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ORIGINAL ARTICLE
Year : 2015  |  Volume : 11  |  Issue : 6  |  Page : 185-190

Relationship between toxicities and clinical benefits of newly approved tyrosine kinase inhibitors in thyroid cancer: A meta-analysis of literature


Department of Medical Oncology, Yijishan Hospital of Wannan Medical College, Wuhu 241000, China

Date of Web Publication26-Oct-2015

Correspondence Address:
Xiaobing Ye
Department of Medical Oncology, Yijishan Hospital of Wannan Medical College, No. 2, Zheshan West Road, Wuhu 241000
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.168182

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 > Abstract 

Background: The aim of this meta-analysis was to analyze the relationship of toxicities and clinical benefits of newly approved lenvatinib and sorafenib to thyroid cancer (TC) in patients.
Materials and Methods: Three major medical databases, PubMed, EMBASE, and ISI web of science were systematically searched to identify all studies on lenvatinib and sorafenib in TC. A meta-analysis was performed to clarify the toxicities and clinical benefits of newly Food and Drug Administration (FDA) approved lenvatinib and sorafenib to thyroid cancer.
Results: Ten studies (n = 749) were included which evaluated the toxicities and clinical benefits of newly FDA approved lenvatinib and sorafenib to thyroid cancer. 537 (71.7%) of the 749 patients bearing TC (radioiodine-refractory, differentiated thyroid cancer) clinical benefits from lenvatinib or sorafenib, and serious adverse events occurred in 430 (57.4%) of the 749 patients ([risk ratio (RR) = 1.27, 95% confidence interval (CI) = (1.05–1.53), P = 0.01]). While 31 (4.1%) of the 749 patients died due to various reasons, that mainly accounts for severe bleeding events and cardiac arrest. The clinical benefit is obvious compared to deaths ([RR = 17.06, 95% CI = (12.08–24.11), P < 0.001]). Subgroup analyses were then conducted according to cancer type (radioiodine-refractory thyroid cancer [RR-TC] and TC). We found that in treating RR-TC, the clinical benefits are close to toxicities. While in treating TC, the clinical benefits are better than toxicities. And we found that sorafenib and lenvatinib might be proper to deal with TC (benefits rate 79.7%) compared to RR-TC (benefits rate 69.5%), taking consider of toxicities.
Conclusions: Lenvatinib and sorafenib are useful in the treatment of TC. Although, their toxicities remain high (57.4%) in the patients, the death rate is controlled (4.1%). Take consider of toxicities, lenvatinib, and sorafenib are more useful for TC compared to RR-TC.

Keywords: Clinical benefits, lenvatinib, meta-analysis, sorafenib, thyroid cancer


How to cite this article:
Ye X, Zhu Y, Cai J. Relationship between toxicities and clinical benefits of newly approved tyrosine kinase inhibitors in thyroid cancer: A meta-analysis of literature. J Can Res Ther 2015;11, Suppl S2:185-90

How to cite this URL:
Ye X, Zhu Y, Cai J. Relationship between toxicities and clinical benefits of newly approved tyrosine kinase inhibitors in thyroid cancer: A meta-analysis of literature. J Can Res Ther [serial online] 2015 [cited 2019 Dec 5];11:185-90. Available from: http://www.cancerjournal.net/text.asp?2015/11/6/185/168182


 > Introduction Top


Thyroid carcinoma (TC) is the most common endocrine malignancy,[1] with an accumulating incidence over the past decades. Differentiated thyroid cancer (DTC, which is composed of papillary TC and follicular TC) is the most common TC type, whereas medullary TC accounts for only 5% of all TCs. Anaplastic TC is rare, as it constitutes 1% of all TCs.[2] Surgery is the main therapy for patients bearing TC, with an important additional role for radioiodine treatment in DTC.

