Lenvatinib induces early tumor shrinkage in patients with advanced thyroid carcinoma

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1 2017, 64 (8), Note Lenvatinib induces early tumor shrinkage in patients with advanced thyroid carcinoma Chie Masaki 1), Kiminori Sugino 1), Naoko Saito 2), Yoshiyuki Saito 1), Tomoaki Tanaka 1), Yuna Ogimi 1), Tetsuyo Maeda 1), Tadatoshi Osaku 1), Junko Akaishi 1), Kiyomi Y. Hames 1), Chisato Tomoda 1), Akifumi Suzuki 1), Kenichi Matsuzu 1), Takashi Uruno 1), Keiko Ohkuwa 1), Wataru Kitagawa 1), Mitsuji Nagahama 1), Hiroshi Takami 1) and Koichi Ito 1) 1) Department of Surgery, Ito Hospital, Tokyo, Japan 2) Department of Diagnostic Radiology, Saitama Medical University, International Medical Center, Hidaka, Japan Abstract. Although advanced thyroid carcinoma patients who cannot be cured by conventional therapy have lacked effective treatment, multitargeted tyrosine kinase inhibitors have recently become available. Phase 3 trials of lenvatinib showed a median time to objective response of 2 (95 % confidence interval (CI) ) months, demonstrating that shrinks tumors rapidly. The phenomenon of immediate tumor shrink is known as early tumor shrinkage (ETS) which is related to clinical outcome in other malignancies. However, precisely when within 8 weeks lenvatinib starts to affect tumors remains unclear. In tumors near the carotid arteries, trachea, or esophagus, a rapid therapeutic effect can induce fistula formation or arterial bleeding. To prevent such treatment-emergent serious adverse events (SAE), early imaging evaluation seems to be very important. In this study, the point in time when lenvatinib started to shrink tumors was retrospectively investigated. The subjects were 16 patients who started lenvatinib administration between May and August Tumor size was evaluated by computed tomography (CT) scans frequently within the first 8 weeks according to the Response Evaluation Criteria In Solid Tumors (RECIST) guideline. Initial tumor response was defined as 10% tumor reduction. Serum thyroglobulin (Tg) level was monitored in 8 differentiated thyroid carcinoma (DTC) without TgAb patients. At the first evaluation, 13 patients (83.3 %) showed tumor reduction and that decreased with time. Thirteen patients (83.3 %) showed >10 % tumor reduction within 8 weeks. In all DTC patients, serum Tg level was markedly decreased. In conclusion, lenvatinib immediately shrinks tumors, the so-called ETS phenomenon. Therefore, careful attention should be paid to fistula formation from the early phase. Key words: Thyroid carcinoma, Lenvatinib, Early tumor shrinkage THYROID CARCINOMA is generally indolent and has a favorable prognosis even if it metastasizes to other organs. However, some patients have thyroid carcinoma that show aggressive, rapid-growth characteristics and have a fatal course. Effective treatments have been lacking for patients who cannot be cured by existing therapy, surgery, or radioactive-iodine (RAI) therapy. Tyrosine kinase inhibitors (TKIs) are a new treatment option for these patients [1, 2]. Of these, lenvatinib [3-5] has proven effective in the treatment Submitted Mar. 15, 2017; Accepted Apr. 18, 2017 as EJ Released online in J-STAGE as advance publication Jun. 28, 2017 Correspondence to: Chie Masaki, M.D., Department of Surgery, Ito Hospital, Jingumae, Shibuya-ku, Tokyo , Japan. c-masaki@ito-hospital.jp The Japan Endocrine Society of differentiated thyroid carcinoma (DTC) with RAIrefractory and/or unresectable progressive disease. A phase 3 trial of lenvatinib reported a median time to objective response for lenvatinib of 2 months (95 % confidence interval (CI), months) [6, 7], which shows that lenvatinib rapidly decreases tumor size in advanced thyroid carcinoma. This result indicates that many cases of the trial already showed tumor size reduction at 8 weeks, which is known as early tumor shrinkage (ETS) and is related to clinical outcome in other malignancies. However, the specific point at which lenvatinib starts to affect tumors within this 8 week period remains unclear, because the trial s initial imaging evaluation set its initiation point at 8 weeks after treatment.

