Clinical features of lenvatinib treatment in elderly patients with advanced thyroid cancer
- Koichi Suyama
- Saori Fujiwara
- Takashi Takeshita
- Aiko Sueta
- Touko Inao
- Mutsuko Yamamoto-Ibusuki
- Yutaka Yamamoto
- Hirotaka Iwase
- Published online on: May 17, 2017 https://doi.org/10.3892/mco.2017.1265
- Pages: 24-26
Copyright: © Suyama et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Differentiated thyroid carcinoma (DTC) typically has a good prognosis; however, effective systemic chemotherapy for advanced DTC had not existed until recently, when lenvatinib, a multi-tyrosine kinase inhibitor was proven an effective treatment option (1). Subsequently, lenvatinib has been introduced into clinical practice for advanced DTC. Unfortunately, there are little safety data for lenvatinib, particularly regarding elderly patients.
Numerous adverse effects of lenvatinib have been reported, including hypertension, hand-foot syndrome (HFS) diarrhea and thrombocytopenia. In the SELECT trial, ~70% of patients receiving lenvatinib presented with hypertension (1); similar results have also been demonstrated in other clinical trials (2–4). Zhu et al (5) analyzed the safety and efficacy profiles of lenvatinib in patients with cancer in a systematic review and meta-analysis; in an analysis of 978 patients treated with lenvatinib, the most frequently observed adverse events of grade 3 or higher were thrombocytopenia (25.4%), hypertension (17.7%) and peripheral edema (15.5%). Additionally, incidences of all-grade and high-grade hypertension were significantly increased (5).
Numerous problems have been reported regarding the use of chemotherapy in elderly patients (6–8). Elderly patients more frequently suffer from the adverse side effects of anticancer chemotherapy than younger patients. There are many clinical reports on the safety and efficacy of lenvatinib (1,5), but none specifically study its safety profile in elderly patients. In clinical practice, lenvatinib is commonly used to treat elderly patients, and there is significant experience in administrating lenvatinib to elderly patients in Kumamoto University Hospital. The present study examined the side effects of lenvatinib in 18 patients grouped by age (younger, <75 years and elderly, ≥75 years) to analyze differences in the adverse events associated with lenvatinib treatment in elderly patients.
Patients and methods
This retrospective, observational, cross-sectional study was designed to evaluate the safety of lenvatinib for elderly patients. A total of 18 consecutive patients with histopathologically-proven DTC treated with lenvatinib at Kumamoto University Hospital between July 2015 and July 2016 were enrolled in the study. Written informed consent was obtained from all patients prior to enrollment. Information regarding adverse events was obtained from medical charts and compared between younger (<75 years) and elderly (≥75 years) patients. When collecting blood pressure (BP) data, the hospital BP was used rather than the home BP. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events version 4.0 (9). The study protocol has been approved by the institutional review board of Kumamoto University.
The Mann-Whitney U test was used to compare the degree of each adverse event (such as BP), and χ2 tests were used to compare the proportions of variables between groups. All statistical analyses were conducted using SAS JMP Pro v12.1.0 (SAS Institute Inc., Cary, NC, USA). P<0.05 was considered to indicate a statistically significant difference.
Clinical characteristics of the 18 enrolled patients are presented in Table I. The proportion of younger and elderly patients and of males and females were the same in the overall cohort and groups. All patients had histologically-confirmed papillary thyroid carcinoma as their primary diagnosis and were administered 24 mg per day lenvatinib, with the exception of 5 patients whose tumors showed vessel invasion (Table II).
The median maximum systolic BP (sBP) was significantly different between the younger patient and elderly patient groups (158 vs. 173 mmHg; P=0.042; Fig. 1A). There were no significant differences between the younger and elderly patients in median maximum diastolic BP (dBP; 94 vs. 95 mmHg; P=1.00; Fig. 1B), median degree of sBP elevation (43 vs. 55 mmHg; P=0.199; Fig. 1C) or median days until a clinical hypertension diagnosis (2.11 vs. 2.33 days; P=0.436; Fig. 1D). There was also no significant difference in the baseline sBP between elderly and young patients. Furthermore, the frequency of other adverse events (grade ≥1 HFS, proteinuria and diarrhea) exhibited no significant differences between groups (Table III).
Comparison of the effects of lenvatinib on hypertension in patients with differentiated thyroid carcinoma <75 and ≥75 years old. (A) Patients ≥75 years old had significantly higher systolic blood pressure than patients <75 years old. There were no significant differences between younger (<75) and elderly (≥75) patients in (B) maximum diastolic blood pressure, (C) systolic blood pressure elevation or (D) median number of days before hypertension diagnosis.
Between the two groups, there were no significant differences in the proportion of patients with hypertension history and using antihypertensive drugs.
The present study performed a retrospective analysis of 18 consecutive lenvatinib-treated advanced DTC patients from Kumamoto University Hospital. The analysis was focused on comparing the degree of adverse events associated with lenvatinib treatment between elderly and younger patient groups. Among several adverse events, hypertension was focused upon, as it has previously been demonstrated to be a major clinical concern for elderly patients receiving chemotherapy (6–8). The results revealed that sBP was significantly elevated in elderly patients compared with younger patients, but the change from baseline to maximum sBP was not significant. As presented in Fig. 1C, the elderly patients had at least the trend to have more elevated sBP than young patients following lenvatinib therapy. This trend may be one of the reasons for elevated sBP in elderly patients. Conversely, there were no indications of increases in other lenvatinib-specific toxicities such as HFS, proteinuria, diarrhea, fatigue and thrombocytopenia among elderly patients.
