Update on the Management of Neuroendocrine Hepatic Metastases

Review Articles Update on the Management of Neuroendocrine Hepatic Metastases David C. Madoff, MD, Sanjay Gupta, MD, Kamran Ahrar, MD, Ravi Murthy, MD, and James C. Yao, MD Neuroendocrine tumors (NETs) are rare and represent a diverse collection of malignancies that occur in many organ systems throughout the body, including the gastrointestinal and respiratory tracts. Unfortunately, the majority of patients with NETs have hepatic metastases at the time of diagnosis. Although some patients may be asymptomatic, others have unusual clinical presentations and variable tumor growth patterns. Although many patients have long indolent courses, without treatment, most patients die within 5 years of diagnosis. This article reviews the care of patients with NETs and hepatic metastases, with emphasis on the increasingly important role of oncologic imageguided interventions. J Vasc Interv Radiol 2006; 17:1235 1250 Abbreviations: IFN interferon, NET neuroendocrine tumor, OS overall survival, PEI percutaneous ethanol injection, PFS progression-free survival, RF radiofrequency, SIRT selective internal radiation therapy, TACE transcatheter arterial chemoembolization, TAE transcatheter arterial embolization From the Division of Diagnostic Imaging, Interventional Radiology Section (D.C.M., S.G., K.A., R.M.) and Department of Gastrointestinal Medical Oncology (J.C.Y.), The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 325, Houston, Texas 77030-4009. Received February 8, 2006; revision requested May 15; final revision received May 18; and accepted May 22. Address correspondence to D.C.M.; E-mail: dmadoff@di.mdacc. tmc.edu R.M. is a paid proctor for Sirtex Medical and J.C.Y has financial relationships with Novartis and Genentech. None of the other authors have identified a conflict of interest. SIR, 2006 DOI: 10.1097/01.RVI.0000232177.57950.71 NEUROENDOCRINE tumors (NETs) are defined as tumors that have the capacity to synthesize and secrete polypeptide products with hormonal activity (1). These tumors are rare and represent a diverse collection of malignancies that occur in many organ systems throughout the body, including the gastrointestinal and respiratory tracts (1 5). Unfortunately, by the time an NET is diagnosed, a significant percentage of patients already have hepatic metastases (6). Hepatic metastases of NET may present with some discrepancy between the severity of clinical symptoms and the extent of tumor growth. In addition, NET hepatic metastases rarely lead to rapid liver dysfunction and failure and are often associated with a long, indolent disease course. Long-term survival of some patients despite the presence of NET hepatic metastases has gained this class of neoplasia the reputation of cancers in slow motion (1). However, without treatment, as many as 80% of patients die of their disease within 5 years of diagnosis. At present, there is substantial controversy regarding how NET metastases in the liver should be managed. Some areas of controversy include whether the goal of therapy is cure or symptomatic palliation, when physicians should initiate treatment (eg, when tumors are small or only when patients are symptomatic), and the optimal means to achieve such objectives (ie, systemic therapy, surgical management, or percutaneous methods). This article reviews the care of patients with NET hepatic metastases, with emphasis on the evolving and increasingly important role of oncologic image-guided interventions in the management of these difficult clinical scenarios. TYPES OF NETs, EPIDEMIOLOGY, AND PATHOLOGY NETs consist of a group of carcinomas with variable clinical courses that arise from neuroendocrine cells dispersed throughout the body. NETs are often indolent but frequently present with incurable metastatic disease. The most common NETs, carcinoid tumors, usually arise from the small bowel, lung, and bronchi, occurring less often in the appendix and very rarely in the pancreas (7). Carcinoid tumors can secrete serotonin as well as other bioactive amines that cause the characteristic carcinoid syndrome. Pancreatic endocrine tumors, also known as islet cell carcinomas, arise from neuroendocrine cells of the pancreas and can produce insulin, glucagon, gastrin, and vasoactive intestinal peptide, causing the characteristic syndromes of insulinoma, glucagonoma, gastrinoma, and vasoactive intestinal peptide secreting tumors known as vipomas (7,8). Another type of NET, medullary thyroid carcinoma, arises from c-cells of the thyroid and is associated with increased plasma levels of calcitonin and carcinoembryonic antigen. Interestingly, it is NETs of gastrointestinal or- 1235

1236 Update on the Management of Neuroendocrine Hepatic Metastases August 2006 JVIR igin that have the predisposition for metastasizing to the liver (9). Although carcinoid tumors are still generally thought to be rare, their reported incidence has been increasing according to the Surveillance, Epidemiology, and End Results registry. The incidences of carcinoid tumors and pancreatic endocrine carcinomas in the Surveillance, Epidemiology, and End Results 11 database in 1999 were 2.9 and 0.3 per 100,000 persons, respectively (7). NET metastases frequently occur in the liver, making locoregional therapeutic strategies attractive. Low- and intermediate-grade tumors tend to be more indolent and are good candidates for liver-directed therapy, whereas high-grade neuroendocrine carcinomas are highly aggressive and are generally treated with systemic chemotherapy rather than in a liver-directed manner. Low-grade NETs are occasionally diagnosed incidentally on the basis of laboratory abnormalities, but more commonly they are diagnosed in advanced stages. Occasionally, they can present in a dramatic fashion, with manifestations that range from asymptomatic massive hepatomegaly to flushing, diarrhea, bronchospasm, and rightsided heart failure (ie, carcinoid syndrome) (10). Pancreatic endocrine tumors located at the head of the pancreas can present with biliary obstruction, whereas those located in the pancreatic tail can cause splenic vein obstruction and present with massive upper gastrointestinal bleeding caused by gastric varices. Low-grade NETs often grow slowly but are resistant to therapy. Therefore, their management requires an understanding of the underlying disease process and the potential of multiple modalities of oncologic therapy. The diagnosis of low-grade NET is made by histopathologic