shown).
Discussion Our meta-analysis summarizes the current evidence about the role of acquired hypothyroidism during treatment with sunitinib or sorafenib as a predictive marker of drug efficacy in patients with mRCC. Our results indicated that this hypothesis is not clearly proven by the current data. The plausible correlation between acquired hypothyroidism during TKI therapy and OS should be interpreted with caution because none of the studies presented data on treatments
Figure 1 Flow Chart Diagram of Study Selection
67 Potentially relevant reports identified and screened for retrieval from electronic search 46 Reports excluded on basis of title or abstract
21 Reports retrieved in full text 15 Reports excluded upon full text search (13 incidence report, 2 duplicates)
5 Eligible abstract (ASCO, ESMO) 11 Eligible cohort trials included in meta-analysis
Abbreviations: ASCO ¼ American Society of Clinical Oncology; ESMO ¼ European Society for Medical Oncology.
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4
Type of Study
TKI (SUN, SOR)
Prior Therapy
Analyzed Patients
Baldazzi et al29 Clemons et al30
Prospective Retrospective
Papazisis et al28 A. Pinto26 Pinto27 Riesenbeck et al31
Retrospective Retrospective Retrospective Prospective
Sabatier et al32 Schmidinger et al33
Prospective Prospective
SUN SUN SOR SUN SUN SUN SUN SOR SUN SUN SOR SUN SOR SUN SUN
No NA e No No No No Yes Yes Yes Yes Yes e NA Yes
22 34 22 45/42 29 50 66 e 69 83 e 30 e 14 39
Reference
Sella et al25
Retrospective
Shinohara et al22 Wolter34
Retrospective Prospective
Number of Patients Who Developed Hypothyroidism
Statistical Method Used For PFS Analysis
Definition of Hypothyroidism Based on TSH Levels
Quality Assessment (Highest Score [ 9)
13 15 6 17 11 20 13 8 42 32 21 16
e e e e e e e e LA LA e LA e e e
TSH >3.5 mIU/La TSH > ULN e TSH >4.0 mIU/L NA TSH >5.5 mIU/L TSH > ULN e TSH >4.5 mIU/La TSH >3.77 mM/mLa e TSH >4.3 mIU/La e TSH >10 mU/L TSH >4.2 mIU/La
7 6 e 5 7 7 6 e 7 7 e 7 e 7 6
11 28
Abbreviations: LA ¼ landmark analyses; PFS ¼ progression-free survival; SOR ¼ sorafenib; SUN ¼ sunitinib; TKI ¼ tyrosine kinase inhibitor; TSH ¼ thyroid stimulating hormone; ULN ¼ upper limit of normal. a Represents the ULN of the reference laboratory value.
Acquired Hypothyroidism in Metastatic Renal Cancer
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Table 1 Characteristics of Eligible Studies
Andreas Nearchou et al Figure 2 Meta-Analysis of Progression-Free Survival of Patients Who Were Treated With Sunitinib and Developed Hypothyroidism Versus Euthyroid Patients. The Size of the Squares Indicate the Weight of the Study. Error Bars Represent 95% CIs. The Diamonds Indicate the Summary Hazard Ratio. Values < 1 Indicate Improved Progression-Free Survival in Patients Who Developed Hypothyroidism
received after first-line therapy. A potential imbalance in treatment strategies among different subgroups of patients make these comparisons prone to bias. However, evidence suggests that sunitinib might enhance antitumor immunity by modulating the tumor microenvironment and increasing the interferon (IFN)-g expression which might favor T-cell activation and T helper type 1 cells mediated responses.35 The activation of the immune system by sunitinib might be one of the pathophysiologic mechanisms of sunitinibinduced hypothyroidism as well. Mazziotti et al have demonstrated that the peripheral CD4-positive (CD4þ) and CD8þ T lymphocytes from hypothyroid patients show a type 1 activation (IFNeg-mediated) strictly correlated to the occurrence of hypothyroidism.36 Moreover, Grossmann et al documented cytological evidence of lymphocytic thyroiditis in patients who developed thyroid
dysfunction during sunitinib treatment.37 In this hypothesis, the hypothyroidism and the effectiveness of TKIs are the 2 sides of the same coin, namely, the expression of enhanced immune activation. This might be a biologic explanation for our observation of a direct correlation between OS and hypothyroidism development in sunitinib-treated patients but not any correlation in PFS. The phenomenon of improved OS without improvement in PFS has also been observed in melanoma patients treated with immunomodulatory therapy with ipilimumab.38 Although we found no association between acquired hypothyroidism and PFS in our main meta-analysis in patients who received sunitinib (meta-analysis with the most patients), a possible association was revealed when we performed a meta-analysis of studies that included patients who received either sunitinib or sorafenib.
