Liver Embolization with Trisacryl Gelatin Microspheres (Embosphere) in Patients with Neuroendocrine Tumors

Acta Radiologica ISSN: 0284-1851 (Print) 1600-0455 (Online) Journal homepage: https://www.tandfonline.com/loi/iard20 Liver Embolization with Trisacryl Gelatin Microspheres (Embosphere) in Patients with Neuroendocrine Tumors D. Granberg, L.-G. Eriksson, S. Welin, H. Kindmark, E. T. Janson, B. Skogseid, K. Öberg, B. Eriksson & R. Nyman To cite this article: D. Granberg, L.-G. Eriksson, S. Welin, H. Kindmark, E. T. Janson, B. Skogseid, K. Öberg, B. Eriksson & R. Nyman (2007) Liver Embolization with Trisacryl Gelatin Microspheres (Embosphere) in Patients with Neuroendocrine Tumors, Acta Radiologica, 48:2, 180-185 To link to this article: https://doi.org/10.1080/02841850601080440 Published online: 09 Jul 2009. Submit your article to this journal Article views: 163 Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalinformation?journalcode=iard20

ORIGINAL ARTICLE ACTA RADIOLOGICA Liver Embolization with Trisacryl Gelatin Microspheres (Embosphere) in Patients with Neuroendocrine Tumors D. GRANBERG, L.-G. ERIKSSON, S.WELIN, H.KINDMARK, E.T.JANSON, B.SKOGSEID, K.ÖBERG, B. ERIKSSON &R.NYMAN Department of Endocrine Oncology and Department of Radiology, University Hospital, Uppsala, Sweden Granberg D, Eriksson L.-G, Welin S, Kindmark H, Janson ET, Skogseid B, Öberg K, Eriksson B, Nyman R. Liver embolization with trisacryl gelatin microspheres (embosphere) in patients with neuroendocrine tumors. Acta Radiol 2007;48:180 185. Purpose: To report our experience of liver embolization with trisacryl gelatin microspheres (Embosphere 2 ) in patients with metastatic neuroendocrine tumors. Material and Methods: Fifteen patients underwent selective embolization of the right or left hepatic artery with Embosphere. One lobe was embolized in seven patients and both lobes, on separate occasions, in eight patients. Seven patients had midgut carcinoids, two had lung carcinoids, one suffered from a thymic carcinoid, and five had endocrine pancreatic tumors. Eight patients suffered from endocrine symptoms, seven of whom had carcinoid syndrome and one WDHA (watery diarrhea, hypokalemia, achlorhydria) syndrome. Results: Partial radiological response was seen after eight embolizations (in six different patients), stable disease was observed after 13 embolizations (after three of these, necroses occurred), while radiological progression was noted after only two embolizations. Only two patients experienced a biochemical response. Clinical improvement of carcinoid syndrome was observed after five embolizations. There were no major complications. Fever w38 C was seen after all but four embolizations, and urinary tract infections were diagnosed after eight embolizations. Conclusion: Selective hepatic artery embolization with Embosphere particles is a safe treatment for patients with metastatic neuroendocrine tumors and may lead to partial radiological response as well as symptomatic improvement of disabling endocrine symptoms. Key words: Embolization; liver; metastases Dan Granberg, Department of Endocrine Oncology, University Hospital, SE-75185 Uppsala, Sweden (tel. +46 18 6110000, fax. +46 18 553943, e-mail. dan.granberg@medsci.uu.se) Accepted for publication 12 October 2006 Most neuroendocrine tumors are malignant, with metastases at diagnosis or later during the course. Metastases most frequently appear in regional lymph nodes and in the liver. Since neuroendocrine tumors are usually slowly growing neoplasms, reduction of tumor burden is an important part of treatment, although survival benefit has so far not been shown in controlled randomized trials. A majority of neuroendocrine tumors secrete hormones, which may give rise to disabling endocrine symptoms. Examples are carcinoid syndrome seen in serotonin-secreting tumors, Cushing s syndrome caused by ectopic ACTH production, and WDHA (watery diarrhea, hypokalemia, achlorhydria) syndrome from VIP secretion. Carcinoid syndrome is usually only seen when liver metastases are present. Except for medical treatment with alpha-interferon and somatostatin analogs, debulking of liver metastases may result in amelioration of carcinoid syndrome and other endocrine symptoms. Debulking of liver metastases can be done by surgery, by hepatic artery embolization, or by radiofrequency ablation (1, 3, 7, 9, 13). Hepatic arterial embolization can be performed with particles that occlude the hepatic artery, e.g., gel-foam powder (Spongostan 2 ) or polyvinyl alcohol particles (Ivalon 2 ), with or without cytotoxic drugs (8, 10, 11). Embolization with gel-foam produces objective responses in 50 80% of patients (4, 6, 12). Since Spongostan is no longer commercially DOI 10.1080/02841850601080440 # 2007 Taylor & Francis