2 820 Masaki et al. Knowledge of the therapeutic response onset time of lenvatinib seems very useful, particularly in structurally progressive cases. For cases with a potential to invade skin, airways, esophagus, and common carotid arteries (CCAs), the therapeutic effect can lead to fistula formation between the tumor and these organs, which is considered a serious adverse event (SAE). Fistulas easily induce local infection, and infection of these sites can cause rupture of the nearby vulnerable CCAs, which can be fatal. For safe management, early imaging evaluation can help identify potential SAEs immediately. In this study, precisely when thyroid carcinoma shrinkage starts to occur with lenvatinib therapy was retrospectively investigated. Patients and Methods Patients Between May and August 2015, a total of 17 patients started lenvatinib treatment at Ito Hospital, Tokyo, Japan. Of these, the 16 patients who underwent regular evaluation by computed tomography (CT) were the subjects of this study. Patient characteristics and the histological subtypes of the tumors are summarized in Table 1. All patients had unresectable, progressive thyroid carcinoma. The main metastatic sites were lungs (87.5 %) and bones (62.5 %). Fifteen patients underwent total thyroidectomy, and the remaining patient had an unresectable primary thyroid lesion because of advanced anaplastic carcinoma. According to the Response Evaluation Criteria In Solid Tumors (RECIST) guideline version 1.1 [8], target lesions (TLs) were defined as soft-tissue metastatic lesions that could be measured in at least one dimension, with longest diameters of at least 1 cm. The soft-tissue component of a bone lesion of any size was not considered a TL in our study. Other lesions less than 1 cm in diameter or that were not measurable were considered non-tls. Eleven patients (68.8%) had symptoms (dyspnea due to lung metastasis or pleural effusion, dysphagia due to digestive tract obstruction, paralysis due to spinal cord compression, and pain due to bone metastasis). All 12 patients with DTC, including poorly differentiated carcinoma, were refractory to RAI. Three patients had received TKI treatment (sorafenib for 2 patients, vandetanib for 1 patient) prior to lenvatinib treatment. This study was approved by the institutional review board at Ito Hospital. Table 1 Patients baseline characteristics Number of patients 16 Age Median [range] 69.5 [40-83] Gender (Male:Female) 4:12 BMI, kg/m 2 Mean ± SD 19.3 ± 3.6 Median [range] 19.6 [ ] ECOG Performance status Histological subtype Papillary 7 Follicular 3 Poorly 2 Anaplastic 2 Medullary 2 Prior TKI treatment Yes 3 A No 13 Metastatic sites Locoregional 6 Lymph notes 11 Lung 14 Bone 10 Liver 7 Others 4 B Target lesions Primary 1 Locoregional 3 Lymph notes 5 Lung 9 Bone 0 Liver 3 Others 1 C A contains 2 cases of sorafenib and a case of vandetanib. B contains cases with metastatic sites of pleura, muscle, kidney, and venous thrombus. C contains cases with target lesions of muscle and kidney. Medication Lenvatinib was prescribed at a starting dose of 24 mg once daily in all patients. All patients required dose interruption and dose reduction due to adverse events (AEs), and the initial dose reduction was seen on day 13 (range, 2-43 days). By 8 weeks after starting administration, the median dose of lenvatinib was 14 mg/day (range, 8-20 mg/day). Median doses in each of the first 8 weeks are shown in Table 2.