Figure 3 Meta-Analysis of Progression-Free Survival of Patients Who Were Treated With Either Sunitinib or Sorafenib and Developed Hypothyroidism Versus Euthyroid Patients. The Size of the Squares Indicate the Weight of the Study. Error Bars Represent 95% CIs. The Diamonds Indicate the Summary Hazard Ratios. Values < 1 Indicate Improved Progression-Free Survival in Patients Who Developed Hypothyroidism
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Acquired Hypothyroidism in Metastatic Renal Cancer Figure 4 Meta-Analysis of Overall Survival of Patients Who Were Treated With Sunitinib and Developed Hypothyroidism Versus Euthyroid Patients. The Size of the Squares Indicate the Weight of the Study. Error Bars Represent 95% CIs. The Diamonds Indicate the Summary Hazard Ratios. Values < 1 Indicate Improved Progression-Free Survival in Patients Who Developed Hypothyroidism
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However, the number of included patients in this meta-analysis was limited and the results were mostly influenced by a positive association in a retrospective study with several biases because of its retrospective nature. A step forward in an effort to explain this positive association would be to investigate the potential role of hypothyroidism as predictive factor in sorafenib-treated patients. However, we were unable to perform a meta-analysis of sorafenibonly treated patients because of the lack of adequate data. A plausible explanation, yet not defined but only speculated, is the induction of hypothyroidism through the Rapidly Accelerated Fibrosarcoma kinase and Mitogen-Activated Protein Kinase pathway. This inhibitory effect extends beyond the inhibitory properties of the TKI sunitinib. If this is the reason that sorafenib patients have a significant reduction in the risk for disease progression, this remains unexplained and any definite biological assumptions cannot be made. There are several issues and potential limitations of the eligible studies, and therefore of our meta-analysis, that deserve comment. First, the time to detection of hypothyroidism in the analysis varied among studies. In retrospective studies, all patients who developed hypothyroidism during sunitinib or sorafenib treatment were included in analyses, regardless of the time point of hypothyroidism detection (all retrospective), except for Sella et al,25 who performed landmark analyses at different months. In the prospective studies, there are some that defined the end point acquired hypothyroidism as the presence of at least 1 increased TSH level at any time during treatment,29,31,34 whereas others used a fixed time point to determine thyroid function, which varied from 1 or 2 months33 to 6 months.25 The different approaches to define the timing of hypothyroidism is an important source of clinical heterogeneity among studies that should be taken into account in the interpretation of our results. The use of the landmark method for the analysis of the 2 prospective studies25,33 was chosen to make the results more applicable in clinical practice, because a predictive marker must be assessed at a
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precise and shared time. However, the most appropriate cutoff time has not been determined. Schmidinger et al33 chose 1 or 2 months as cutoff points and they did not include in their analysis any other thyroid abnormalities developed after the 2-month time point. This cutoff point is short and does not reflect the daily clinical practice considering the fact that acquired hypothyroidism due to sunitinib or sorafenib has been observed from 1 to 36 months after the initiation of treatment.39 We performed a sensitivity analysis by excluding this study from the meta-analysis and this did not affect our results (data not shown). Sabatier et al chose a cutoff of 6 months for their landmark analysis.25 This cutoff time point seems to be reasonable but it is still unknown if it is the most appropriate. One study included patients with early progressive disease in the euthyroid group resulting in a risk of misclassification because these patients could develop an alteration of thyroid function later in the disease course.34 We performed a sensitivity analysis with the exclusion of this study and the results remained unchanged (data not shown). To overcome these limitations of current studies, we propose the conduction of a prospective cohort study of consecutive patients with mRCC who are treated with sunitinib or sorafenib. Baseline thyroid function tests should be checked in all included patients and then periodically tested until the end of the study. Initiation of substitution treatment has to be in consistency with international guidelines and not with local routines. A landmark analysis at different clinical relevant time points should be performed to investigate whether acquired hypothyroidism at any of the points predict treatment efficacy, and if this is the case, which time point has the best correlation. A separate analysis for sunitinib and sorafenib is essential to reveal whether acquired hypothyroidism could serve as predictive marker of efficacy in any of these agents. Sequential treatments after progression to sunitinib or sorafenib should be documented. Finally, the sample size should be large enough to reveal if there are any statistically significant differences with an acceptable level of power.
