Attainment of a Long-Term Favorable Outcome by Sunitinib Treatment For

□ CASE REPORT □

Attainment of a Long-term Favorable Outcome by Sunitinib Treatment for Pancreatic Neuroendocrine Tumor and Renal Cell Carcinoma Associated with von Hippel-Lindau Disease

Akihiro Kobayashi 1, Masanobu Takahashi 1,2,HirooImai1,2, Shoko Akiyama 2, Shunsuke Sugiyama 1,2, Keigo Komine 1,2, Ken Saijo 1,2, Masahiro Takahashi 1,2, Shin Takahashi 1,2, Hidekazu Shirota 1,2,NaomiSato3, Fumiyoshi Fujishima 3, Taro Shuin 4, Hideki Shimodaira 1,2 and Chikashi Ishioka 1,2

Abstract

von Hippel-Lindau (VHL) disease, caused by germline mutations in the VHL gene, is a hereditary autosomal-dominant disorder which predisposes the individual to various malignant and benign tumors. VHL acts as a tumor suppressor, mainly through the negative regulation of hypoxia-inducible factors. Molecular- targeted drugs against vascular endothelial growth factor-signaling pathways, a target of hypoxia-inducible factors, have recently been introduced into clinical practice for the treatment of patients with sporadic renal cell carcinoma and pancreatic neuroendocrine tumors. However, whether such treatments are effective in patients with VHL disease remains to be elucidated. We herein report a Japanese patient with VHL disease who was successfully treated with sunitinib for approximately 5 years.

Key words: sunitinib, pancreatic neuroendocrine tumor, renal cell carcinoma, von Hippel-Lindau disease

(Intern Med 55: 629-634, 2016) (DOI: 10.2169/internalmedicine.55.5796)

an increased intracellular level of HIFs and the activation of Introduction their downstream pathways including vascular endothelial growth factor (VEGF)-, platelet-derived growth factor von Hippel-Lindau (VHL) disease is a hereditary (PDGF)-, and transforming growth factor (TGF)-β-related autosomal-dominant tumor syndrome characterized by the pathways (3). Moreover, somatic mutations or promoter occurrence of multiple malignant and benign tumors of vari- methylation in the VHL gene, along with the loss of het- ous organs, including retinal hemangioma, hemangioblas- erozygosity in the VHL locus, are observed in more than toma of the central nervous system, pancreatic neuroendo- 90% of patients with sporadic clear cell renal cell carcinoma crine tumor or cystadenoma, pheochromocytoma, and clear (RCC), according to a recent comprehensive molecular cell renal cell carcinoma (RCC) (1, 2). VHL disease is analysis (4). Thus, loss-of-function alterations in VHL con- caused by germline mutations in the VHL gene, which is lo- tribute to the process of carcinogenesis of VHL disease, as cated on chromosome 3p25-26. The VHL protein exerts well as most sporadic cases of clear cell RCC. tumor-suppressive functions, mainly by directly regulating For recurrent or unresectable RCC, therapeutic outcomes hypoxia-inducible factors (HIFs) such as HIF-1α and HIF- obtained through classical cytokine therapies, such as 2α through ubiquitylation and proteasomal degradation (3). interferon-α and interleukin-2 therapies, have been limited. Mutated VHL loses its ubiquitin ligase activity, resulting in Recently, based on the causative role of activation of the

１Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Japan, ２Department of Medical Oncology, Tohoku University Hospital, Japan, ３Department of Pathology, Tohoku University Hospital, Japan and ４Department of Urology, Kochi Medical School, Japan Received for publication May 19, 2015; Accepted for publication June 25, 2015 Correspondence to Dr. Chikashi Ishioka, [email protected]

629 Intern Med 55: 629-634, 2016 DOI: 10.2169/internalmedicine.55.5796

A B

Figure 1. Pathological examinations reveal the presence of pancreatic neuroendocrine tumors (A) and liver metastasis (B). Each left lower panel represents immunohistochemical staining for synaptophysin. Synaptophysin, along with chromogranin A and CD56 (data not shown), were positively stained in both the pancreatic neuroendocrine tumors and liver metastasis.