3 Lenvatinib treatment for thyroid cancer 821 Table 2 Time-series dosage within 8 weeks Week No. of cases (interruption) 16 (0) 16 (1) 16 (0) 14 (4) 14 (4) 13 (4) 13 (1) 12 (4) Dosage (mg/day) Median (range) 24 (24-24) 24 (20-24) 20 (14-24) 20 (14-24) 20 (8-24) 17 (8-24) 14 (8-20) 14 (8-20) AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, and protocol-directed dose interruptions and dose reductions were applied. Hypertension in 6 patients (35.3 %), hand-foot syndrome in 3 patients (17.7 %), proteinuria in 8 patients (47.1 %), and decreased platelet count in 9 patients (52.9 %) led to dose interruptions and reductions. No patients discontinued lenvatinib due to AEs. Morphological assessment To assess drug effects, CT was performed using a 64-detector row scanner (Aquilion CX; Toshiba Medical Systems, Tokyo, Japan). Non-enhanced images were obtained from 5 patients (31.3%) who were allergic to contrast media or had lung and/or bone metastases as TLs. Contrast-enhanced images were obtained for the remaining 11 patients. Baseline CT from brain to pelvis was performed within 4 weeks before starting lenvatinib treatment, and subsequent examination by CT only for TLs was performed approximately every 2 weeks within the first 8 weeks to investigate morphological changes in TLs. Changes in TL size over time were evaluated according to the RECIST guideline. Although partial response (PR) is defined as a decrease of at least 30 % in the size of TLs in the guideline, the aim of this study was to investigate the initial timing of the response to lenvatinib. A reduction in size of 10% was thus regarded as the initial response in this study. Serum creatinine levels were measured in all patients before the use of contrast media to avoid contrast-induced nephropathy. Measurement of serum thyroglobulin (Tg) Serum Tg (Elecsys TgII; Roche, Tokyo, Japan) was monitored every week as another index of therapeutic efficacy. Of 12 DTC patients, 4 with thyroglobulin antibody (TgAb) were excluded because TgAb affects serum Tg level. Change rates from the baseline Tg levels were calculated with time. Interruption induced a rapid elevation of serum Tg levels, which promptly diminished after resumption. Therefore, interruption-affected Tg data were excluded. Results Patients Thirteen patients (81.3 %) continued treatment over 8 weeks, whereas 3 patients (18.7 %) discontinued at 3, 3, and 4 weeks, respectively due to poor general condition rather than tumor progression. CT was carried out 2.4 times on average (range, 1-3 times) during the first 8 weeks; once in 1 patient (6.2 %), 2 times in 7 patients (43.8 %), and 3 times in 8 patients. The first CT assessment after lenvatinib administration was performed at a median of 16 days (range, 6-35 days) after starting treatment. Nephropathy due to contrast media was not observed in any patients throughout the study. Tumor changes within the first 8 weeks Time-dependent change rates in tumor size are shown in Fig. 1. Thirteen patients (81.3 %) showed tumor reduction at the first evaluation. Tumor size continued to decrease in almost all patients within the first 8 weeks. At 2, 4, 6, and 8 weeks after starting treatment, the median tumor size change rates from baseline were 88.6 % (n=6), 87.0 % (n=14), 74.2 % (n=10), and 73.9 % (n=8), respectively. Of the 16 patients, 13 patients (81.3 %) showed a 10% decrease within the first 8 weeks; of special note, 9 patients (56.2 %) showed a decrease within 4 weeks. Two patients had a 10 % decrease after 8 weeks, and 1 remaining patient showed no tumor size change. The time distribution to achieve a 10% decrease in tumor size is shown in Fig. 2. Representative CT images of 2 patients showing early tumor shrinkage are shown in Fig. 3. Fig. 3A shows a hilar-mediastinal lymph node metastasis of follicular carcinoma in an 81-year-old woman (a). All TLs have already shown a 10 % decrease with decline of contrast agent uptake 6 days after initiation of lenvatinib (b), and continued to decrease thereafter (c).

4 822 Masaki et al. Fig. 1 Change rate in tumor size over time shows the time point of initial evaluation. At initial evaluation, 13 patients (81.3%) show tumor shrinkage to any degree. In 15 patients (93.8%), gradual decreases in tumor size were observed within 8 weeks. PTC, papillary thyroid carcinoma; FTC, follicular thyroid carcinoma; MTC, medullary thyroid carcinoma; Poorly, poorly differentiated thyroid carcinoma; ATC, anaplastic thyroid carcinoma. Fig. 2 Patients with 10% reduction in tumor size Thirteen patients (81.3%) show a 10% decrease in tumor size within the first 8 weeks.