Andreas Nearchou et al Conclusion The development of hypothyroidism during TKI therapy is not clearly shown to be predictive in patients with mRCC. The observed advantage in OS for the patients with hypothyroidism should be interpreted with caution; however, enhanced immune response could be the answer to this puzzle. We propose a prospective study with a suitable study design to give a definite answer as to whether hypothyroidism can serve as predictive marker for treatment efficacy of TKIs in patients with mRCC.
Acknowledgments The authors thank Dr Wolter and Dr Papazisis for providing additional data for our meta-analysis. The meta-analysis was supported by grants from the County Council of Sörmland, Sweden. The funding source had no role in study design, data collection and analysis, decision to publish, or preparation of the report.
Disclosure The authors have stated that they have no conflicts of interest.
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15. Patard JJ, Porta C, Wagstaff J, Gschwend JE. Optimizing treatment for metastatic renal cell carcinoma. Expert Rev Anticancer Ther 2011; 11:1901-11. 16. Haddad H, Rini BI. Current treatment considerations in metastatic renal cell carcinoma. Curr Treat Options Oncol 2012; 13:212-29. 17. Zustovich F, Lombardi G, Farina P. Treating patients with metastatic renal carcinoma: an escape from phase III. Expert Rev Anticancer Ther 2012; 12:919-27. 18. Eisen T, Sternberg CN, Robert C, et al. Targeted therapies for renal cell carcinoma: review of adverse event management strategies. J Natl Cancer Inst 2012; 104:93-113. 19. Gotink KJ, Verheul HM. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis 2010; 13:1-14. 20. Makita N, Iiri T. Tyrosine kinase inhibitor-induced thyroid disorders: a review and hypothesis. Thyroid 2013; 23:151-9. 21. Ravaud A, Schmidinger M. Clinical biomarkers of response in advanced renal cell carcinoma. Ann Oncol 2013; 24:2935-42. 22. Shinohara N, Takahashi M, Kamishima T, et al. The incidence and mechanism of sunitinib-induced thyroid atrophy in patients with metastatic renal cell carcinoma. Br J Cancer 2011; 104:241-7. 23. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007; 8:16. 24. DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986; 7:177-88. 25. Sella A, Hercbergs AH, Hanovich E, Kovel S. Does sunitinib-induced hypothyroidism play a role in the activity of sunitinib in metastatic renal cell carcinoma? Chemotherapy 2012; 58:200-5. 26. Pinto A, Moreno V, Espinosa E, Redondo A, Gonzalez Baron M. New onset hypothyroidism and macrocytosis as surrogate markers for the efficacy of sunitinib in the treatment of advanced renal cell carcinoma. Genitourinary Cancers Symposium 2010, abstract 338. 27. Pinto FAI, Pereira AAR, Formiga MN, Fanelli MF, Chinen LTD, Lima VC, et al. Association of hypothyroidism with improved outcomes in first-line treatment of renal cell carcinoma with sunitinib. J Clin Oncol 2012; 30, abstract 466. 28. Papazisis KT, Kontovinis L, Pazaitou K, Kontovini M, Mouratidou D, Vassileiadis T. Thyroid-stimulating hormone (TSH) levels in patients with metastatic renal cell cancer treated with sunitinib. Ann Oncol 2010; 21:289. 29. Baldazzi V, Tassi R, Lapini A, Santomaggio C, Carini M, Mazzanti R. The impact of sunitinib-induced hypothyroidism on progression-free survival of metastatic renal cancer patients: a prospective single-center study. Urol Oncol 2012; 30:70410. 30. Clemons J, Gao D, Naam M, Breaker K, Garfield D, Flaig TW. Thyroid dysfunction in patients treated with sunitinib or sorafenib. Clin Genitourin Cancer 2012; 10:225-31. 31. Riesenbeck LM, Bierer S, Hoffmeister I, et al. Hypothyroidism correlates with a better prognosis in metastatic renal cancer patients treated with sorafenib or sunitinib. World J Urol 2011; 29:807-13. 32. Sabatier R, Eymard JC, Walz J, et al. Could thyroid dysfunction influence outcome in sunitinib-treated metastatic renal cell carcinoma? Ann Oncol 2012; 23: 714-21. 33. Schmidinger M, Vogl UM, Bojic M, et al. Hypothyroidism in patients with renal cell carcinoma: blessing or curse? Cancer 2011; 117:534-44. 34. Wolter P, Steffan C, Decallonne B, Dumez H, Fieuws S, Wildiers H, et al. Evaluation of thyroid dysfunction as a candidate surrogate marker for efficacy of sunitinib in patients (pts) with advanced renal cell cancer (RCC). J Clin Oncol 2008; 26, abstract 5126. 35. Ozao-Choy J, Ma G, Kao J, et al. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenviroment for immune-based cancer therapies. Cancer Res 2009; 69:2514-22. 36. Mazziotti G, Sorvillo F, Naclerio C, et al. Type-1 response in peripheral CD4þ and CD8þ T cells from patients with Hashimoto’s thyroiditis. Eur J Endocrinol 2003; 148:383-8. 37. Grossmann M, Premaratne E, Desai J, Davis ID. Thyrotoxicosis during sunitinib treatment for renal cell carcinoma. Clin Endocrinol (Oxf) 2008; 69:669-72. 38. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711-23. 39. Wong E, Rosen LS, Mulay M, et al. Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. Thyroid 2007; 17:351-5.