evaluation, and this histopathologic analysis dictates treatment. Microscopically, lowgrade NET cells are small and uniform in appearance, with round to oval regular nuclei (11). Immunohistochemical markers frequently used for diagnosis include synaptophysin, chromogranin, cytokeratin, and CD56. Although neuron-specific enolase is also usually present in low-grade NETs, it is less specific as a marker and may also be positive in other tumors such as solid cystic tumor of the pancreas (11). Low-grade tumors should have two or fewer mitoses per 10 high-power fields and 2% or less Ki-67 staining. Tumors with more than two mitoses per 10 high-power fields are considered intermediate grade and are more aggressive. Poorly differentiated tumors with many mitoses and, frequently, central necrosis are considered high-grade neuroendocrine carcinomas. DIAGNOSTIC TESTING Low-grade NETs frequently present with an unknown primary site. The goals of diagnostic testing are to identify the location of the primary tumor and to establish the extent of disease. In 2005, a panel of experts published comprehensive guidelines and recommendations for the detailed workup of patients with gastroenteropancreatic NETs to aid clinicians in this purpose (12). In addition to a routine history and physical examination, blood and urine laboratory studies (eg, thyroid function tests, parathyroid hormone, calcium, prolactin, 5-hydroxyindole acetic acid, and fasting hormones such as gastrin and insulin) and tumor marker measurements including serum chromogranin A, pancreatic polypeptide (fasting) neuron-specific enolase and 24-h urine. 5-Hydroxyindole acetic acid (5-HIAA) should be obtained. Gastrin, insulin, and glucagon should be obtained as warranted by clinical presentation. Calcium and parathyroid hormone should be obtained if the history is suggestive of multiple endocrine neoplasia type 1 (MEN-1) syndrome. Detailed anatomic and functional imaging studies are also performed to assess tumor localization and for posttherapeutic assessment. Although many different imaging methods are used for NET hepatic metastases, the optimal imaging method most likely depends on the clinical scenario and on the equipment, techniques, and expertise available at the institution where the tests are performed. At many institutions, the current practice is to obtain high-resolution multidetector, multiphasic computed tomography (CT) images with 2.5- to 3-mm slice thickness (13,14). Because these tumors are hypervascular, it is important to obtain imaging in the arterial phase of contrast enhancement. However, depending on the tumor type, size, and location, the portal and parenchymal phases of contrast enhancement may also be important for improved detection (15 18). Magnetic resonance (MR) imaging can also be helpful, especially in patients unable to receive iodinated contrast agents. A recent study compared CT, MR imaging, and somatostatin receptor scintigraphy among patients with liver metastases from NET (19). MR imaging detected more liver lesions. In addition, T2-weighted imaging may detect the most lesions when contrast agents cannot be given. Nuclear imaging is also frequently used in diagnosing NETs: [DTPA-d- Phe1]-octreotide (OctreoScan; Mallinckrodt, St. Louis, MO), an indium In 111 labeled somatostatin analogue, shares the receptor-binding profile of octreotide, making it a good agent for the imaging of tumors positive for somatostatin receptors 2 and 5 (20). The overall sensitivity of OctreoScan appears to be approximately 80% 90% (20). With the ongoing development of peptide receptor radiation therapy with indium-, yttrium-, and lutecium-labeled somatostatin analogues, OctreoScan may also help to identify candidates for these novel therapeutic strategies. MEDICAL MANAGEMENT OF HORMONAL SYNDROMES Low-grade NETs are capable of making a variety of bioactive amines that can cause hormonal syndromes. Importantly, secretion from many NETs is inhibited by natural somatostatin. Before the introduction of somatostatin analogues (eg, octreotide) in the United States, refractory carcinoid syndrome was a frequent cause of morbidity and mortality. Analyses of the Surveillance, Epidemiology, and End Results 9 database show an improvement in overall survival (OS) among patients with metastatic carcinoid tumors concurrent with the commercial introduction of octreotide. The median survival duration of patients with metastatic carcinoid tumors improved from 17 months during the time period 1973 to 1987 to 37 months during the time period 1988 to 1999 (P.0001; hazard ratio, 1.5) (7). Much of this improvement is believed to result from the improved control of hormonal syndromes. Additionally, octreotide has been described as having significant cytostatic activity (21,22). In a colon cancer study (23), octreotide

Volume 17 Number 8 Madoff et al 1237 decreased expression of tumor vascular endothelial growth factor as well as levels of plasma vascular endothelial growth factor. Somatostatin analogues have also been shown to decrease plasma insulin-like growth factor 1 levels among patients with cancer (24). Octreotide is an intermediate-acting somatostatin analogue that can be administered every 6 12 hours. It provides complete or partial relief from flushing and diarrhea in approximately 85% of patients and produces a biochemical response rate as high as 72% (10). The dose of octreotide varies from 50 g to500 g subcutaneously three times per day. However, longacting somatostatin analogues (eg, lanreotide) have obviated multiple daily injections in most patients, and depot octreotide is usually given once every 3 4 weeks (25). Intermediate-acting somatostatin analogues should still be used to supplement long-acting agents until a steady state is reached, which may take 2 3 half-lives. Somatostatin analogues are generally well tolerated. Rarely, sinus bradycardia and cardiac conduction abnormalities have been observed, and caution should be observed in patients with preexisting cardiac disease. Gallstones and sludge may develop with long-term use of somatostatin analogues. Hypoglycemia and, more commonly, hyperglycemia may occur, especially among patients with brittle diabetes. Steatorrhea may also occur but can be managed with pancreatic enzyme supplementation. Interferon (IFN), which is similar to octreotide, is also effective in controlling hormonal syndromes in more than 50% of patients. However, because of its less favorable toxicity profile, IFN is rarely used for