Liver Embolization with Embosphere in Patients with Neuroendocrine Tumors 181 available in Sweden, we have started to use trisacryl gelatin microspheres (Embosphere 2 ) for liver embolization. This drug can be used either alone or in combination with various cytotoxic drugs for chemoembolization (15). In this retrospective analysis, we report our initial experiences of liver embolization with Embosphere particles in patients with metastatic neuroendocrine tumors. The primary aim was to evaluate radiological response, but biochemical and symptomatic response as well as complication rates were also evaluated. Material and Methods Patients Fifteen patients with neuroendocrine tumors harboring liver metastases were studied. Informed consent to evaluate data was obtained from all patients. There were six men and nine women with a mean age of 57 years (range 21 77 years). Patient characteristics are shown in Table 1. The indication for liver embolization was progressive liver disease, except patient 9 (Table 1), who was embolized because of intolerance to medical treatment with alpha-interferon. Seven patients had midgut carcinoids, two had lung carcinoids, one was suffering from a thymic carcinoid, and the remaining five patients had endocrine pancreatic tumors (two nonfunctioning, one VIPoma suffering from WDHA syndrome, one serotonin-producing tumor presenting with carcinoid syndrome, and one ACTHproducing tumor; the symptoms of ectopic Cushing s syndrome in this patient had previously been cured by bilateral adrenalectomy). Altogether, eight patients suffered from endocrine symptoms: one from WDHA syndrome and seven from carcinoid syndrome. At the time of embolization, 11 patients were treated with somatostatin analogs, four received alpha-interferon, and two were given chemotherapy. During follow-up, treatment was changed in six patients. Only two patients did not receive any systemic therapy. The left liver lobe was embolized in three patients, the right liver lobe was embolized in four patients, and both lobes were embolized, on separate occasions, in eight patients. Altogether, 23 embolizations were performed. All patients were followed clinically and with computed tomography (CT) scan and hormone analyses every 3 to 4 months. CT scans were reviewed by one of the authors (RN) according to RECIST criteria (14). Each embolized liver lobe was analyzed separately. Biochemical progression was defined as >25% increase in at least one tumor marker (plasma chromogranin A, urinary 5 HIAA), Table 1. Patient and embolization characteristics Patient no. Age, years Sex Diagnosis Lobe Particle size Follow-up, months Pre-embolization treatment Post-embolization treatment 1 D 70 F Carcinoid C left 300 500 mm+500 12.4 octreotide octreotide 700 mm 2 67 M EPT (serotonin) C right 500 700 mm 17.5 interferon+octreotide *octreotide+chemo 3 56 F Carcinoid C left 300 500 mm 19.8 interferon+octreotide interferon+octreotide 3 right 300 500 mm 3.0 interferon+octreotide interferon+octreotide 4 50 F Lung carcinoid right 500 700 mm 18.2 octreotide *octreotide+chemo 4 left 300 500 mm 13.6 octreotide *octreotide+chemo 5 D 69 M Carcinoid C left 500 700 mm 4.3 interferon+octreotide interferon+octreotide 6 D 65 M EPT (NF) right 500 700 mm 6.6 octreotide *octreotide+chemo 6 D left 500 700 mm 3.4 octreotide *octreotide+chemo 7 D 46 M Lung carcinoid right 500 700 mm 2.4 8 D 21 F Thymic carcinoid right 700 900 mm 2.5 9 61 F Carcinoid C left not known 12.9 octreotide octreotide 9 right 500 700 mm 3.9 octreotide octreotide 10 60 F EPT (VIPoma) right 500 700 mm+700 900 mm 14.3 octreotide +chemo *octreotide+chemo +interferon 10 left 500 700 mm 10.8 *octreotide+chemo +interferon *octreotide+chemo +interferon 11 D 35 F EPT (NF) right 500 700 mm 13.0 *chemo 11 D left 500 700 mm+700 11.2 *chemo 900 mm 12 D 55 F EPT (ACTHoma) right 500 700 mm+700 11.8 chemo *chemo 900 mm 12 D left 300 500 mm 9.7 chemo *chemo 13 77 M Carcinoid C right 500 700 mm 7.4 octreotide octreotide 14 65 F Carcinoid C right 300 500 mm 5.6 octreotide octreotide 14 left 300 500 mm 3.1 octreotide octreotide 15 64 M Carcinoid right 300 500 mm 5.1 interferon+octreotide interferon+octreotide C : carcinoid syndrome; D : died due to disease during follow-up; carcinoid: midgut carcinoid; EPT: endocrine pancreatic tumor; NF: nonfunctioning; chemo: chemotherapy. * Indicates that the systemic treatment was altered during follow-up.