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Acquired Hypothyroidism as a Predictive Marker of Outcome in Patients With Metastatic Renal Cell Carcinoma Treated With Tyrosine Kinase Inhibitors: A Literature-Based Meta-Analysis Andreas Nearchou,1,2 Antonis Valachis,2,3 Pehr Lind,1,2 Olof Akre,4 Per Sandström1 Abstract Hypothyroidism in patients with metastatic renal cell carcinoma (mRCC) during treatment with the tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib is a well-established side effect. Furthermore, the potential role of hypothyroidism as predictive marker of outcome has been studied but with conflicting results. The aim of the present metaanalysis was to assess the predictive value of hypothyroidism for progression-free (PFS) and overall survival (OS) in patients with mRCC during TKI therapy. We searched PubMed and the electronic abstract databases of the major international congresses’ proceedings to identify all eligible studies that reported a correlation between the development of hypothyroidism during TKI treatment and outcome in patients with mRCC. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS and OS were obtained from these publications and pooled in a meta-analysis. Eleven studies with a total of 500 patients fulfilled the inclusion criteria. We found no statistical significant difference in PFS between patients who developed hypothyroidism during sunitinib therapy and unaffected patients (HR, 0.82; 95% CI, 0.59-1.13; P ¼ .22; 6 studies; 250 patients). The HR for OS was 0.52 (95% CI, 0.31-0.87; P ¼ .01) for patients who developed hypothyroidism during sunitinib therapy compared with patients who did not (4 studies; 147 patients). The development of hypothyroidism during TKI therapy is not clearly shown to be predictive of efficacy in patients with mRCC. The observed advantage in OS for the patients with acquired hypothyroidism should be interpreted with caution. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: mRCC, sorafenib, sunitinib, thyroid function, TKI
Introduction Renal cell carcinoma (RCC) accounts for approximately 90% of all renal malignancies.1 Approximately 20% to 30% of all new RCC patients are diagnosed with metastatic disease. In addition, another 40% of surgically treated patients will have a relapse and develop metastatic RCC (mRCC) during follow-up.2 Historically, the prognosis of patients with mRCC was extremely poor and the therapeutic options limited. However, presently 7 1
Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden Centre for Clinical Research Sörmland, Uppsala University, Uppsala, Sweden 3 Department of Radiology, Oncology and Radiation Science, University of Uppsala, Uppsala, Sweden 4 Department of Medicine, Karolinska Institute, Stockholm, Sweden 2
Submitted: Jul 20, 2014; Revised: Oct 1, 2014; Accepted: Oct 20, 2014 Address for correspondence: Andreas Nearchou, MD, Z1:00, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2014.10.002
different molecular targeted therapies (either targeting the Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor or the mammalian target of rapamycin [mTOR] pathway) have been approved for the treatment of mRCC.3-8 In this new era of targeted therapies, the median survival for patients with mRCC has been extended to 30 to 36 months.9-11 The oncologists are facing a challenge in treatment decision-making for patients with mRCC because there are 4 alternatives as first-line treatment and 3 more that serve as second- or third-line therapies. During the past years, many investigators have therefore tried to find predictive factors that could help the treating physicians choose the most ideal sequence of targeted therapies for each individual.12-18 Currently there is, however, no clear consensus about the sequence of targeted therapies and the efforts to identify factors that predict outcome for each treatment option continue. The tyrosine kinase inhibitors (TKIs) are designed to selectively inhibit the enzymes that are responsible for the signal transduction
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Acquired Hypothyroidism in Metastatic Renal Cancer cascades. In addition to their beneficial antitumor activity, clinical toxicities have also been observed. These might be caused by multiple so-called “off-target” effects and downstream signaling pathways of target kinases.19 A potential side effect of TKIs, the pathophysiological mechanism of which has not yet been completely explained, is the development of hypothyroidism. Specifically, sunitinib and sorafenib have been associated with the development of hypothyroidism.20 Several studies have found that some drug-specific toxicities of targeted therapies might serve as predictive factors for treatment efficacy.21 A similar hypothesis that the development of hypothyroidism during the treatment of mRCC with sunitinib or sorafenib could predict treatment efficacy has been proposed. Several investigators have studied this hypothesis but their results are conflicting. Because of the large spectrum of treatment alternatives and the increasing need for predictive markers, we conducted a metaanalysis of relevant studies to determine whether acquired hypothyroidism during TKI therapy can serve as a predictive marker of efficacy in patients with mRCC.