control of hormonal output (10). The combination of octreotide and IFN- may have a synergistic effect on symptom control. Biochemical responses to this combination have been demonstrated among patients in whom single-agent octreotide and IFN have sequentially failed (26 28). MEDICAL MANAGEMENT OF ADVANCED LOW-GRADE NETs Carcinoid Tumors Current systemic therapies for bulky metastatic carcinoid tumors have low biologic activity, an unfavorable toxicity profile, or both. In the recently reported Eastern Cooperative Oncology Group phase III study (29) of systemic chemotherapy in carcinoid tumors (study E1281), the response rates for streptozocin plus doxorubicin or 5-fluorouracil were both 16%, and the median progression-free survival (PFS) durations were 4.5 and 5.3 months, respectively. IFN- has also been widely studied in this disease. Pooling the data from patients with carcinoid tumors involved in these trials, researchers found that only 37 of 309 patients (12%) had objective tumor responses (10). In a recent randomized trial (30), lanreotide (ie, long-acting octreotide) was compared with IFN and with the combination of lanreotide and IFN. The objective response rates for the three groups were only 4%, 4%, and 7%, respectively. Because current systemic therapy options are associated with such low response rates, systemic treatment should be considered only in the setting of a clinical trial. A recent randomized phase II trial (31) of the vascular endothelial growth factor inhibitor bevacizumab (Avastin; Genentech, South San Francisco, CA) showed promising activity, with suppression of tumor blood flow and improvement in PFS. Islet Cell Carcinoma Islet cell carcinoma, a low-grade neuroendocrine carcinoma arising from the pancreas, can be more aggressive than midgut carcinoid tumors. Islet cell carcinomas also result in shorter survival durations than do carcinoid tumors (32) but are reported to be more responsive to streptozocinbased chemotherapy. The combinations of 5-fluorouracil plus streptozocin and 5-fluorouracil plus doxorubicin have been reported to achieve response rates ranging from 27% to 69% (33 37). However, the response criteria used in these older trials had not been standardized. By contrast, two more recent retrospective studies of 16 patients each reported response rates of only 6% after therapy with streptozocin and doxorubicin (38,39). Triplet chemotherapy consisting of 5-fluorouracil, doxorubicin, and streptozocin was reported to result in improved response rates to 40% and 55% in two small series (40,41). A 39% response rate was noted in a recent review of 84 consecutive patients with islet cell carcinoma treated with 5-fluorouracil, doxorubicin, and streptozocin (8), as were a 2-year PFS rate of 41% and a 2-year OS rate of 74%. Dacarbazine was also studied in a phase II trial that included 42 patients with islet cell carcinoma, and a 33% response rate was observed (42). More recently, clinical activity has been observed in clinical trials of temozolomide, a new oral imidazole tetrazinone similar to dacarbazine (43). Promising activity has also recently been described with the vascular endothelial growth factor receptor tyrosine kinase inhibitor sunitinib (SU11248; Sutent; Pfizer, New York, NY). In a phase II trial with 61 patients (44), a 13% response rate was observed. SURGICAL MANAGEMENT OF NETs Primary Tumor Resection Little controversy exists regarding the role of surgical resection in the treatment of isolated primary NETs. Excision is safe, effective, associated with low recurrence rates, and therefore potentially curative in patients with isolated, sporadic pancreatic islet cell tumors (45). However, when multiple tumors are present, MEN-1 syndrome should be considered when the role of surgery in the treatment of patients with multiple islet cell tumors and MEN-1 syndrome is not clear. Also, resection of primary gastrointestinal carcinoid tumors is highly effective for treatment of tumor-related symptoms and may be curative in more than 50% of patients, depending on their disease stage at presentation. Resection of Hepatic Metastases Controversy does exist about the role of surgical treatment of patients with NET liver metastases, because the potential survival benefit from surgery must be considered relative to the risk of surgical morbidity and mortality in these slow-growing cancers with long and frequently unpredictable natural histories (7,46). In recent studies, surgical resection has been performed safely and has extended survival in

1238 Update on the Management of Neuroendocrine Hepatic Metastases August 2006 JVIR selected patients. Yao et al (47) used specific selection criteria to direct patients (n 36) to hepatic resection or transcatheter arterial chemoembolization (TACE). Of the patients who underwent hepatic resection (n 16), all had complete resections (ie, the entire tumor burden was removed) without operative mortality, and the 5-year actuarial survival rate was 70%. A group of investigators from the Mayo Clinic reviewed records of patients (n 37) who underwent curative (n 17) or palliative (n 20) hepatic resection for metastatic NETs and found that most patients had short-term symptom relief (mean duration, 6 months) if more than 90% of the tumor bulk was removed (48). Of the 17 patients who underwent potentially curative resections, 11 were tumor free after a median follow-up time of 19 months after resection; three were alive with disease at 52, 59, and 92 months; and three died of recurrent disease at 13, 49, and 60 months. Additional and more recent reports from the Mayo Clinic confirmed earlier findings of symptom improvement and acceptable survival rates in patients with surgically resected disease (49,50). In 2003, Sarmiento et al (50) reported results from a retrospective study of 170 patients who underwent hepatic resections for carcinoid (n 120), functioning islet cell (n 32), and nonfunctioning islet cell tumors (n 18) over a 22-year period (1977 1998). Of the 108 patients who presented with hormonal symptoms, 104 had their symptoms controlled by resection. Although the recurrence rate was 84% at 5 years, the OS rates were 61% and 35% at 5 and 10 years, respectively, without a statistically significant difference between patients with carcinoid and islet cell tumors. Other investigators (51) reviewed the records of 38 patients with liver-only metastases (carcinoid tumor, n 21; pancreatic islet cell tumor, n 13; and atypical NET, n 4) and compared patients who