VEGF pathway in the pathogenesis of RCC, molecular- present condition and his family history, as mentioned be- targeted therapies against components of the VEGF pathway low, he was diagnosed with VHL disease. The research pro- have been developed for the treatment of sporadic RCC. Ty- ject was approved by the Ethical Committee of Tohoku Uni- rosine kinase inhibitors that target VEGFRs, such as axit- versity Graduate School of Medicine, and we obtained in- inib (5), sorafenib (6), sunitinib (7), and pazopanib (8); formed consent from the patient to perform a direct se- mammalian target of rapamycin (mTOR) inhibitors, such as quencing analysis for the VHL gene in the patient’s germ- everolimus and temsirolimus; and a monoclonal anti-VEGF line DNA, obtained from his peripheral leucocytes. The ge- antibody, bevacizumab (9), are currently available in the netic analysis detected a germline missense mutation in the USA for treating patients with sporadic RCC. Moreover, VHL gene (c. 233 A>G; p.N78S). Because codon 78 is lo- sunitinib and an mTOR inhibitor, everolimus, have been in- cated within the HIFα-binding domain, and this is one of corporated into clinical use for patients with pancreatic the recurrently reported mutations in patients with VHL dis- neuroendocrine tumors (10, 11). However, due to the rarity ease (12), this mutation was considered to be a pathogenic of VHL disease, there are few large and prospective studies mutation, further corroborating the diagnosis of VHL dis- analyzing the efficacies of drug therapies in patients with ease. Tumors of the spinal cord in C1 and C2 were surgi- VHL disease. Thus, it remains to be clarified whether treat- cally resected and pathological examinations revealed that ments with such targeted therapies against the VEGF signal- the tumors were hemangioblastomas. Three months later, tu- ing pathway are similarly effective for patients with VHL mors of the pancreatic body and tail were also surgically re- disease-associated tumors. sected. The pathological findings revealed a neuroendocrine We herein report the case of a Japanese patient with VHL tumor of the pancreas (mitotic count: 1/10 high-power field, disease who was successfully treated with sunitinib for ap- Ki67 index: 12%, G2, according to the WHO 2010 classifi- proximately 5 years. cation (13), Fig. 1A). After a 10-month follow-up, multiple liver tumors (3.5 mm in S2, 4 mm in S3, 28 mm and 18 Case Report mminS4,12mmand6mminS6,and21mmand18mm in S6-7) were subsequently resected because of their in- A 19-year-old man experienced abnormal vision in his creased size, and the pathological examination revealed me- right eye and consulted an ophthalmologist. Consequently, tastasis of the pancreatic neuroendocrine tumors to the liver he was found to have retinal angiomatosis of his right eye. (mitotic count: 1/10 high-power field, Ki67 index: 20%, G2, At 23 years of age, he experienced abnormal vision in his according to the WHO 2010 classification, Fig. 1B). Radiof- left eye and presented to the Department of Ophthalmology requency ablation was added to the two residual liver metas- in our hospital. He repeatedly received retinal cryopexy for tases in S2 and S3. Due to the presence of the other two tu- both eyes between 23 and 24 years of age. When he was 24 mors in S7, temozolomide (200 mg/body, day 1-5, q4w) years of age, he suffered paralysis of the upper and lower was administered for three cycles, however, this treatment limbs on his right side. At 25 years of age, he was again re- unfortunately resulted in further progression of the tumors. ferred to our hospital due to deteriorating paralysis, and a Thereafter, transcatheter arterial chemoembolization using 40 computed tomography (CT) scan and magnetic resonance mg of epirubicin and 10 mL of lipiodol, an ethyl ester of io- imaging detected tumors in a number of organs, including dinated poppy-seed oil fatty acid, was performed. Neverthe- the spinal cord, kidney, pancreas, and liver. According to his less, the S7 metastases further enlarged and new liver metas-