Materials and Methods Search Strategy Two independent investigators (AN and AV) searched the PubMed and the electronic abstract databases of the major international congresses’ proceedings (the American Society of Clinical Oncology [ASCO] Annual Meeting, the ASCO Genitourinary Cancers Symposium, and the European Society for Medical Oncology [ESMO] congresses) using the following searching algorithm: (sunitinib OR sorafenib OR pazopanib OR axitinib) AND renal cancer AND hypothyroidism. There were no restrictions on the language or the year of publication and the search was updated in June 2014. Furthermore, all reference lists of eligible studies and relevant reviews were also scrutinized to identify relevant articles missed by the electronic searches. When more than 1 publication was identified from the same study, we used the report with the longest follow-up or with the largest cohort to avoid duplication of results.
Selection Criteria The studies were considered eligible if they included patients with mRCC who were treated with TKIs and reported rates of acquired hypothyroidism and efficacy data. We excluded studies that included patients with different types of cancer and studies that did not provide any efficacy data on patients with euthyroidism versus hypothyroidism. We also excluded case reports.
Data Extraction
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Two independent authors (AN and AV) extracted the data from the studies and consensus was achieved in all the cases. From each study we extracted the following information (in a prespecified form): author names, year and journal of publication, country of origin, type of study (prospective or retrospective), the definition of hypothyroidism as stated by the authors; type of TKIs given, previous treatment, treatment setting; number of eligible and analyzed patients, sex, age; median follow-up; number of patients with acquired hypothyroidism and time to development of hypothyroidism; outcome measures (as described herein); type of analysis used
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in each outcome (bivariate or multivariate), and variables in multivariate analysis. In case of lack of data, we contacted the primary investigators of each study to provide us with supplementary data.
Risk of Bias and Publication Bias Two authors (AN and AV) independently assessed the risk of bias in each eligible study using the NewcastleeOttawa (NOS) quality assessment scale for cohort studies. The NOS ranges between 0 and 9 stars, with the highest quality studies awarded with a maximum of 9 stars. Publication bias was assessed using the construction of contourenhanced funnel plots.
Outcome Measures The primary outcome of the meta-analysis was the progressionfree survival (PFS) difference between patients who developed hypothyroidism during TKI therapy versus euthyroid patients. The definition of PFS was equal among studies and defined as time from initiation of TKI therapy to disease progression or death (except from 1; Shinohara et al22). The secondary end point was difference in overall survival (OS; defined as time from initiation of TKI therapy to death from any cause).
Statistical Analysis Meta-analyses were performed only if more than 2 studies presented adequate data for the outcome of interest. For the time to event outcomes (PFS and OS), we performed a meta-analysis first by transforming the hazard ratio (HR) and their errors into their log counterparts, and then by using the inverse of variance method and then transformed back into the HR scale. In case of inadequate data (lack of HR with confidence intervals [CIs]) we calculated the HR by using the KaplaneMeier curves or logrank P values and the number of events and total number of patients according to the method described by Tierney et al.23 We assessed the presence of statistical heterogeneity among the studies using the Q statistic and the magnitude of heterogeneity by using the I2 statistic. We considered P < .10 or an I2 > 50% as indicative of substantial heterogeneity. In case of substantial heterogeneity, the pooled odds ratio was calculated based on the random-effects model by DerSimonian and Laird.24 Otherwise, the fixed-effects model with the ManteleHaenszel method was used. Subgroup analyses were performed based on type of study (prospective vs. retrospective), type of treatment used (sunitinib, sorafenib, and sunitinib or sorafenib). All data used in the metaanalyses were derived from bivariate analyses because of the lack of data from multivariate analyses. All reported P values are 2-sided, with significance set at P < .05. All statistical analyses were performed using the Review Manager software (version 5.0; The Nordic Cochrane Centre, The Cochrane Collaboration).