underwent potentially curative hepatic resection (n 15) with patients with comparable liver disease who did not undergo resection (n 23). They found that the actuarial 5-year survival rate improved from 29% to 73% with resection. Chamberlain et al (6) reviewed the records of 34 patients with metastatic NETs who were selected for hepatic resection (potentially curative [n 15] or palliative [n 19]). The median survival duration of the patients who underwent surgery had not been reached, and estimated 5-year survival rates were 85% in the patients who had potentially curative resections and 63% in the patients who had palliative resections. Soreide et al (52) found that patients with NET hepatic metastases who underwent surgical debulking, which included planned repeat operations, had a three- to fourfold longer median survival time compared with those who did not. However, complication and mortality rates were high (33% and 9%, respectively), and the duration of symptom relief in most cases was 6 24 months. Recently, Osborne and colleagues (53) reported the first series (N 120) specifically comparing the outcomes of intraoperative cytoreduction (n 61: curative resection, n 38; palliative resection, n 23) with those of embolization (n 59) for patients with symptomatic NET hepatic metastases whose pretreatment performance status was similar. Of those patients who underwent embolization, complete and partial symptomatic relief was achieved in 59% and 32%, respectively, with a mean symptom-free interval of 22 13.6 months. For those who underwent cytoreduction, complete and partial symptomatic relief was achieved in 69% and 23%, respectively (P.08 vs embolization). The mean duration of relief was 35 22.0 months compared with 22 13.6 months (P.001 vs embolization). The differences in mean survival were also statistically significant (cytoreduction, 43 26 months; embolization, 24 15.8 months; P.001). Survival in patients who underwent palliative cytoreduction was 32 18.9 months (P.001 vs embolization), whereas it was 50 27.6 months in patients who underwent curative resection (P.001 vs embolization; P.001 vs palliative therapy). They concluded that cytoreduction for NET hepatic metastases resulted in improved symptomatic relief and survival compared with embolotherapy and should be pursued whenever possible, even if complete resection is not achievable (53). Although reports show that limited resections for NET hepatic metastases are safe and effective, controversy remains as to the upper limits of resection and indications for more aggressive procedures. To this end, prognostic factors that may help in patient selection for surgery are being sought. Yao et al (47) showed that resection of the primary neoplasm first and subsequent resection of a maximum of four liver metastases significantly improved disease-free survival after hepatic resection. Patients whose primary tumor had been enucleated previously had a median disease-free interval after hepatic resection of 42 months, compared with 28 months for patients who had concurrent resections of their primary tumors and liver metastases. In addition, the number of metastatic lesions has an impact on median disease-free survival (maximum of four metastases, 46 months; more than four metastases, 20 months). Sarmiento et al (54) reviewed the records of 23 patients who underwent simultaneous resections of pancreatic NETs and hepatic metastases and found an OS rate of 71% at 5 years, with a tendency toward improved survival in patients who had complete resection of all gross disease compared with those who had residual disease at the completion of surgery. In addition, Chamberlain et al (6) found that the percentage of liver involvement by tumor was the only prognostic factor to significantly affect OS after resection. Also, Norton et al (55) reported a series of 20 patients who underwent aggressive resections of advanced NETs, including liver resections, complex pancreatic procedures, mesenteric vascular reconstructions, and en bloc organ resections. No operative deaths were reported, and the morbidity rate was 30%. All patients had recurrence within 7 years, even though the actuarial 5-year survival rate was 60%. The major limitations of all the series cited are clear, as nearly all are single-institution retrospective studies that lack comparable control groups treated nonoperatively. Despite these limitations, these studies are the basis for surgical resection of metastatic NETs in selected patients. For selected patients with bilobar disease who are candidates for extended hepatectomy for complete tumor resection, preoperative portal vein embolization has been performed to induce hypertrophy of anticipated

Volume 17 Number 8 Madoff et al 1239 Figure 1. Images of transhepatic ipsilateral right portal vein embolization extended to segment IV performed in a 73-year-old woman with a carcinoid tumor metastatic to the liver and carcinoid syndrome. (a) Axial CT scan obtained before treatment shows the intended future liver remnant (white arrows). The ratio of future liver remnant to total estimated liver volume ratio was 19% before embolization. (b) Anteroposterior flush portogram obtained before treatment with use of a 6-F vascular sheath in a right portal vein branch and a 5-F flush catheter in the main portal vein. (c) Postprocedural portogram shows occlusion of segments IV VIII portal veins (white arrows show coils within segment IV portal veins and black arrows show coils within proximal anterior and posterior sector right portal veins), with continued patency of the veins supplying the left lateral lobe (segments II/III). (d) Axial CT images obtained 1 month after treatment show the future liver remnant (segments I III; white arrows). Black arrow shows coils within the right posterior sector portal vein. The ratio of future liver remnant to total estimated liver volume was 33% after right portal vein embolization extended to segment IV, an increase of 14%. The patient subsequently underwent successful extended right hepatectomy. (Figure used with permission from Madoff et al [56].) marginal remnant livers, as determined by CT volumetry (46,56,57) (Fig 1). Hepatic Transplantation Hepatic transplantation is an attractive, although not yet proven, option for patients with extensive NET metastases that are not amenable to resection. The largest reported series on the subject come from two multicenter studies. Le Treut et al (58) reported 36% and 17% OS and recurrence-free survival rates, respectively, at 5 years in 31 patients, and Lehnert (59) reported 47% and 24% 5-year OS and recurrence-free survival rates, respectively, in 103 patients. Although these survival rates are lower than those reported for resection, patients who underwent transplantation might have had more advanced disease and hence lower chances of survival. More recently, Rosenau et al (60)