630 Intern Med 55: 629-634, 2016 DOI: 10.2169/internalmedicine.55.5796 A

Figure 2. CT imaging of the liver tumors and a renal tumor (A) before and (B) 9 and (C) 57 months after beginning sunitinib treatment. The two left panels show multiple liver tumors and the right panel shows a renal tumor. The target lesions that were used for the response evaluation are indicated by yellow arrows.

tases occurred (Fig. 2A). The patient was then referred to in Japan when the patient began receiving sunitinib treat- the Department of Medical Oncology in our hospital to re- ment. Three months later, the sum of the diameter of the ceive systemic drug therapy. two liver tumors decreased from 67.9 (42.4+25.5) mm to As shown in Fig. 3, his mother had pancreatic and renal 52.1 (35.0+17.1) mm, a 23% reduction. The size of the re- cysts at 37 years of age and retinal angiomatosis at 47 years nal tumor changed from 17.3 mm to 12.0 mm, a 31% re- of age. His maternal grandmother lost her eyesight and died duction. According to the response evaluation criteria in from renal cancer and brain tumors at 58 years of age. Ac- solid tumors (RECIST) version 1.1 (14), the response evalu- cording to his family history, the patient was considered to ation of the liver and renal tumors were stable disease (SD) carry type I VHL disease (3). and partial response (PR), respectively. Nine months after As a first-line therapy, the patient started taking sorafenib beginning the sunitinib treatment, the liver tumor size re- 800 mg/day orally. Ten days after beginning the treatment, duced to 43.0 mm with a 37% reduction, considered to be his treatment was stopped because of the side effect of a PR (Fig. 2B). The liver and kidney tumors had continuously grade 3 erythema multiforme rash. As a second-line therapy, reduced in sized compared with the baseline size of the tu- he successfully continued taking sunitinib 50 mg/day orally mors following sunitinib treatment, although the liver tu- (day 1-28, every 6 weeks), with grade 2 toxicities such as mors were slightly increasing. Forty-three months after be- hand-foot syndrome, diarrhea and stomatitis. For the treat- ginning the sunitinib treatment, several cerebellar metastatic ment of this patient, we selected this dose, which is the lesions occurred with concurrent symptoms of headache. standard regimen for RCC, because the patient had both The main tumor of the cerebellum (25 mm of heman- RCC and pancreatic neuroendocrine tumors and because gioblastoma) was resected, and gamma radiation therapy (to- sunitinib at a 37.5 mg/day schedule had not yet been ap- tal 20 Gy, 4 Gy ×5) was additionally performed against the proved for treatments of pancreatic neuroendocrine tumors other three small residual metastases (up to 5 mm). Fifty-

631 Intern Med 55: 629-634, 2016 DOI: 10.2169/internalmedicine.55.5796

90 81 85 58 30s Lost sight of her eye 81 Gastrointestinal disease 58 Renal cancer and brain tumor

54 49 37 Pancreatic and renal cysts 47 Retinal angiomatosis

27 27 23

19 Retinal angiomatosis (of the right eye) 2 23 Retinal angiomatosis (of the left eye) 25 Hemangioblastoma of the spinal cord, Pancreatic neuroendocrine tumor, and Renal tumor