Results Study Selection Our initial search identified a total of 67 potentially relevant studies in PubMed and 5 relevant trials in the ASCO and ESMO online databases. Of these, 46 were excluded leading to 26
Andreas Nearchou et al potentially eligible studies. After scrutiny, a total of 11 studies were considered eligible for the meta-analysis. The selection process and reasons for exclusion of studies from the meta-analysis are shown in Figure 1.
Study Quality The NOS quality assessment scale was performed for all cohort studies for the purpose of quality stratification. Of the 11 trials, 3 were landmark analyses. Furthermore, 5 studies were prospective and 6 retrospective. Trial Characteristics and Study Quality. A total of 500 patients were analyzed in 11 eligible studies. Two studies (Shinohara et al,22 Sella et al25) were excluded for the calculations of meta-analysis because of lack of adequate data for about our primary and secondary end points, despite our effort to retrieve this information from the primary investigators. Besides this, both studies were retrospective and included a limited number of patients. Of the remaining 9 studies that were included in the meta-analytical calculations, 5 were prospective and 4 retrospective. Six studies used the definition of the American Thyroid Association and the American Association of Clinical Endocrinologists to categorize the patients with hypothyroidism and 3 studies defined hypothyroidism with different criteria (ie, Pinto et al26 give no definition of hypothyroidism; Pinto et al27 define hypothyroidism as thyroid-stimulating hormone [TSH] concentration > 5 mU/L and Papazisis et al28 define that as TSH > 4.0 mU/L). The number of stars in the NOS that reflects the quality of eligible studies ranged between 5 and 7. The characteristics of eligible studies are shown in Table 1.22,25-34 Primary Outcome. Six studies reported data on PFS in patients treated with sunitinib (260 patients). No statistically significant
difference in PFS between patients with acquired hypothyroidism during sunitinib treatment and those without hypothyroidism was observed (HR, 0.82; 95% CI, 0.59-1.13; P ¼ .220; Figure 2). For studies that included patients treated with either sunitinib or sorafenib (3 studies; 205 patients), the difference in PFS was statistically significant (HR, 0.59; 95% CI, 0.42-0.84; P ¼ .003) in favor of patients with acquired hypothyroidism (Figure 3). No separate meta-analysis for studies including patients treated only with sorafenib could be performed because there was only 1 study with adequate data on this category (Schmidinger et al33). Secondary Outcome. Four studies, including 147 patients reported data on OS (Schmidinger et al,33 Wolter,34 Pinto et al,26,27). The HR for OS was 0.52 (95% CI, 0.31-0.87; P ¼ .01), which indicates a statistically significant survival benefit for patients who developed hypothyroidism during sunitinib therapy compared with patients who did not (Figure 4). We were unable to perform a meta-analysis of OS in patients treated with sorafenib because of the lack of a sufficient number of studies. Publication Bias Assessment. All meta-analyses funnel plots were symmetrical, indicating that publication bias was unlikely to have had a major influence in the analyses (not shown).
Discussion Our meta-analysis summarizes the current evidence about the role of acquired hypothyroidism during treatment with sunitinib or sorafenib as a predictive marker of drug efficacy in patients with mRCC. Our results indicated that this hypothesis is not clearly proven by the current data. The plausible correlation between acquired hypothyroidism during TKI therapy and OS should be interpreted with caution because none of the studies presented data on treatments
Figure 1 Flow Chart Diagram of Study Selection
67 Potentially relevant reports identified and screened for retrieval from electronic search 46 Reports excluded on basis of title or abstract
21 Reports retrieved in full text 15 Reports excluded upon full text search (13 incidence report, 2 duplicates)
5 Eligible abstract (ASCO, ESMO) 11 Eligible cohort trials included in meta-analysis
Abbreviations: ASCO ¼ American Society of Clinical Oncology; ESMO ¼ European Society for Medical Oncology.
