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Case Report *Corresponding author Laetitia Dahan, Department of Digestive Oncology, Aix –Marseille University, Service d’Oncologie Chemoembolization with Digestive, CHU Timone, 264 rue Saint Pierre, 13385 Marseille cedex 5, France, Tel: 0491386023; Fax: in the Treatment of 0491384873; Email: Submitted: 10 March 2016 Accepted: 10 November 2016 Malignant Published: 10 November 2016 Camille Sibertin-Blanc1, Ecaterina Ileana1, Laetitia Dahan1*, ISSN: 2333-6692 Guillaume Louis2, Muriel Duluc1, Yves-Patrice Le Treut3, and Copyright © 2016 Dahan et al. Jean-François Seitz1 1Department of Digestive Oncology, Aix –Marseille University, France OPEN ACCESS 2Department of Radiology, Aix –Marseille University, France 3Department of Digestive Surgery, Aix –Marseille University, France Keywords • Insulinoma • metastases Abstract • Chemoembolization Insulinoma liver metastases are rare because only a minority of (10%) is malignant. We report a case of a 54 year-old patient diagnosed with malignant insulinoma with synchronous liver metastases, treated first by systemic by Streptozotocin and 5- without clinical control of symptoms (), then by pancreatic resection and seven chemoembolization with Epirubicin of liver metastases. After the first chemoembolization with Epirubicin the patient presented a total control of hypoglycemia and an objective response on liver metastases. Because of difficulties of catheterization of the hepatic artery after seven chemoembolizations, the patient was treated by somatostatin analogs, by Sunitinib (in the SUTENT study) for 1 year and then by Everolimus (in the RADIANT-3 study) for 1 year. In front of the progression of liver metastases and recurrence of hypoglycemia, a new chemoembolization with streptozotocin was performed without clinical, biological or radiological response. A second chemoembolization with Epirubicin was performed with a major biological response on tumor markers, reduction of 30% of liver metastases and a total control of symptoms.

INTRODUCTION

Insulinoma is an -secreting, rare neuroendocrine withStreptozotocin-based sterptozocin [4]. Theadministration combinations remain of targeted the first therapies line tumor, derived from the beta cells of the . The incidence (sunitinibstandard, epirubicin or everolimus) had also may shown also improve its efficacy progression-free in association in the general population is 4 cases per million a year. Insulinoma survival, overall survival, and the objective response rate among is the most common form of pancreatic patients with advanced pancreatic neuroendocrine tumors [5,6]. accounting for 60% of cases [1] and is most commonly seen The somatostatin analogue octreotide may help control between the age of 40 to 60 years, in females. Most of them are secretion. adenomas. Malignant insulinoma is a rare disease, representing 10% of these islet cell tumors and the invasion of adjacent organs Hepatic arterial chemoembolization (HACE) is an or the presences of distant metastases are common [1,2]. In the accepted treatment option of liver metastases of pancreatic management of metastatic insulinoma, patients with rapidly neuroendocrine tumor, not amenable to surgical resection progressive disease, with local symptoms caused by tumor bulk, or local ablation. Numerous studies have shown that HACE is or with uncontrolled symptoms related to hormone secretion effective in controlling hormonal symptoms and reducing tumor require aggressive medical or surgical intervention [3]. size in patients with hepatic from neuroendocrine tumors. It is controversial that chemotherapy in HACE has a Currently, the only curative treatment for malignant insulinoma is complete surgical resection of the tumor and of the chemotherapy had demonstrated its superiority [7-8] and some metastases. Surgical resection of metastatic disease may offer major impact on efficacy especially in carcinoid tumors since no palliative relief of symptoms related to hormone secretion in [9]. carefully selected patients. authors suggested that embolization alone should be sufficient We report a case of malignant insulinoma with liver Chemotherapy may be used for when ablative techniques metastases illustrating an aggressive multimodal therapy very have failed or when significant extrahepatic disease is present. Cite this article: Sibertin-Blanc C, Ileana E, Dahan L, Louis G, Duluc M, et al. (2016) Chemoembolization with Epirubicin in the Treatment of Malignant Insu- linoma. J Endocrinol Diabetes Obes 4(3): 1095. Dahan et al. (2016) Email:

Central Bringing Excellence in Open Access good outcome to chemoembolization with Epirubicin, but hypoglycemia and a progression of the size of the liver metastases. without response to the chemoembolization with Streptozotocin A treatment by Octreotid30mg LP was administrated every 28 what substantiates the positive impact of chemotherapy in HACE. days, with a good symptoms control. CASE PRESENTATION In October 2007, new liver metastases appeared and the patient was included in the SUTENT trial (Sunitinib vs Placebo). A 54-years old man presented several seizures in December The patient presented a good overall response with reduction of 2003 and he was found to be hypoglycemic (grade 2). The patient underwent a formal fast that resulted in hypoglycemia after he presented a new progression of the disease. 24 hours. An abdominal ultrasound discovered several hepatic 37 % the tumor mass after RECIST criteria, until July 2008, when metastases. A body CT scan found a tumor of the tail of pancreas In September 2008 the patient was includes in the RADIANT III trial (RAD001 vs Placebo). In May 2009, the patient was the neuroendocrine origin of the tumor (well differentiated insulinomaand liver metastaseswith Ki-67 <5%). (Figure 1). A liver biopsy confirmed under Placebo. After three months, the patient presented severe hyperglycemiaincluded in the (grade extension 3) and phase weight of the loss. trial, He becamebecause diabetic he was After multidisciplinary team discussion a systemic treatment with an HbA1c 8.5% and he required insulin NPH and rapid with Streptozotocin and 5-Fluorouracil was started in mars insulin treatment. Everolimus was reduced to 5 mg daily because 2004, but in the absence of control of the symptoms, after one cycle of chemotherapy, a surgical resection was decided. The treatment was stopped because of adverse events with grade 3 patient underwent a distal pancreatectomy with splenectomy a grade II-III stomatitis with influence on the alimentation. The and cholecystectomy in May 2004. and progression in size and number of the liver metastases. hypersensitivity pneumonitis and long term unexplained fever, A new chemoembolization with streptozocin was performed 2004, with 50mg Epirubicin dissolved in 10 ml of normal saline A first chemoembolization of liver metastases was done in June (0.9%) combined with 10 ml of iodized oil (Lipiodol), which is 2) or on the Chromogranine A serum levels (4330ng/ml after the injected into the branches of the hepatic artery distal to the origin HACEin October vs 4600 2010 ng/ml without before any – Normalefficacy valueon < 100 ng/ml), (grade or on of the gastroduodenal artery. This was followed by embolization tumor diameters on CT scan (stable disease in RECIST criteria with gelatin sponge 2–3 mm particles or microspheres (Spongel) (+15%)) (Figure 3). which are placed distally in the distribution of the hepatic artery A second chemoembolization with Epirubicin was done in recurrenceuntil a marked of hypoglycemia) decrease in bloodand a major flow, istumor observed. mass reduction After the dramatic improvement of Chromogranine A levels (from 4330 to (Figurefirst HACE 2). theA new patient chemoembolization presented a total was control repeated of symptoms every 3 (no- 4 300February ng/ml) 2011 and with a major an immediateobjective response efficacy onin mRECISThypoglycemias, criteria. a (reduction of the tumor diameters of 35%) (Figure 4). 7 chemoembolizations. The HACE was abandoned because the months. From June 2004 to February 2006 the patient underwent DISCUSSION Malignant or metastatic insulinoma is rare. Patients with cathatherism of the hepatic artery became very difficult. malignant insulinoma present with two fundamental challenges In June 2006, the patient presents new episodes of

Figure 1 Tomodensitometry at diagnosis showing lot of liver metastases.

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Figure 2

Tomodensitometry after first chemoembolization with Epirubicin.

Figure 3 Tomodensitometry before and after Hepatic arterial chemoembolization (HACE) with Streptozocine.

or pain due to tumor-related hepatomegaly. Liver metastases from functional gastrointestinal endocrine tumors can reduce ofto insulin the managing and proinsulin-related clinician. The first products is that that the leads tumor to severe is, by 5-year survival from 90% to 40% [7]. Complete resection of hypoglycemia.definition, metastatic. The second is the unregulated secretion liver metastases should be considered in all cases. Indeed, after The main cause of death of patients with malignant be achieved, with low rates of surgery-related mortality (0- insulinoma is liver metastasis that is often present at the time of hepatectomy, prolonged survival (41-86% at five years) can diagnosis. Some liver metastases are asymptomatic while others Since liver metastases are usually multi-focal and diffuse, they produce highly debilitating symptoms due to hormone secretion are6.7%) not [10]. amenable Extended to partial liver resectionhepatectomy. is required Liver transplantation in most cases.