1240 Update on the Management of Neuroendocrine Hepatic Metastases August 2006 JVIR Figure 2. Images from a 53-year-old man with carcinoid liver metastases who experienced flushing and diarrhea despite receiving long-acting octreotide therapy. Contrast agent enhanced CT scans of the liver show (a) multiple metastatic lesions in a bilobar distribution and (b) substantial reduction in the tumor burden after four courses (two courses to each lobe) of bland embolization. After the last embolization procedure, the patient was symptom free. reported retrospective data from the largest single-institution series of transplantation for NET hepatic metastases to date. In their series (N 19), the 5-year and 10-year OS rates were 80% and 50%, respectively. Of the 19 patients, six were recurrencefree, with three of these patients followed up for more than 8 years. Because of the uncontrolled nature of the study, the benefit of hepatic transplantation is difficult to prove, but the investigators found that their survival and recurrence rates compared favorably with nonsurgical options. In addition, the investigators were able to use the expression of specific immunohistochemical markers, Ki-67 and E- cadherin, for identification of patients who would have a favorable prognosis after hepatic transplantation for NET hepatic metastases. Despite the results described, transplantation still remains investigational and should be considered only for patients with disease not amenable to hepatic resection or other forms of liver-directed therapy. PERCUTANEOUS LIVER- DIRECTED THERAPIES As described earlier, patients with NET hepatic metastases present a difficult problem for medical and surgical oncologists alike. Unfortunately, hepatic resection is possible in fewer than 10% of patients, and systemic chemotherapy has limited effectiveness, particularly for patients with carcinoid tumors. In addition, although somatostatin analogues have been shown to be effective in controlling symptoms in many of these patients, the disease can become refractory to treatment. Also, despite chemotherapy, tumor bulk may progress to the point at which other treatment options are required to palliate local symptoms. It is in the management of such refractory, unresectable, or recurrent disease that interventional radiologists have the primary role. The specific treatment must be individualized according to the therapeutic goal (ie, reduction of tumor bulk, hormonal palliation, conversion to resectable status), magnitude of tumor replacement of liver parenchyma, distribution of disease, and patient performance status. Depending on these factors, transarterial embolotherapy, selective internal radiation therapy (SIRT), or locally ablative techniques may be used. Transcatheter Arterial Embolization and Chemoembolization Liver metastases from NETs are invariably hypervascular, with a blood supply primarily from the hepatic artery. This feature, combined with the fact that the liver has a dual vascular supply, provides a good rationale for the use of hepatic transcatheter arterial embolization (TAE) to treat these metastases by inducing tumor ischemia (Fig 2). Several reports have established that such an approach can reduce hormone levels, palliate symptoms, and reduce the tumor burden in many patients with NET hepatic metastases (Fig 3). Since the report by Moertel et al (61), which demonstrated a higher disease regression rate and a longer duration of regression with systemic chemotherapy after hepatic arterial occlusion (Fig 4) than with occlusion alone, many authors have favored TACE (the addition of chemotherapy to the embolic material) over TAE. There are several theoretic advantages of combining intraarterial chemotherapy and embolization: regional delivery of chemotherapy can potentially offer pharmacokinetic advantages compared with systemic administration; certain drugs such as doxorubicin, mitomycin C, and streptozocin are more active in hypoxic tumor cells; and slowing of the blood flow by embolization can increase intratumoral drug concentration and exposure time. Although several studies have established the beneficial therapeutic effects of TAE and TACE in patients with NET hepatic metastases, it is unclear whether chemoembolization offers any therapeutic advantage over bland embolization. A compilation of results from various disparate studies reporting varying use of chemotherapy, embolic agents, and techniques (61 76) indicates that there is no difference in the response rates for the two treatment methods (Table 1). In addition, there is no consensus on which chemotherapeutic agent to use for TACE. As is evident from Table 2 (61 77), various chemotherapeutic agents have been used, without a significant difference in response rates. A recently published series by Gupta et al (78) suggested that, although TACE did not show any therapeutic benefit compared with particulate embolization alone in patients with metastatic carcinoid tumors, patients with islet cell carcinomas seemed to benefit from the addition of intraarterial chemotherapy to the embolization. In this study, the addition of intraarterial chemotherapy to embolization did not improve the OS or PFS times in patients with carcinoid tumors. By contrast, a clear tendency toward prolonged survival (31.5 months vs 18.2 months) and an improved radiologic response rate (50%