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Type of Study
TKI (SUN, SOR)
Prior Therapy
Analyzed Patients
Baldazzi et al29 Clemons et al30
Prospective Retrospective
Papazisis et al28 A. Pinto26 Pinto27 Riesenbeck et al31
Retrospective Retrospective Retrospective Prospective
Sabatier et al32 Schmidinger et al33
Prospective Prospective
SUN SUN SOR SUN SUN SUN SUN SOR SUN SUN SOR SUN SOR SUN SUN
No NA e No No No No Yes Yes Yes Yes Yes e NA Yes
22 34 22 45/42 29 50 66 e 69 83 e 30 e 14 39
Reference
Sella et al25
Retrospective
Shinohara et al22 Wolter34
Retrospective Prospective
Number of Patients Who Developed Hypothyroidism
Statistical Method Used For PFS Analysis
Definition of Hypothyroidism Based on TSH Levels
Quality Assessment (Highest Score [ 9)
13 15 6 17 11 20 13 8 42 32 21 16
e e e e e e e e LA LA e LA e e e
TSH >3.5 mIU/La TSH > ULN e TSH >4.0 mIU/L NA TSH >5.5 mIU/L TSH > ULN e TSH >4.5 mIU/La TSH >3.77 mM/mLa e TSH >4.3 mIU/La e TSH >10 mU/L TSH >4.2 mIU/La
7 6 e 5 7 7 6 e 7 7 e 7 e 7 6
11 28
Abbreviations: LA ¼ landmark analyses; PFS ¼ progression-free survival; SOR ¼ sorafenib; SUN ¼ sunitinib; TKI ¼ tyrosine kinase inhibitor; TSH ¼ thyroid stimulating hormone; ULN ¼ upper limit of normal. a Represents the ULN of the reference laboratory value.
Acquired Hypothyroidism in Metastatic Renal Cancer
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Table 1 Characteristics of Eligible Studies
Andreas Nearchou et al Figure 2 Meta-Analysis of Progression-Free Survival of Patients Who Were Treated With Sunitinib and Developed Hypothyroidism Versus Euthyroid Patients. The Size of the Squares Indicate the Weight of the Study. Error Bars Represent 95% CIs. The Diamonds Indicate the Summary Hazard Ratio. Values < 1 Indicate Improved Progression-Free Survival in Patients Who Developed Hypothyroidism
received after first-line therapy. A potential imbalance in treatment strategies among different subgroups of patients make these comparisons prone to bias. However, evidence suggests that sunitinib might enhance antitumor immunity by modulating the tumor microenvironment and increasing the interferon (IFN)-g expression which might favor T-cell activation and T helper type 1 cells mediated responses.35 The activation of the immune system by sunitinib might be one of the pathophysiologic mechanisms of sunitinibinduced hypothyroidism as well. Mazziotti et al have demonstrated that the peripheral CD4-positive (CD4þ) and CD8þ T lymphocytes from hypothyroid patients show a type 1 activation (IFNeg-mediated) strictly correlated to the occurrence of hypothyroidism.36 Moreover, Grossmann et al documented cytological evidence of lymphocytic thyroiditis in patients who developed thyroid
dysfunction during sunitinib treatment.37 In this hypothesis, the hypothyroidism and the effectiveness of TKIs are the 2 sides of the same coin, namely, the expression of enhanced immune activation. This might be a biologic explanation for our observation of a direct correlation between OS and hypothyroidism development in sunitinib-treated patients but not any correlation in PFS. The phenomenon of improved OS without improvement in PFS has also been observed in melanoma patients treated with immunomodulatory therapy with ipilimumab.38 Although we found no association between acquired hypothyroidism and PFS in our main meta-analysis in patients who received sunitinib (meta-analysis with the most patients), a possible association was revealed when we performed a meta-analysis of studies that included patients who received either sunitinib or sorafenib.