182 D. Granberg et al. partial biochemical response was defined as >50% decrease in at least one tumor marker, and minor biochemical response was defined as (50% decrease in at least one tumor marker. Median patient follow-up was 11.8 months (2.4 19.8 months). Seven patients (nos. 1, 5, 6, 7, 8, 11, and 12; Table 1) died from their disease during follow-up. Method Digital subtraction angiography was performed on a Siemens Multistar system (Siemens, Erlangen, Germany) manufactured in 1999 with a 40-cm image intensifier. A transfemoral approach was used in all cases with placement of a 5F introducer into the common femoral artery. The celiac trunk and the superior mesenteric artery were selectively catheterized with a 4F catheter (SHK; Cordis, Miami Lakes, Fla., USA) to clarify the anatomy of the arterial blood supply to the liver and to verify patency of the portal vein. Selective catheterization of the right or left hepatic artery (Fig. 1A) was performed with the 4F catheter or with a 3F Microcatheter system (Embocath; BioSphere Medical Inc., Rockland, Mass., USA). The embolization was performed with Embosphere (BioSphere Medical Inc., Rockland, Mass., USA) particles sized 300 500 mm, 500 700 mm, and/or 700 900 mm. The embolization started with 2 ml of either 300 500-mm or 500 700-mm-sized microspheres. If there still was substantial flow left in the artery, another 1 2 ml of a larger-size microsphere (500 700 mm or 700 900 mm) was added until almost total circulatory arrest was obtained after the injection. Octreotide infusion at a dose of 100 mg/hour was started directly after the injection of the Embosphere particles to all patients suffering from carcinoid syndrome and to the patient displaying WDHA syndrome. Antibiotics were given in cases of persisting fever or high C-reactive protein, and if positive cultures were obtained. No patient received prophylactic treatment with antibiotics. Results Radiological response Partial radiological remission (Fig. 1B and C) was observed after eight embolizations in six different patients during a median of 6.2 months (3.0 17.5 months). Stable disease was noted after 13 embolizations in eight patients during a median of 5.6 months (2.4 14.3 months). In three of the patients demonstrating stable disease, necroses were observed in the liver metastases (Fig. 2). Finally, two embolizations, in different patients, resulted in progressive disease already at the first evaluation, one of whom was embolized in both lobes and was stable at evaluation after the second embolization (patient 6). The results are summarized in Table 2. Biochemical response A partial biochemical response was noted in two patients (9%). The duration of the responses was 8.7 and 5.1 months. Another patient showed a minor biochemical response after 7.4 months. Seven embolizations (30%) in five patients resulted in Fig. 1. A. Selective catheterization of the left hepatic artery with a microcatheter (arrow) in a patient with a midgut carcinoid (patient 3) before embolization with Embosphere. The tumor is clearly visible (arrowheads). B. CT image demonstrating a large metastasis (arrowheads) in the left liver lobe before embolization with Embosphere. C. CT image demonstrating partial remission of metastasis (arrowheads) 3.7 months after embolization of the left liver lobe with Embosphere particles, sized 300 500 mm.