Volume 17 Number 8 Madoff et al 1241 Figure 3. Images from a 71-year-old woman with a single carcinoid lesion and carcinoid syndrome despite long-acting octreotide therapy. Preoperative TAE was performed to improve her performance status before extended left hepatectomy. Contrast agent enhanced CT scans of the liver show the single lesion (a) at the bifurcation of the middle and left hepatic veins and (b) causing left (arrowheads) and right biliary duct obstruction. Immediately after embolization, the patient s carcinoid syndrome resolved. She gained 30 pounds within 2 months and underwent successful extended left hepatectomy. vs 25%) was noted in patients with islet cell tumors undergoing TACE compared with those treated with particulate embolization alone; however, these differences did not reach statistical significance. This difference in response between the two tumor types is in keeping with the fact that carcinoid tumors are generally resistant to chemotherapy (systemic single-drug or combination chemotherapy has had only limited success in the treatment of metastatic carcinoid tumors, with tumor regression rates seldom exceeding 15%), whereas islet cell carcinomas generally exhibit a better response rate (30% 69%). Hence, it is not unreasonable to presume that intraarterial chemotherapy will be more effective in patients with islet cell carcinomas. The generally accepted indications for TAE or TACE in patients with NET hepatic metastases include (i) symptoms related to hormonal excess, (ii) symptoms related to tumor bulk, and (iii) rapid progression of liver disease. It remains unclear whether embolization should be performed early or late in the clinical course of the disease. Some investigators advocate early embolization to reduce the tumor burden before the initiation of systemic therapy. In a randomized study, patients with carcinoid tumors treated at the time of diagnosis with liver embolization followed by IFN therapy had a higher objective response rate after 1 year (86%) than did patients who received IFN only (42%) (63). However, embolization was not shown to have any significant effect on survival. In another study, aggressive surgery followed by octreotide treatment and unilobar or bilobar liver embolization in 40 patients with midgut carcinoid tumors produced a 55% reduction in urinary 5-hydroxyindoleacetic acid (a serotonin byproduct excreted in urine), and the 5-year survival rate was 56% (66). However, in the report by Eriksson et al (68), in which TAE or TACE was performed at a median of 37 months after diagnosis, the median patient life expectancy after embolization was 80 months and the 5-year survival rate was 60%, indicating that late embolization is also very effective. This is in agreement with the report of Gupta et al (78), in which the duration of liver disease before embolization had no effect on response rates or OS or PFS duration in either group of patients on univariate and multivariate analyses. Involvement of more than 50% of the liver has been used as an exclusion criterion in many reports. In a report by Kress et al (79), the majority of patients with a tumor burden of more than 75% died 30 days to 6 months after TACE as a result of liver failure or tumor progression. This is in concordance with the observations of Carrasco et al (70), who reported a high mortality rate for patients with a tumor burden of more than 50% of the liver. In the recent experience of Gupta et al (78), there was a clear tendency toward worse outcomes in patients with more than 75% liver involvement by metastatic disease; this was noted in both tumor types by univariate analysis for OS. However, the extent of liver involvement was not confirmed as an independent prognostic factor on multivariate analysis. The radiologic response rate also correlated with the extent of liver disease in patients with carcinoid tumors; patients with 75% or less liver involvement were three and a half times more likely to respond than were patients with more than 75% liver involvement (P.06). However, many patients with more than 75% liver involvement were able to be treated safely and successfully when only a small portion of the liver was embolized in each treatment session. Of the patients treated in this manner, the carcinoid tumor group had a response rate of 43% and an OS duration of 20.1 months, whereas the islet cell carcinoma group showed a response rate of 25% and an OS duration of 16 months. These results suggest that, although the median survival durations and response rates are lower in patients with more than 75% liver disease, many of these patients can benefit from selective embolizations that are well separated in time. Another important question to ask is how much of the liver should be embolized during each treatment session. Embolization of the whole liver in a single treatment session should be avoided because of the risk of prolonged postembolization syndrome or liver failure. For most patients, only one lobe of the liver is subjected to embolization during each session; in most cases, the hepatic lobe with the greatest tumor burden is treated first. To avoid liver failure in patients with extensive ( 75%) liver involvement, only a small portion of the liver lobe is subjected to embolization during each treatment session. Patients with extensive disease in the untreated portion of the liver, persistent symptoms, or inadequate hormonal response require additional sessions. The timing of subsequent embolizations is determined primarily by the patient s symptoms, biochemical or tumor status, and ability to tolerate the procedure. However, despite the best efforts to perform selective embolization, complications such as carcinoid crisis (Fig 5) or other symptoms of acute hormone release, acute liver failure with or without hepatic encephalopathy (Fig 6), and tu-

1242 Update on the Management of Neuroendocrine Hepatic Metastases August 2006 JVIR Figure 4. Images from a 66-year-old man with pancreatic islet cell liver metastases and left upper quadrant pain, weakness, weight loss, and hypercalcemia. (a) Contrast agent enhanced CT scan of the liver shows two lesions, with the larger lesion extending from the right lobe to segment IV (arrow). (b) CT performed 1 month after embolization shows necrosis of the smaller lesion (arrowhead) and normalization of the serum calcium level. (c) Contrast agent enhanced CT scan of the liver after four cycles of intravenous 5-fluorouracil, doxorubicin, and streptozocin shows further tumor shrinkage (arrow). (d) After portal vein embolization, the patient underwent successful extended right hepatectomy and was tumor free at 1-year follow-up. mor lysis syndrome (Fig 7) may still occur. As mentioned earlier, the natural history of NETs is unpredictable and varied. The reported median survival times in patients with metastatic NETs after TAE or TACE vary considerably, ranging from 13 to 80 months in various studies. Comparison of the results of these studies is hampered by the marked heterogeneity of the patient study groups, marked differences in the treatment protocols used, and different methods used to report survival among the various trials. In addition, most of the previous studies have not taken into account the