Figure 3 Meta-Analysis of Progression-Free Survival of Patients Who Were Treated With Either Sunitinib or Sorafenib and Developed Hypothyroidism Versus Euthyroid Patients. The Size of the Squares Indicate the Weight of the Study. Error Bars Represent 95% CIs. The Diamonds Indicate the Summary Hazard Ratios. Values < 1 Indicate Improved Progression-Free Survival in Patients Who Developed Hypothyroidism
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Acquired Hypothyroidism in Metastatic Renal Cancer Figure 4 Meta-Analysis of Overall Survival of Patients Who Were Treated With Sunitinib and Developed Hypothyroidism Versus Euthyroid Patients. The Size of the Squares Indicate the Weight of the Study. Error Bars Represent 95% CIs. The Diamonds Indicate the Summary Hazard Ratios. Values < 1 Indicate Improved Progression-Free Survival in Patients Who Developed Hypothyroidism
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However, the number of included patients in this meta-analysis was limited and the results were mostly influenced by a positive association in a retrospective study with several biases because of its retrospective nature. A step forward in an effort to explain this positive association would be to investigate the potential role of hypothyroidism as predictive factor in sorafenib-treated patients. However, we were unable to perform a meta-analysis of sorafenibonly treated patients because of the lack of adequate data. A plausible explanation, yet not defined but only speculated, is the induction of hypothyroidism through the Rapidly Accelerated Fibrosarcoma kinase and Mitogen-Activated Protein Kinase pathway. This inhibitory effect extends beyond the inhibitory properties of the TKI sunitinib. If this is the reason that sorafenib patients have a significant reduction in the risk for disease progression, this remains unexplained and any definite biological assumptions cannot be made. There are several issues and potential limitations of the eligible studies, and therefore of our meta-analysis, that deserve comment. First, the time to detection of hypothyroidism in the analysis varied among studies. In retrospective studies, all patients who developed hypothyroidism during sunitinib or sorafenib treatment were included in analyses, regardless of the time point of hypothyroidism detection (all retrospective), except for Sella et al,25 who performed landmark analyses at different months. In the prospective studies, there are some that defined the end point acquired hypothyroidism as the presence of at least 1 increased TSH level at any time during treatment,29,31,34 whereas others used a fixed time point to determine thyroid function, which varied from 1 or 2 months33 to 6 months.25 The different approaches to define the timing of hypothyroidism is an important source of clinical heterogeneity among studies that should be taken into account in the interpretation of our results. The use of the landmark method for the analysis of the 2 prospective studies25,33 was chosen to make the results more applicable in clinical practice, because a predictive marker must be assessed at a
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precise and shared time. However, the most appropriate cutoff time has not been determined. Schmidinger et al33 chose 1 or 2 months as cutoff points and they did not include in their analysis any other thyroid abnormalities developed after the 2-month time point. This cutoff point is short and does not reflect the daily clinical practice considering the fact that acquired hypothyroidism due to sunitinib or sorafenib has been observed from 1 to 36 months after the initiation of treatment.39 We performed a sensitivity analysis by excluding this study from the meta-analysis and this did not affect our results (data not shown). Sabatier et al chose a cutoff of 6 months for their landmark analysis.25 This cutoff time point seems to be reasonable but it is still unknown if it is the most appropriate. One study included patients with early progressive disease in the euthyroid group resulting in a risk of misclassification because these patients could develop an alteration of thyroid function later in the disease course.34 We performed a sensitivity analysis with the exclusion of this study and the results remained unchanged (data not shown). To overcome these limitations of current studies, we propose the conduction of a prospective cohort study of consecutive patients with mRCC who are treated with sunitinib or sorafenib. Baseline thyroid function tests should be checked in all included patients and then periodically tested until the end of the study. Initiation of substitution treatment has to be in consistency with international guidelines and not with local routines. A landmark analysis at different clinical relevant time points should be performed to investigate whether acquired hypothyroidism at any of the points predict treatment efficacy, and if this is the case, which time point has the best correlation. A separate analysis for sunitinib and sorafenib is essential to reveal whether acquired hypothyroidism could serve as predictive marker of efficacy in any of these agents. Sequential treatments after progression to sunitinib or sorafenib should be documented. Finally, the sample size should be large enough to reveal if there are any statistically significant differences with an acceptable level of power.
Andreas Nearchou et al Conclusion The development of hypothyroidism during TKI therapy is not clearly shown to be predictive in patients with mRCC. The observed advantage in OS for the patients with hypothyroidism should be interpreted with caution; however, enhanced immune response could be the answer to this puzzle. We propose a prospective study with a suitable study design to give a definite answer as to whether hypothyroidism can serve as predictive marker for treatment efficacy of TKIs in patients with mRCC.
Acknowledgments The authors thank Dr Wolter and Dr Papazisis for providing additional data for our meta-analysis. The meta-analysis was supported by grants from the County Council of Sörmland, Sweden. The funding source had no role in study design, data collection and analysis, decision to publish, or preparation of the report.
Disclosure The authors have stated that they have no conflicts of interest.
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