Figure 3. Patient pedigree. The number below the squares (men) or circles (women) represents the age of onset, and the number above the squares or circles represents the present age or age at death. A diagonal line represents a death. Arrow indicates the proband. seven months after beginning the sunitinib treatment, the introduced into clinical use for the treatment of patients with treatment was stopped because of the increased size of the RCC. Sunitinib, an oral multi-kinase inhibitor that targets liver tumors (80.7 mm with a 19% increase compared with VEGFR, platelet-derived growth factor receptors (PDGFR), the baseline size of the tumors before beginning the sunit- KIT, and FLT3 (16), is currently used for the treatment of inib treatment, Fig. 2C). However, the kidney tumors had recurrent or unresectable RCC, as well as other VEGFR- retained PR. In total, the patient successfully received sunit- targeted drugs including axitinib, sorafenib, and pazopanib, inib treatment for approximately 5 years, with maintenance and an anti-VEGF antibody, bevacizumab. Inhibitors against of PR and SD for the liver tumors and PR for the renal tu- mTOR, everolimus and temsirolimus (17), have also become mors. therapeutic options in the treatment of RCC. Similarly, For a third-line therapy, we had two options: axitinib, an- sunitinib and everolimus are currently available as treat- other tyrosine kinase inhibitor targeting VEGFR-1, VEGFR- ments for patients with sporadic pancreatic neuroendocrine 2, and VEGFR-3, and everolimus (15), an mTOR inhibitor. tumors (10, 11). In the present case, the patient was able to We chose axitinib treatment due to the following reasons. continuously receive multiple molecular-targeted drug thera- First, we speculated that axitinib, whose targets overlapped peutics involving sorafenib, sunitinib, axitinib, and ever- those of sunitinib, might also be effective in both RCC and olimus. In our patient, treatment with sunitinib conferred pancreatic neuroendocrine tumors in this patient that had long-term efficacy without severe side effects, whereas long been sensitive to sunitinib treatment. Second, a phase sorafenib and everolimus showed severe toxicities resulting III trial showed that axitinib exerts better efficacy as a in the discontinuation of the therapies, and axitinib, used af- second-line treatment than sorafenib for patients with RCC, ter sunitinib, demonstrated no efficacy. including those who have previously received sunitinib treat- Several recent data from pilot or small retrospective stud- ment (5), establishing axitinib efficacy as a second-line ies have suggested the promising efficacy of sunitinib for treatment even after sunitinib failure. However, one month patients with VHL disease. A phase II trial by Jonasch et al. after beginning axitinib treatment, it was stopped because of showed that among 15 patients with VHL disease who were the progression of liver metastases. One week after treat- treated with sunitinib, including a total of 20 RCCs and 20 ment with everolimus was initiated as a fourth-line therapy, hemangioblastomas, PR was obtained in 33% of RCC and the patient complained of dyspnea and was diagnosed as in 0% of hemangioblastoma, and disease control (PR + SD) having severe respiratory failure. He was subsequently diag- was observed in 90% of RCC and in 91% of hemangioblas- nosed as having pneumocystis pneumonia with a marked toma cases (18). Kim et al. reported that all four patients elevationofKL-6andβ-D-glucan in his blood. Despite in- with VHL disease-associated metastatic RCC treated with tensive treatment with corticosteroids and antibiotic agents, sunitinib exhibited PR with a treatment duration of 19-51 he died from pneumocystis pneumonia, 27 days after the months (19). More recently, Roma et al. have shown in their suspension of everolimus treatment. retrospective analysis that 9 of 14 (64%) patients with recurrent or advanced RCC who received sunitinib treatment as a Discussion first-line therapy achieved PR, with a 2-year PFS of 71% (20). These studies, despite a relatively small number In recent years, new molecular-targeted drugs have been of patients analyzed, suggest that sunitinib treatment is even

632 Intern Med 55: 629-634, 2016 DOI: 10.2169/internalmedicine.55.5796 more effective in patients with VHL disease compared to Byer, Pfeizer, Mochida, Asahi Kasei, Bristol-Myers Squibb, those with sporadic RCC or pancreatic neuroendocrine tu- Daiichi-Sankyo, Merk Serono and Novartis; Research funding, mor. The results from a phase III trial showed PR of 31% Chugai, Taiho, Bristol-Myers Squibb, Daiichi-Sankyo, Merk Se- and progression-free survival (PFS) of 11 months in patients rono, Yakult, Ono and Novartis. with sporadic RCC (7, 21). Moreover, another international phase III trial for sporadic pancreatic neuroendocrine tumors References demonstrated a relatively lower efficacy of sunitinib, PR of 9% and PFS of 11 months (10), whereas a phase II trial for 1. Gossage L, Eisen T. Alterations in VHL as potential biomarkers in sporadic pancreatic neuroendocrine tumors conducted in Ja- renal-cell carcinoma. 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