Liver Embolization with Embosphere in Patients with Neuroendocrine Tumors 183 Fig. 2. A. CT image demonstrating large metastasis (arrowheads) in the left liver lobe before embolization with Embosphere in a patient with a midgut carcinoid (patient 9). B. CT image demonstrating a large necrosis of the metastasis 5 months after embolization of the left liver lobe with Embosphere particles, sized 300 500 mm (patient 9). stable disease during a median of 4.3 months (2.4 12.9 months), while biochemical progression was found at the first evaluation after 13 embolizations (55%) in eight patients. Symptomatic response Four patients suffering from carcinoid syndrome experienced relief of flushing and/or diarrhea after the embolization. In one of these patients (no. 3, Table 2), the embolizations in both lobes resulted in symptomatic improvement, while one patient (no. 9) had more flushing after the first embolization but less flushing after the embolization in the other lobe. In the remaining three patients with carcinoid syndrome as well as in the patient suffering from WDHA syndrome, no change in symptoms was noted. Table 2. Summary of the responses to embolizations Patient no,, lobe Radiological response Duration of response, months Biochemical response Duration of response, months Symptomatic response 1, left PR 3.4 PD PR 2, right PR 17.5 PD PR 3, left PR 11.7 PR 8.7 PR 3, right PR 3.0 SD 3.9 PR 4, right SD 6.9 PD NES 4, left SD 13.6 PD NES 5, left SD 4.3 SD 4.3 SD 6, right PD PD NES 6, left SD, necroses 3.4 PD NES 7, right SD, necroses 2.4 SD 2.4 NES 8, right PD 2.5 PD NES 9, left PR, necroses 12.9 SD 12.9 PD 9, right PR, necroses 3.9 SD 3.9 PR 10, right SD 14.3 SD 11.3 SD 10, left SD 10.8 SD 7.8 SD 11, right SD 13.0 PD NES 11, left SD 6.9 PD NES 12, right SD, necroses 5.1 PD NES 12, left SD 3.0 PD NES 13, right PR 7.4 mr 7.4 SD 14, right SD 5.6 PD SD 14, left SD 3.1 PD SD 15, right PR, necroses 5.1 PR 5.1 NES PR: partial remission; SD: stable disease; PD: progressive disease; mr: minor response; NES: no endocrine symptoms.

184 D. Granberg et al. Complications No major complications occurred. Fever (w38 C) was noted after all but six embolizations. One patient who was embolized in both lobes had fever only after the first embolization. Intravenous antibiotics were given after five embolizations because of persisting high fever and/or C-reactive protein elevation, and oral antibiotics were given after 10 embolizations, including three patients who received antibiotics intravenously followed by oral administration. Urinary tract infections, verified by cultures, were seen after eight embolizations. Five patients required blood transfusions, two due to verified gastrointestinal bleeding and in the remaining three due to anemia of unknown cause. None of the patients experienced severe nausea or vomiting. Mean time of hospital admission was 10 (5 20) days. Discussion Hepatic artery embolization is a recognized method for the debulking of liver metastases in patients with neuroendocrine tumors. In this report, a reduction in tumor size was noted after 8/23 embolizations, and another three patients showed necroses in the metastases, which may represent a decrease in the total tumor burden (Fig. 2). Thus, 48% of the embolizations led to a decrease in the tumor mass. Another 10 embolizations (43%) were followed by stabilization of the disease. These results are consistent with a previous, more comprehensive study of hepatic artery embolization with gel-foam in patients with metastatic neuroendocrine tumors (4). In another, more recent report, the objective response rate was higher. These authors, however, evaluated their patients after a cycle of four embolizations, two in each lobe (12). A substantial amount of our patients received altered chemotherapy after the embolization. It is possible that this may have influenced the results, but to what extent is difficult to evaluate. Improvement of endocrine symptoms was seen after 42% of the embolizations, which is slightly lower than in previous studies (2, 12). All symptomatic responses in our study occurred in patients with partial radiological response, and one of these patients also responded biochemically. The biochemical response rate (9% of the embolizations) was considerably lower than that reported in other studies (2, 4, 16). The explanation for this is unclear, but may partially be explained by the fact that some of the patients had considerable tumor disease outside the liver. Another factor of possible importance is patient selection. The indication for liver embolization in our department is progressive disease during medical treatment with alpha-interferon or chemotherapy, while other authors use liver embolization as first-line treatment in patients with neuroendocrine tumors. This may indicate that our patients had more advanced liver involvement and were less responsive to the embolization. No major complications occurred in our patients. In previous reports, deaths have been observed (2, 4). It is possible that the routine use of octreotide infusion in all patients with functioning tumors contributed to the low complication rate in our patients. The question of which debulking method is preferred is still under debate. Surgery should always be considered in patients with solitary or a limited number of metastases, especially if they are larger