5 Lenvatinib treatment for thyroid cancer 823 Fig. 3 Lenvatinib promptly decreased tumor size of thyroid carcinoma Serial contrast-enhanced computed tomography shows the target lesions changing time-dependently over 8 weeks. A) Hilar-mediastinal lymph node metastasis in an 81-year-old woman with follicular carcinoma at baseline (a), day 6 (b) and day 23 (c) after initiation of treatment. A 10% reduction in tumor size was observed, and it continued to decrease over time. Tumor enhancement decreased, which suggests tumor lysis. B) Supraclavicular lymph node metastasis in a 77-year-old man with papillary carcinoma. The tumor surrounds the common carotid artery (CCA) with skin infiltration at baseline (a). On the day 9, a pinhole fistula was observed on tumor invaded skin, with massive necrotic tissue discharge (b). Open air infiltrated necrotic tissue was observed near the CCA at day 16(c). This can lead to CCA perforation induced by local infection. Fig. 3B shows supraclavicular lymph node metastasis in a 77-year-old man with papillary carcinoma. Before lenvatinib administration, the tumor surrounded the CCA with skin invasion at baseline (a). On day 9, skin pinhole fistula occurred, from which massive necrotic tissue was discharged (b). Although the tumor was decreased, open air infiltrated near the CCA at day 16(c), and persistently increased with tumor reduction. This status is very risky because local infection can lead to CCA perforation. Measurement of serum Tg Serum Tg level was measured in 8 DTC with TgAb negative patients. At 2, 4, 6, and 8 weeks after starting of lenvatinib, serum Tg level decreased to 82.0 %, 25.0 %, 15.0 %, and 9.1 % of the baseline Tg level, respectively. Serum Tg level was dramatically decreased in a short time. Five weeks later, serum Tg level decreased >20 % from baseline and sustained a low level in all 8 patients (Fig. 4). In 3 patients, Tg increased markedly just after starting treatment, but decreased thereafter. Discussion Lenvatinib is a new treatment option approved for RAI-refractory metastatic or recurrent thyroid carcinoma patients, which achieved outstanding results in comparison with other previous TKIs such as sorafenib [2], vandetanib, and pazopanib. It is an oral multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor (VEGFR)1-3, fibroblast growth factor receptor (FGFR)1-4, platelet-derived growth factor receptor alpha (PDGFR-α), ret proto-oncogene (RET), and KIT proto-oncogene [3-5]. In the phase 3 trial, lenvatinib prolonged progression-free survival (PFS; hazard ratio for progression or death, 0.21; 99 %CI, , p<0.001) by 14.7 months (lenvatinib median PFS, 8.3 months) compared with placebo (median PFS, 3.6 months) [6]. Notably, lenvatinib treatment also resulted in an overall response rate (ORR) of 64.8%, compared with an ORR of 1.5% in placebo-treated patients, and the median time to objective response was 2 months (95% CI, months) [6]. This result

6 824 Masaki et al. Fig. 4 Serum thyroglobulin (Tg) changes in 8 patients with TgAb negative differentiated thyroid carcinoma Serum Tg level decreased dramatically in all patients. PTC, papillary thyroid carcinoma; FTC, follicular thyroid carcinoma; Poorly, poorly differentiated thyroid carcinoma. shows that lenvatinib promptly induced tumor shrinkage [7]. However, it was unclear when lenvatinib started to exert its efficacy, particularly within the initial 8 week period, because 8 weeks was the earliest assessment time point in that trial. Given the result of the trial, lenvatinib may have started to decrease tumor size far earlier than 8 weeks. In structurally progressive cases, tumors near the trachea or a major artery are often observed, and they may invade these organs. For these lesions, lenvatinib can induce devastating effects in the short term, which can lead to fistula formation or massive arterial bleeding. Actually, we experienced skin fistula formation as shown in Fig. 3B. In that particular case, skin fistula formation had a risk of CCA perforation following local infection. Lenvatinib had to be discontinued to avoid fatal SAEs, which have already been reported in other organ malignancies with MKI therapy [9]. Thus, particularly in structural progressive cases, early tumor evaluation with CT scan is considered very important. In the present study, initial response was defined as more than a 10% decrease. The degree of change in tumor size is generally central to measuring response to therapy, with partial response (PR) defined as a decrease of at least 30% in the size of TLs in the RECIST guideline [8]. However, in the present study, the aim was to detect the initial response, not the degree of tumor size decrease. In the present series, 15 patients (93.8 %) showed tumor shrinkage