different biologic and clinicopathologic behaviors of carcinoid and pancreatic islet cell tumors, and both types are evaluated together, thereby making comparative evaluation impossible. However, results of many studies indicate that patients with pancreatic islet cell tumors may have much poorer survival rates than those with carcinoid tumors. In the study by Eriksson et al (68), the median survival duration in patients with carcinoid tumors (80 months) was higher than that in patients with islet cell tumors (20 months). Moertel et al (61) also reported a longer median survival (27 months vs 9 months) in patients with carcinoid tumors treated with liver embolization or surgical ligation of the hepatic artery compared with those with islet cell tumors. Similar findings have been reported in the surgical literature as well. In a study by Nave et al (80) that involved 21 patients with carcinoid tumors and 10 patients with pancreatic islet cell carcinomas who underwent liver resection for metastatic disease, no patients with pancreatic islet cell carcinoma survived 5 years, whereas the 5-year survival rate of patients with metastatic carcinoid tumors was 58%. In a retrospective analysis of 69 patients with carcinoid tumors and 54 patients with pancreatic islet cell carcinomas treated with TAE or TACE (77), patients with carcinoid tumors had better outcomes than patients with islet cell tumors, as evidenced by significantly higher radiologic response rates (66.7% vs 35.2%; P.0001) and longer median PFS (22.7 months vs 16.1 months; P.046) and OS durations (33.8 months vs 23.2 months; P.012). Although several reports have described the role of TAE and TACE, to the best of our knowledge, the prognostic factors for survival or PFS in patients with metastatic carcinoid tumors and islet cell carcinomas undergoing TAE or TACE have not been studied. A recent analysis (78) showed that, in patients with carcinoid tumors, male sex had a negative effect on survival, and the concomitant use of octreotide seemed to prolong PFS. An intact primary tumor, extensive liver disease, and bone metastases are associated with an unfavorable outcome in patients with islet cell tumors treated with TAE or TACE. Selective Internal Radiation Therapy There has been considerable interest in two radioactive microsphere devices recently approved by the Food and Drug Administration for liver-directed therapy. TheraSphere (MDS Nordion; Ottawa, ON, Canada) consists of nonbiodegradable glass microspheres and is approved for the treatment of unresectable hepatocellular carcinoma as a neoadjuvant therapy to surgery or transplantation. SIR- Spheres (Sirtex Medical, Lane Cove, Australia) consist of resin microspheres and are approved for the treatment of unresectable colorectal cancer metastases to the liver with adjuvant floxuridine (Roche, Nutley, NJ). Both devices contain yttrium-90 ( 90 Y) as the active moiety and range in size from 20 m to40 m, with a typical dose consisting of millions of microspheres. 90 Y is a pure high-energy

Volume 17 Number 8 Madoff et al 1243 Table 1 Reported Series of Hepatic TACE and Transcatheter Arterial Embolization in Patients with Metastatic Carcinoid Tumors and Islet Cell Carcinomas TACE Study CR PR (%) Study CR PR (%) Carcinoid Tumors Hazarizadeh et al (62) 50 (4 of 8) Hanssen et al (63) 71 (5 of 7) Rusznieweski et al (64) 33.3 (6 of 18) Moertel et al (61) 69.6 (16 of 23) Therasse et al (65) 35 (6 of 17) Wangberg et al (66) 42.5 (17 of 40) Kim et al (67) 25 (4 of 16) Eriksson et al (68) 38 (11 of 29) Dominguez et al (69) 50 (4 of 8) Carrasco et al (70) 83 (5 of 6) Roche et al (71) 43 (6 of 14) Loewe et al (72) 73 (16 of 22) Drougas et al (73) 6.7 (1 of 15) Gupta et al (74) 81 (34 of 42) Gupta et al (74) 44.4 (12 of 27) Average 32 (31 of 96) Average 55 (70 of 127) Islet Cell Carcinomas Carrasco et al (70) 100 (3 of 3) Carrasco et al (70) 50 (3 of 6) Mavligit et al (75) 80 (4 of 5) Moertel et al (61) 82 (14 of 17) Kim et al (67) 50 (7 of 14) Eriksson et al (68) 17 (2 of 12) Dominguez et al (69) 57 (4 of 7) Gupta et al (74) 28 (9 of 32) Rusznieweski et al (64) 0 (0 of 5) Ajani et al (76) 60 (12 of 20) Gupta et al (74) 50 (11 of 22) Average 53 (18 of 34) Average 56 (31 of 55) Note. CR complete response; PR partial response. TAE Table 2 Chemotherapeutic Agents Used for TACE in Patients with Neuroendocrine Tumors Study No. of Pts. Intraarterial Chemotherapy CR PR (%) Symptoms (%) 5-HIAA (%) Islet Cell Tumors Carrasco et al (70) 3 Multiple regimens 100 NA NA Mavligit et al (75) 5 Cisplatin, vinblastine 80 NA NA Kim et al (67) 14 Streptozocin, 5-FU 50 NA 90 Dominguez et al (69) 7 Streptozocin 57 75 57 Rusznieweski et al (64) 5 Doxorubicin 0 NA NA Gupta et al (74) 22 Multiple regimens 50 NA NA Stokes et al (77) 7 Doxorubicin NA 100 90 Carcinoid Tumors Hazarizadeh et al (62) 8 Cisplatin, doxorubicin, mitomycin C (5-FU) 50 Rusznieweski et al (64) 18 Doxorubicin 33.3 73 57 Therasse et al (65) 17 Doxorubicin 35 100 91 Kim et al (67) 16 Cisplatin, doxorubicin 25 NA 75 Dominguez et al (69) 8 Streptozocin 50 60 50 Drougas et al (73) 15 Cisplatin, doxorubicin, mitomycin C (5-FU) 6.7 67 100 Roche et al (71) 14 Doxorubicin 43 NA NA Gupta et al (74) 27 Cisplatin with or without other agents 44.4 NA NA Stokes et al (77) 13 Doxorubicin NA 100 90 Note. CR complete response; 5-HIAA 5-hydroxyindolacetic acid; 5-FU 5-fluorouracil; NA not applicable; PR partial response. -emitter with a mean tissue penetrance of 2.5 mm. The principle surrounding the technology is the preferential distribution of the microspheres into the peritumoral vasculature, thereby allowing the delivery of high doses of radiation to the tumor with relative sparing of normal liver parenchyma. It is important to recognize that SIRT, also referred to as radioembolization, has distinct dissimilarities from other hepatic embolization procedures (81). Results from clinical studies in Canada, Australia, Hong Kong (where these products were developed), and now the United States (82 84) of SIRT for the treatment of hepatocellular carcinoma and colorectal cancer are promising. Although a direct comparison has not been performed within