DTC includes papillary and follicular histologies and accounts for ≥90% of all thyroid cancers,[3] 2% of all cancers (180,000 globally), but <0.5% of all cancer deaths, and 90% of patients survive ≥10 years.[4],[5],[6] However, patients with radioiodine-refractory DTC have a 10-year survival rate of only 10% from the detection of distant metastases.[7],[8] Consensus guidelines have recommended clinical trials with systemic therapies targeted to specific molecules because traditional cytotoxic agents have demonstrated marginal efficacy and significant toxicities.[9],[10],[11] A well-established effective treatment is still lacking for these patients.

Small molecule tyrosine kinase inhibitors (TKIs) are a promising new class of systemic therapy for TC patients with progressive disease (PD). These agents target the molecular TC signaling pathway at single or multiple sites.[12] Many different TKIs have been studied,[12] and several combinations are currently under investigation. Nevertheless, the effectiveness and toxicity of various TKIs in TC patients have not been directly compared, although this would be of great importance for clinical decision-making. Sorafenib is a nonselective kinase inhibitor already approved by the USA Food and Drug Administration (FDA) for the treatment of advanced renal and hepatocellular carcinoma and could represent an effective tool in this field as it is able to strike different steps of the mitogen-activated protein kinase signalling pathway and control neoangiogenesis, which is considered crucial for progression of the disease.[13] Lenvatinib (Lenvima) is a multitargeted receptor kinase inhibitor that inhibits the kinase activities of vascular endothelial-derived growth factor receptors 1, 2 and 3, fibroblast growth factor receptors 1, 2, 3, and 4, platelet-derived growth factor receptor alpha, RET, and KIT. In addition to their role in normal cellular function, these kinases have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression. Lenvatinib is being developed by Eisai Co., Ltd for the treatment of solid tumors, primarily for DTC, and other malignancies.[14]

The aim of this meta-analysis was to systematically summarize the relationship of clinical benefits, toxicities, and deaths of treatment with sorafenib or lenvatinib in patients with TC.


 > Materials and Methods Top


Identification and eligibility of relevant studies

We performed a search of three major medical database PubMed (MEDLINE), EMBASE, and ISI web of science of the literature on the relevance of clinical trial and thyroid carcinoma using the search terms "sorafenib," "lenvatinib," "E7080," "thyroid tumor," and "thyroid cancer" from 1970 onward. We also hand searched the reference sections of all obtained publications to find out any studies missed by the search strategies.

After read by two independent reviewers, the candidate articles were identified for the analysis studies based on title and abstract, which were both restricted to English. When cannot be confirmed, the full-text review was retrieved except the ones not in English. Reported data required for meta-analysis were then extracted by two independent reviewers. Because no such score had received general agreement for meta-analyses of observational studies, prespecified quality-related inclusion or exclusion criteria were not used, and each study had not been weight by a quality score.[15] The effort was made to contact investigators by e-mail to get unpublished data regarding clinical trial, lenvatinib or sorafenib, and thyroid cancer by the reviewers. Finally, 10 publications were selected and included in the present meta-analysis.[16],[17],[18],[19],[20],[21],[22],[23],[24],[25]

Definitions and standardizations

The patients with TCs under lenvatinib or sorafenib treatment were counted divided into clinical benefits group, toxicities group, and deaths group. The main reported data required for our meta-analysis were, for clinical benefits group, complete response (CR), partial response (PR), stable disease (SD), and for toxicities, serious adverse events, or grade 3 or 4 adverse events, or reduction of dose due to adverse events. We also listed major country, sexuality, the number of patients in the clinical trial, subtype of cancer, and death reasons if there is a death case in the clinical trial.

Data extraction

Two reviewers independently extracted data from all clinical studies. The primary data were the CR, PR, SD, serious adverse events, grade 3 or 4 adverse events, a reduction due to adverse events, and death from the patients treated with lenvatinib or sorafenib. Additional data obtained from the studies included a publication year, the first author, major country, number of patients, patient's sexuality, thyroid cancer subtype, and death reasons. Disagreements were resolved by consensus between the two readers and studies were all retrospective.