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Central Bringing Excellence in Open Access has been proposed as a possible treatment for metastatic While this is highly desirable, patients with minimal or indolent endocrine tumors. In contrast to nonendocrine tumors, therapy for hepatic metastases from neuroendocrine tumors with considered the primary source of morbidity [13]. liver transplantation is reasonable because the disease may be extrahepatic disease may be candidates if the liver disease is doses. Another advantage is that chemoembolization produces [11]. As a result, systemic toxicity is minimized even at high confined to the liver for extended periods and the growth is slow profound tumor ischemia at the time of drug administration. One Le Treut et al., in a 213 transplantation for liver metastases of endocrine tumors series, which is the largest in the literature, inhibitingphysiologic intracellular consequence P-glycoprotein of ischemia, tumor pumps hypoxia, and increasingis known survival rate of 52%. Although this rate seems disappointing, it to potentiate the effect of cytotoxic drugs such as epirubicin by mustshows be that recalled liver that transplantation patients indicated leads for to liver a five transplantation years overall represent a ‘worst-case’ group because liver transplantation producingtumor cell uptaketumor cell of drug. apoptosis Hypoxia either has directly also been or associatedin combination with is generally used only after all other alternatives have been withp53 stabilization, other ischemic which stresses should such augment as acidosis therapeutic and hypoglycemia. efficacy by O’Toole and Ruszniewski showed in a metanalysis that the 69%, i.e. far better than the 20–30% reported in past series of chemoembolization has proven effective in symptom relief in 63– untreatedexhausted. MET Five-year [12]. survival after diagnosis of metastasis was 100% of patients treated. In patients with either progressive or Chemoembolization is a dual therapeutic approach involving concomitant hepatic artery embolization and infusion of a concentrated dose of chemotherapeutic drugs. This combined treatmentsymptomatic [13]. endocrine tumours and if metastases are confined technique offers several advantages over either individual to the liver, chemoembolization can be proposed as a first-line treatment modality. First, the addition of embolic agents slows therapeutic effects of chemoembolization for hepatic metastases fromAlthough neuroendocrine several tumors, studies there have is established no consensus the on beneficial the most concentrations to reach levels 10- to 25-fold higher than those effective chemotherapeutic agent for use in this procedure. achievedefflux of drug by simple from the intra-arterial hepatic circulation, infusion. allowing The most hepatic important drug factor when considering patients for regional chemoembolization Streptozocin, 5-FU, , Miriplatin (a cisplatin derivative Various chemotherapeutic agents including , is whether their metastatic disease is confined to the liver. with a high affinity for iodized oil), ,

Figure 4 ChA= chromogranin A, N<98ng/mL; OR: objective response; SD: stable disease; Prog= progression in RECIST criteria; HACE=Hepatic arterial chemoembolization M= months

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Central Bringing Excellence in Open Access and a combination of these agents have been used to perform In conclusion, this case report we presented a patient with chemoembolization for hepatic metastases of neuroendocrine tumors [8]. There are several studies that show no difference patient didn’t respond to traditional chemotherapy, but he between the chemotherapeutic drug used for chemoembolisation, hadseveral a major approved response treatments under two in targeted malignant therapies insulinoma. (Sunitinib Ţhis and they conclude that the response is due to hepatic arterial and Everolimus) and he had a total control of symptoms under embolisation (HAE) with or without chemotherapeutic agent Somatostatin analogs. He became diabetic under the treatment [9]. In a retrospective study at MD Anderson, that included 69 patients with metastatic carcinoid tumors and 54 patients with pancreatic NETs, showed that HAE had higher response chemoembolizationwith Everolimus. Ţhe with major epirubicin founding compared of this with case the report hepatic is rates in patients with carcinoids, whereas HACE seems to be that the patient had a significant response the hepatic arterial theory that the drug used in chemoembolization is not important French study including 67 patients (24 small bowel and 19 andarterial that chemoembolization the response is related with with Streptozotocin, the simply embolization.that infirmes the pancreatic)more benefit suggestsin patients Streptozocine with pancreatic is atumors positive [14]. predictive A recent REFERENCES (HR=21.3 IC 95% 1,48-306,p = 0,025), delaying the time we will 1. factor of radiological response in comparison with doxorubicine Hirshberg B, Cochran C, Skarulis M, Libutti SK, Alexander HR, Wood with Streptozotocin, but he had a major clinical (absence of the Cancer. 2005; 104: 264-272. BJ, et al. Malignant insulinoma. 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Cite this article Sibertin-Blanc C, Ileana E, Dahan L, Louis G, Duluc M, et al. (2016) Chemoembolization with Epirubicin in the Treatment of Malignant Insulinoma. J Endocrinol Diabetes Obes 4(3): 1095.

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