|Year : 2015 | Volume
| 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
Xiaobing Ye, Yiping Zhu, Juan Cai
Department of Medical Oncology, Yijishan Hospital of Wannan Medical College, Wuhu 241000, China
|Date of Web Publication||26-Oct-2015|
Department of Medical Oncology, Yijishan Hospital of Wannan Medical College, No. 2, Zheshan West Road, Wuhu 241000
Source of Support: None, Conflict of Interest: None
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 2022 Oct 2];11, Suppl S2:185-90. Available from: https://www.cancerjournal.net/text.asp?2015/11/6/185/168182
| > Introduction|| |
Thyroid carcinoma (TC) is the most common endocrine malignancy, 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. 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, 2% of all cancers (180,000 globally), but <0.5% of all cancer deaths, and 90% of patients survive ≥10 years.,, However, patients with radioiodine-refractory DTC have a 10-year survival rate of only 10% from the detection of distant metastases., Consensus guidelines have recommended clinical trials with systemic therapies targeted to specific molecules because traditional cytotoxic agents have demonstrated marginal efficacy and significant toxicities.,, 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. Many different TKIs have been studied, 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. 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.
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|| |
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. 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.,,,,,,,,,
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.
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.
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, 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.
| > Results|| |
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, one in Japanese, one is a case report, and three are reviews ,, [Figure 1]. Finally, 10 studies (n = 749 patients) were eligible for this meta-analysis.
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].
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,, 20, ,, 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.,,,,, 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)|
Click here to view
|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)|
Click here to view
| > Discussion|| |
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  or unpublished or ignored studies.
| > Conclusion|| |
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
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300.
Sherman SI. Thyroid carcinoma. Lancet 2003;361:501-11.
Busaidy NL, Cabanillas ME. Differentiated thyroid cancer: Management of patients with radioiodine nonresponsive disease. J Thyroid Res 2012;2012:618985.
National Cancer Institute. Surveillance E, and End, Program. RS: SEER Cancer Statistics Factsheets. Thyroid Cancer. Bethesda, MD: National Cancer Institute; 2014. Available from: http://www.seercancergov/statfacts/html/thyrohtml
. [Last accessed on 2014 Apr 09].
DeLellis RA, Lloyd RV, Heitz P, Eng C, editors. Pathology and Genetics of Tumours of Endocrine Organs. IARC World Health Organization Classification of Tumours. Lyon, France: IARC Press; 2004.
Links TP, van Tol KM, Jager PL, Plukker JT, Piers DA, Boezen HM, et al.
Life expectancy in differentiated thyroid cancer: A novel approach to survival analysis. Endocr Relat Cancer 2005;12:273-80.
Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli JP, et al.
Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: Benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006;91:2892-9.
Sun C, Xu X, Wang X, Sheng W, Wen S, Han J. Thymic carcinoma with tumor thrombus protruding into the superior vena cava and the right atrium. Thorac Cancer 2013;4:333-4.
Pacini F, Castagna MG, Brilli L, Pentheroudakis G; ESMO Guidelines Working Group. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23 Suppl 7:vii110-9.
NCCN. NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Version 2.2013. Fort Washington, PA: NCCN; 2013.
Sherman SI. Cytotoxic chemotherapy for differentiated thyroid carcinoma. Clin Oncol (R Coll Radiol) 2010;22:464-8.
Kapiteijn E, Schneider TC, Morreau H, Gelderblom H, Nortier JW, Smit JW. New treatment modalities in advanced thyroid cancer. Ann Oncol 2012;23:10-8.
Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, et al.
BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst 2006;98:326-34.
Scott LJ. Lenvatinib:First global approval. Drugs 2015;75:553-60.
Altman DG. Systematic reviews of evaluations of prognostic variables. BMJ 2001;323:224-8.
Marotta V, Ramundo V, Camera L, Del Prete M, Fonti R, Esposito R, et al.
Sorafenib in advanced iodine-refractory differentiated thyroid cancer: Efficacy, safety and exploratory analysis of role of serum thyroglobulin and FDG-PET. Clin Endocrinol (Oxf) 2013;78:760-7.
Gupta-Abramson V, Troxel AB, Nellore A, Puttaswamy K, Redlinger M, Ransone K, et al.
Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol 2008;26:4714-9.
Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, et al.
Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015;372:621-30.
Capdevila J, Iglesias L, Halperin I, Segura A, Martínez-Trufero J, Vaz MÁ, et al.
Sorafenib in metastatic thyroid cancer. Endocr Relat Cancer 2012;19:209-16.
Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, et al.
Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: A randomised, double-blind, phase 3 trial. Lancet 2014;384:319-28.
Kloos RT, Ringel MD, Knopp MV, Hall NC, King M, Stevens R, et al.
Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol 2009;27:1675-84.
Lam ET, Ringel MD, Kloos RT, Prior TW, Knopp MV, Liang J, et al.
Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol 2010;28:2323-30.
Schneider TC, Abdulrahman RM, Corssmit EP, Morreau H, Smit JW, Kapiteijn E. Long-term analysis of the efficacy and tolerability of sorafenib in advanced radio-iodine refractory differentiated thyroid carcinoma: Final results of a phase II trial. Eur J Endocrinol 2012;167:643-50.
Ahmed M, Barbachano Y, Riddell A, Hickey J, Newbold KL, Viros A, et al.
Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: A phase II study in a UK based population. Eur J Endocrinol 2011;165:315-22.
Cabanillas ME, Schlumberger M, Jarzab B, Martins RG, Pacini F, Robinson B, et al.
A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment. Cancer 2015;121:2749-56.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88.
Begg CB, Berlin JA. Publication bias and dissemination of clinical research. J Natl Cancer Inst 1989;81:107-15.
Willhauck MJ, Schott M, Kreissl MC, Fassnacht M, Spitzweg C. New therapeutic options for advanced thyroid cancer. Dtsch Med Wochenschr 2011;136:1165-8.
Okamura R, Sugitani I. Current progress and management in molecular targeted therapy for advanced thyroid cancer. Gan To Kagaku Ryoho 2014;41:148-52.
Cully M. Trial watch: Multikinase-targeting therapy finds potential niche in thyroid cancer. Nat Rev Drug Discov 2015;14:229.
Mayor S. Lenvatinib improves survival in refractory thyroid cancer. Lancet Oncol 2015;16:e110.
Lee HJ, Yun HJ, Kim S. Lenvatinib in radioiodine-refractory thyroid cancer. N Engl J Med 2015;372:1868.
Killock D. Neuroendocrine cancer: SELECT – Lenvatinib in thyroid cancer. Nat Rev Clin Oncol 2015;12:189.
Shrivastava SR, Shrivastava PS, Ramasamy J. Negating the impact of radiation in the development of cancers. Asia Pac J Oncol Nurs 2015;2:52-3.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
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