Elderly patients suffer more chemotherapy-induced toxicities than younger patients with cancer (6–8). In clinical trials the majority of patients are relatively young and in good condition; thus, there is often a lack of information from these studies regarding efficacy and safety for elderly patients. Among studies investigating the efficacy of lenvatinib for thyroid carcinoma, to the best of our knowledge there have been no studies analyzing the degree of lenvatinib-specific adverse effects in elderly patients. The present results revealed a trend of increased maximum sBP in elderly patients treated with lenvatinib compared with younger patients; however, the frequency of other toxicities did not increase, indicating that lenvatinib is relatively safe for elderly patients.
In general, elderly patients tend to have increased sBP and decreased dBP, caused by decreased elasticity and extensibility of large arteries occurring due to the extension of arteriosclerosis associated with increasing age. Although the precise mechanisms of BP elevation following lenvatinib treatment are unclear, one possible explanation may be lenvatinib-induced vascular endothelial cell injury (10). The underlying mechanism of the high sBP in elderly patients receiving lenvatinib may involve effects on the vascular endothelial cells that surround arteriosclerotic vessels. There is no evidence that demonstrates that elderly patients tend to have HFS, diarrhea and other toxicities, which might explain the lack of increased frequencies of these adverse events in patients over 75 in the present study.
There were several limitations to the current study. First, this was a retrospective observational study, not a case-controlled study; therefore, the study design cannot avoid confounding and selection biases. Second, the number of patients was small, the results are not able to be extrapolated without subsequent studies with larger patient cohorts. Thus, we cannot regard this study as high quality.
In conclusion, a trend of hypertension in elderly patients receiving lenvatinib but not in younger patients was observed, suggesting that lenvatinib should be introduced carefully to elderly patients. However, lenvatinib-induced hypertension may easily be controlled using anti-hypertensive drugs or adjusting the dose of lenvatinib. Overall, lenvatinib was tolerable, even in elderly patients >75.
Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, Habra MA, Newbold K, Shah MH, Hoff AO, et al: Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 372:621–630. 2015. View Article : Google Scholar : PubMed/NCBI
Boss DS, Glen H, Beijnen JH, Keesen M, Morrison R, Tait B, Copalu W, Mazur A, Wanders J, OBrien JP, et al: A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours. Br J Cancer. 106:1598–1604. 2012. View Article : Google Scholar : PubMed/NCBI
Nakamichi S, Nokihara H, Yamamoto N, Yamada Y, Honda K, Tamura Y, Wakui H, Sasaki T, Yusa W, Fujino K and Tamura T: A phase 1 study of lenvatinib, multiple receptor tyrosine kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 76:1153–1161. 2015. View Article : Google Scholar : PubMed/NCBI
Cabanillas ME, Schlumberger M, Jarzab B, Martins RG, Pacini F, Robinson B, McCaffrey JC, Shah MH, Bodenner DL, Topliss D, et al: A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: a clinical outcomes and biomarker assessment. Cancer. 121:2749–2756. 2015. View Article : Google Scholar : PubMed/NCBI
Zhu C, Ma X, Hu Y, Guo L, Chen B, Shen K and Xiao Y: Safety and efficacy profile of lenvatinib in cancer therapy: a systematic review and meta-analysis. Oncotarget. 7:44545–44557. 2016.PubMed/NCBI
Chrischilles EA, Pendergast JF, Kahn KL, Wallace RB, Moga DC, Harrington DP, Kiefe CI, Weeks JC, West DW, Zafar SY and Fletcher RH: Adverse events among the elderly receiving chemotherapy for advanced non-small-cell lung cancer. J Clin Oncol. 28:620–627. 2010. View Article : Google Scholar : PubMed/NCBI
Townsley CA, Selby R and Siu LL: Systematic review of barriers to the recruitment of older patients with cancer onto clinical trials. J Clin Oncol. 23:3112–3124. 2005. View Article : Google Scholar : PubMed/NCBI
Clough-Gorr KM, Stuck AE, Thwin SS and Silliman RA: Older breast cancer survivors: geriatric assessment domains are associated with poor tolerance of treatment adverse effects and predict mortality over 7 years of follow-up. J Clin Oncol. 28:380–386. 2010. View Article : Google Scholar : PubMed/NCBI
US Department of Health and Human Services, . National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. simplehttps://evs.nci.nih.gov/ftp1/CTCAE/Archive/CTCAE_4.02 _2009-09-15_QuickRef erence_5x7_Locked.pdfSeptember 1–2016
Keizer RJ, Gupta A, Mac Gillavry MR, Jansen M, Wanders J, Beijnen JH, Schellens JH, Karlsson MO and Huitema AD: A model of hypertension and proteinuria in cancer patients treated with the anti-angiogenic drug E7080. J Pharmacokinet Pharmacodyn. 37:347–363. 2010. View Article : Google Scholar : PubMed/NCBI