Statistical analyses

All patients were filtrated in lenvatinib or sorafenib treat group, and the counts of CR, PR, and SD ≥6 months were considered as clinical benefits, and the counts of serious adverse events, or grade 3 or 4 adverse events, or imperative reduction due to adverse events were considered as toxicities, and the counts of death due to whatever reason were considered as deaths. The results of the study were considered significant when the P < 0.05 in univariate analysis. Risk ratio (RR) with 95% confidence interval (CI) synthesized were used to assess the strength of association. Considering the many sources of heterogeneity between studies and consequently between their individual RR estimates, we calculated the overall RR according to the Der Simonian and Laird's method,[26] with a random effect model when homogeneity was not fine (P > 0.10, I2 > 50%). An observed RR > 1 indicated better outcomes for the clinical benefits relative to toxicities group, the clinical benefits relative to deaths group and the toxicities relative to deaths group, and would be considered statistically significant if the 95% CI did not overlap 1, with P < 0.05. Forest plots were used to estimate the relationship between clinical benefits, toxicities, and deaths, created by RevMan version 5.3 (Cochrane Collaboration, Oxford, UK) in our meta-analysis. Potential publication bias was evaluated using the Begg's test, and funnel plots were created by STATA version 12.0 (STATA Corporation, College Station, TX, USA). It was considered that there is no publication bias when the P value was more than 0.05.[27]


 > Results Top


Eligible studies

Our electronic search algorithm retrieved a total of 1672 references for levatinib, sorafenib and TC. After removal of duplicated articles, studies of tumors from other origins, animal and laboratory studies, and studies on other pathway, 117 candidate studies were retrieved for abstract reading. After further evaluation, 16 studies were retrieved for full-text assessment. Of all the 16 reports, eight were excluded: One in German,[28] one in Japanese,[29] one is a case report,[30] and three are reviews [31],[32],[33] [Figure 1]. Finally, 10 studies (n = 749 patients) were eligible for this meta-analysis.
Figure 1: Selection of studies

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Characteristics of the 10 eligible studies are listed in [Table 1]. All of the eligible studies were observational retrospective studies. Five reports originated from America, five from Europe. According to the information, the clinical trials are reported ranged from the year 2008 to 2015, the percentage of the female is nearly 45.0%. Of all the 749 patients with TC, 31 (12.1%) died. The major reasons are hemorrhage and cardiac arrest, others are liver failure, PD, and so on [Table 1].
Table 1: Characteristics of the eligible studies

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Relationship between clinical benefits, toxicities and deaths

Sorafenib and lenvatinib were useful in the treatment of DTC. As between-study heterogeneity was significant (I2 > 50%), the random model was used in all of our analysis. Total clinical benefits were 1.25-fold higher in patients compared to the toxicities [n = 749, RR = 1.27, 95% CI = (1.05–1.53), P = 0.01; [Figure 2]. The between-study heterogeneity (I2 = 77%) showed a moderate heterogeneity, two studies were obviously differ from others – One is from Italy, the other is from The Netherlands. Test drug of these two studies is sorafenib.
Figure 2: Meta-analysis of the association between clinical benefits and toxicities. Each study is shown by the name of the first author. The summary risk ratio, 95% confidence intervals (according to random effect calculations) and P value are also shown (ALL)

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While for benefits and deaths, the benefits were dramatically higher than deaths caused by sorafenib and lenvatinib [RR = 15.24, 95% CI = (6.99–33.21), P < 0.00001; [Figure 3]. For toxicities and deaths, the toxicities were dramatically higher than deaths caused by sorafenib and lenvatinib [RR = 11.88, 95% CI = (5.84–24.16), P < 0.00001; [Figure 4]. The between-study heterogeneity of benefits-deaths and toxicities-deaths (I2 = 74% and I2 = 69%, respectively) showed a high heterogeneity for a reason of similarity of clinical benefits and toxicities. Begg's test and the funnel was used to evaluate publication bias. No significant publication biases were found in the meta-analysis of clinical benefits and toxicity [P = 0.688; [Figure 5]a, clinical benefits and deaths [P = 0.502; [Figure 5]b, toxicities and deaths [P = 0.518; [Figure 5]c of sorafenib and lenvatinib.
Figure 3: Meta-analysis of the association between clinical benefits and deaths. Each study is shown by the name of the first author. The summary risk ratio, 95% confidence intervals (according to random effect calculations) and P value are also shown (ALL)