to some degree over the subsequent periods. Shrinkage 10% was observed within the first 2 months in 13 patients (81.3 %). At 8 weeks, the maximum percent change in tumor size was -35 %. These results show that lenvatinib induced an early-on-treatment response within 8 weeks. This phenomenon is called ETS in other malignancies [10-12]. If this aspect plays a role in lenvatinib for thyroid carcinoma, ETS can be a surrogate marker of efficacy, making early imaging evaluation more meaningful. However, TKI therapy includes several clinical problems, such as complicated and cumbersome AE management [13], rapid regrowth after temporal interruption of TKI, and expensive treatment costs. Thus, lenvatinib cannot be simply said to be a promising

7 Lenvatinib treatment for thyroid cancer 825 agent only because ETS is observed. To analyze the association between ETS and outcome, further studies are needed. Another index of efficacy in thyroid carcinoma is serum Tg [14]. Whereas morphologic assessment is routinely adopted to evaluate treatment efficacy, the role of serum Tg is not entirely clear. Although serum Tg has been considered a useful biomarker of treatment effectiveness in phase 3 studies or other clinical reports [15, 16], it has not yet been fully investigated. All patients showed a short-term sharp decrease and reached a level of less than 20% within 5 weeks. In 3 patients, serum Tg increased markedly just after starting treatment and then decreased, which seems to reflect tumor destruction, not tumor progression. Furthermore, the decreased serum Tg level was maintained time-dependently after a significant reduction. Serum Tg level was slightly increased in the final observation phase in some patients. This is due to dose reduction by time as shown in Table 2. However, the mechanism of the effect of lenvatinib on the Tg secretory system in cancer cells is unclear. Lenvatinib inhibits the VEGF pathway, which plays a role in angiogenesis of tumor growth. Tg secretion might be influenced by pathway inhibition, or it might result in a direct tumor volume decrease. Whatever the mechanism, the kinetics of Tg do not totally correspond to imaging evaluation. The initial Tg response occurs slightly earlier than the morphologic response. Furthermore, the serum Tg level reflects whole body tumor volume, and morphological assessment is needed to evaluate the relationships of individual tumors and nearby organs. Therefore, assessment by serum Tg measurement alone has a potential of providing an inaccurate evaluation, particularly in structurally progressive cases. Thus, imaging evaluation in the early phase is very important, and as for the mechanism of serum Tg kinetics during lenvatinib treatment, further study is needed. The limitation of this study is that it is a small, retrospective study, and the histological subtypes varied. In conclusion, lenvatinib immediately decreased in tumor size, the so-called ETS. Therefore, when lenvatinib is used, much attention should be paid to fistula formation from the early stages of therapy. Author Disclosure Statement None of the authors has any potential conflicts of interest associated with this research. References 1. Klein Hesselink EN, Steenvoorden D, Kapiteijn E, Corssmit EP, van der Horst-Schrivers AN, et al. (2015) Therapy of endocrine disease: response and toxicity of small-molecule tyrosine kinase inhibitors in patients with thyroid carcinoma: a systematic review and metaanalysis. Eur J Endocrinol 172: R Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, et al. (2014) Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 384: Tohyama O, Matsui J, Kodama K, Hata-Sugi N, Kimura T, et al. (2014) Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res 2014: Yamamoto Y, Matsui J, Matsushima T, Obaishi H, Miyazaki K, et al. (2014) Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell 6: Okamoto K, Ikemori-Kawada M, Jestel A, von Konig K, Funahashi Y, et al. (2015) Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization. ACS Med Chem Lett 6: Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, et al. (2015) Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 372: Robinson B, Schlumberger M, Wirth LJ, Dutcus CE, Song J, et al. (2016) Characterization of Tumor Size Changes Over Time From the Phase 3 Study of Lenvatinib in Thyroid Cancer. J Clin Endocrinol Metab 101: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, et al. (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45: Hui EP, Ma BB, King AD, Mo F, Chan SL, et al. (2011) Hemorrhagic complications in a phase II study of sunitinib in patients of nasopharyngeal carcinoma who has previously received high-dose radiation. Ann Oncol 22:

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