than 3 to 4 cm in diameter and in patients with metastases limited to a certain part of the liver. Radiofrequency ablation may be an option in patients with a limited number of metastases less than 3 cm in diameter, provided that the metastases are not located too close to a vessel or to the bile duct. In our department, radiofrequency ablation is always performed under general anesthesia, making it possible to treat up to five metastases during a single session. In the case of widespread multiple metastases in both liver lobes, embolization remains the only available method for debulking the tumor burden. Our results confirm that selective hepatic artery embolization with Embosphere particles is an alternative in those cases. A recent publication suggested that chemoembolization is more efficient in patients with endocrine pancreatic tumors (16). Since Embosphere and other embolization particles may be coupled to various cytotoxic drugs, this may be an option for patients with metastatic endocrine pancreatic tumors. Embosphere particles have a more homogenous size than polyvinyl alcohol and gel-foam. The smaller size of gel-foam particles (50 150 mm) and polyvinyl alcohol (150 250 mm) leads to more peripheral embolization and occlusion of smaller vessels compared to the Embosphere particles used in this study. It is possible that this may affect the results, and that embolization with Embosphere particles 100 300 mm in diameter may produce better biochemical, radiological, and symptomatic responses. In the future, use of smaller-sized Embosphere particles should be evaluated. Since Embosphere particles are not degradable, vessel occlusion is more permanent than after embolization with gel-foam, and a longer duration of response might be expected. However, degradable particles, such as gel-foam, have the advantage that

Liver Embolization with Embosphere in Patients with Neuroendocrine Tumors 185 the artery can be revascularized, allowing several repetitions of embolizations. In conclusion, hepatic artery embolization with Embosphere microspheres is a safe method for the debulking of liver metastases in patients with neuroendocrine tumors, and may lead to partial radiological remission and relief of disabling endocrine symptoms in a substantial number of patients. It seems to have a similar effect to other embolization particles. In order to estimate the effects on survival, a more comprehensive study with longer follow-up is warranted. References 1. Ahlman H, Olausson M. Cytoreduction of neuroendocrine tumors. In: Schwartz A, Pertsemidis D, Gagner M, editors. Endocrine surgery. New York: Marcel Dekker; 2003. p. 671 83. 2. Carrasco CH, Charnsangavej C, Ajani J, Samaan NA, Richli W, Wallace S. The carcinoid syndrome: palliation by hepatic artery embolization. Am J Roentgenol 1986;147:149 54. 3. Elias D, Lasser P, Ducreux M, Duvillard P, Ouellet J-F, Dromain C, et al. Liver resection (and associated extrahepatic resections) for metastatic well-differentiated endocrine tumors: a 15-year single center prospective study. Surgery 2003;133:375 82. 4. Eriksson BK, Larsson EG, Skogseid BM, Löfberg A-M, Lörelius L-E, Öberg KE. Liver embolizations of patients with malignant neuroendocrine gastrointestinal tumors. Cancer 1998;83:2293 301. 5. Gupta S, Johnson MM, Murthy R, Ahrar K, Wallace MJ, Madoff DC, et al. Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors. Cancer 2005;104:1590 602. 6. Gupta S, Yao JC, Ahrar K, Wallace MJ, Morello FA, Madoff DC, et al. Hepatic artery embolization and chemoembolization for treatment of patients with metastatic carcinoid tumors: the M.D. Anderson experience. Cancer J 2003;9:261 7. 7. Henn AR, Levine EA, McNulty W, Zagoria RJ. Percutaneous radiofrequency ablation of hepatic metastases for symptomatic relief of neuroendocrine syndromes. Am J Roentgenol 2003;181:1005 10. 8. Kress O, Wagner HJ, Wied M, Klose K, Arnold R, Alfke H. Transarterial chemoembolization of advanced liver metastases of neuroendocrine tumors a retrospective single-center analysis. Digestion 2003;68: 94 101. 9. O Toole D, Maire F, Ruszniewski P. Ablative therapies for liver metastases of digestive endocrine tumours. Endocr Relat Cancer 2003;10:463 8. 10. Roche A, Girish BV, de Baere T, Baudin E, Boige V, Elias D, et al. Trans-catheter arterial chemoembolization as first-line treatment for hepatic metastases from endocrine tumors. Eur Radiol 2003;13:136 40. 11. Ruszniewski P, Malka D. Hepatic arterial chemoembolization in the management of advanced digestive endocrine tumors. Digestion 2000;62 Suppl 1:79 83. 12. Schell SR, Camp ER, Caridi JG, Hawkins IF Jr. Hepatic artery embolization for control of symptoms, octreotide requirements, and tumor progression in metastatic carcinoid tumors. J Gastrointest Surg 2002;6:664 70. 13. Sutcliffe R, Maguire D, Ramage J, Rela M, Heaton N. Management of neuroendocrine liver metastases. Am J Surg 2004;187:39 46. 14. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205 16. 15. Vallee J-N, Lo D, Guillevin R, Reb P, Adem C, Chiras J. In vitro study of the compatibility of tris-acryl gelatin microspheres with various chemotherapeutic agents. J Vasc Interv Radiol 2003;14:621 8. 16. Wängberg B, Westberg G, Tylen U, Tisell L, Jansson S, Nilsson O, et al. Survival of patients with disseminated midgut carcinoid tumors after aggressive tumor reduction. World J Surg 1996;20:892 9.