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Figure 4: Meta-analysis of the association between toxicities and deaths. Each study is shown by the name of the first author. The summary risk ratio, 95% confidence intervals (according to random effect calculations) and P value are also shown (ALL)

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Figure 5: Funnel plots of publication bias summary for the corresponding meta-analysis in Figure 2 (a), Figure 3 (b) and Figure 4 (c)

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Subsequently, we were curious about the relationship between clinical benefits and toxicities in radioiodine-refractory thyroid cancer [RR-TC] or TC. Subgroup analyses were then conducted according to cancer type (RR-TC and TC). Interestingly, we found that in treating RR-TC,[18], 20, [23],[24],[25] the clinical benefits are close to toxicities [RR = 1.15, 95% CI = (0.99–1.34), P = 0.07; [Figure 6], but the between-study heterogeneity is improved to median heterogeneity (I2 = 52%). While in treating TC.[16],[17],[19],[21],[22],[34] the clinical benefits are better than toxicities [RR = 1.54, 95% CI = (0.96–2.44), P = 0.07; [Figure 7], the between-study heterogeneity is improved to a very high heterogeneity (I2 = 86%). And we found that the rates of clinical benefits are 69.5% and 79.7%, respectively in RR-TC and TC, suggesting that sorafenib and lenvatinib might be proper to deal with TC taking consider of toxicities.
Figure 6: Meta-analysis of the association between clinical benefits and toxicities in radioiodine-refractory-TC. Each study is shown by the name of the first author. The summary risk ratio, 95% confidence intervals (according to random effect calculations) and P value are also shown (ALL)

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Figure 7: Meta-analysis of the association between clinical benefits and toxicities in TC. Each study is shown by the name of the first author. The summary risk ratio, 95% confidence intervals (according to random effect calculations) and P value are also shown (ALL)

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 > Discussion Top


Sorafenib and lenvatinib are promising targets specified drugs for a multiple solid tumor or other malignancies. They are both FDA approved, and plenty of studies have been carried on: Phase II or III clinical trials. Our meta-analysis reviewed 10 clinical trials, summarized the clinical benefits, toxicities and deaths caused by sorafenib and lenvatinib, and found that the drug derived deaths mainly concentrate upon hemorrhage and cardiac arrest, others are liver failure, PD, and lung relative diseases. We found the clinical effect of sorafenib and lenvatinib are better than the toxicities in patients [RR = 1.27, 95% CI = (1.05–1.53), P = 0.01; [Figure 2], and dramatically better than deaths [RR = 15.24, 95% CI = (6.99–33.21), P < 0.00001; [Figure 3]. For toxicities and deaths, the toxicities were dramatically higher than deaths caused by sorafenib and lenvatinib [RR = 11.88, 95% CI = (5.84–24.16), P < 0.00001; [Figure 4]. In our meta-analysis, between-study heterogeneity were significant in our study (I2 = 77%, 74%, and 69%). We tried to reduce the variability by screening the literature using the same standard and dividing studies into subgroups, such as the same patient origination in our meta-analysis. Although the heterogeneity could not be eliminated totally, the heterogeneity had decreased in some subgroups such as Europe and America. In addition, the limitations still exist in the present detection methods. We attempted to minimize publication bias by searching completely, but it was unavoidable that some data were missed for various reasons such as publishing language only in Japanese [29] or unpublished or ignored studies.


 > Conclusion Top


The meta-analysis suggested that newly approved drugs sorafenib and lenvatinib are useful for patients with RR-TC and TC. Taking consider of toxicities, treating TC might be a good choice, and there are still a lot of work have to be done in treating RR-TC in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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