1244 Update on the Management of Neuroendocrine Hepatic Metastases August 2006 JVIR therapy performed with somatostatin analogues that carry a -emitter has been a major therapeutic advancement for the treatment of NET hepatic metastases (91). Because many patients have large-volume liver disease, intravenous administration is problematic, given that a substantial portion of the dose is dissipated within the systemic circulation and a reduced dose reaches the target. In 2005, McStay et al (92) reported the intraarterial use of 90 Y- DOTA-lanreotide administered directly to liver metastases to ensure that a higher therapeutic dose reaches the tumor. Thirty-six selective hepatic intraarterial injections were administered in patients (N 23) with largevolume disease (85% tumor burden) with or without subsequent embolization performed in 8-week intervals. Partial response and stable disease were noted in 16% and 63% of patients, respectively. Clinical improvement and reduction in biologic markers was achieved in approximately 60% of patients with a 63% 1-year survival rate and minimal toxicities. Although this study showed that 90 Y- DOTA-lanreotide is effective therapy for patients with progressive largevolume disease, further investigation is warranted LOCALLY ABLATIVE PERCUTANEOUS TECHNIQUES Radiofrequency Ablation the context of a clinical trial, the acute and subacute toxicities associated with SIRT appear to be more tolerable than those associated with other hepatic embolization procedures. SIRT with 90 Y microspheres has been used to treat hepatic metastatic neuroendocrine tumors (85 88) in a limited number of patients, and morphologic changes and tumor marker reductions were noted. A recent study of 84 patients who received an approximate tumor dose of 1,000 Gy reported stable disease for as long as 12 months in 67% of patients, relief of symptoms in 80%, and responses following progression after previous hepatic artery therapies, confirming the viability of this therapy (89,90). Further investigation of these agents, including some ongoing clinical trials, will assist in determining the exact role of SIRT in the management of NET hepatic metastases. Recently, intravenous radionuclide Figure 5. Carcinoid crisis in a 72-yearold man with uncontrolled carcinoid syndrome who underwent TAE. He was pretreated with 200 g octreotide subcutaneously. (a) Contrast agent enhanced CT scan of the liver shows multiple hepatic metastases. Celiac (b) and selective (c) arteriographic images show an uneventful embolization of the artery supplying segments VI and VII, and no additional octreotide was given intravenously. Immediately after the procedure, the patient experienced accelerated hypertension, with a systolic blood pressure of more than 230 mm Hg. Intravenous medications administered without success to reduce the blood pressure included 300 g octreotide, 5 mg metoprolol, and 10 mg labetalol. Last, 10 mg hydralazine was used to normalize the blood pressure. Despite increasing interest in the field of thermal ablation and application of these therapies to primary and metastatic liver tumors, only a few reports of radiofrequency (RF) ablation in patients with NET liver metastases have been published. The largest series consisted of 34 patients with 234 tumors who were treated in 42 sessions with laparoscopic RF ablation (93). The intent of therapy was palliative in 28 patients (82%) and curative in six others. Of these 34 patients, 19 had hormone-related symptoms at the time of RF ablation. The number of tumors treated in each patient ranged from one to 16, with a mean tumor diameter of 2.3 cm (range, 0.5 10 cm). There were two complications: transient atrial fibrillation and liver abscess. Eleven patients received adjuvant therapy (eg, octreotide, TACE) in addition to RF ablation. Complete or significant symptom relief was achieved in 80% of the symptomatic patients and lasted an average of 10 months (range, 6 24 months). The mean survival duration was 1.6 years, and although the majority of patients had progressive disease, 41% had no evidence of progression. In another series (94), 25 patients with 189 tumors underwent 66 sessions of percutaneous image-guided laser ablation (30 sessions) or RF ablation (36 sessions). Hormone-related symptoms were alleviated in nine of 14 patients (69%) who were symptomatic at the time of ablation. In 19 patients, imaging follow-up was available for a median of 21 months (range, 4 75 months). Of this group, six patients had complete responses, seven had partial responses, and one had stable disease. Therefore, liver metastases were controlled in 14 of 19 patients (74%). Overall, there were eight

Volume 17 Number 8 Madoff et al 1245 Figure 6. Acute liver failure in a 68-year-old man with metastatic carcinoid tumor whose disease progressed despite aggressive chemotherapy. (a) Contrast agent enhanced axial CT image shows innumerable lesions in a bilobar distribution. (b) Selective arteriogram shows posterior division of the right hepatic artery after embolization. Note that the embolization was not complete, as tumor neovascularity is visualized. The evening after the procedure, the patient experienced acute liver failure with hepatic encephalopathy that required management in the intensive care setting. Figure 7. Tumor lysis syndrome in a 77-year-old woman with carcinoid tumor metastatic to the liver and carcinoid syndrome who was admitted for TAE. (a) CT image obtained before TAE shows near-complete replacement of the hepatic parenchyma with tumor. Two days after uneventful embolization of the anterior division of the right hepatic artery, the patient experienced acute renal failure and cardiac arrest. (b) Contrast agent enhanced CT scan of the liver shows massive necrosis of numerous tumors within the right lobe and ascites. The patient died 8 months later of progression of disease. patients, alleviating those symptoms in 69% 80% of cases. In addition, RF ablation may achieve local control of liver metastases in as many as 74% of patients (Fig 8). A major limitation of RF ablation is that achieving complete necrosis becomes increasingly difficult in tumors larger than 3 cm in diameter (97). Preliminary results of combination therapy with TACE and RF ablation in patients with large hepatocellular carcinomas are promising (98). This approach may be superior to embolization or RF ablation alone in the management of NET liver metastases and warrants further investigation. Cryoablation Hepatic cryotherapy involves the freezing and thawing of liver tumors by means of a cryoprobe and has been used to treat NET metastases in the intraoperative setting for years (99). During freeze/thaw cycles, intracellular and extracellular ice formation in an area termed the iceball leads to destruction of the tumor. Although this method of treatment has resulted in successful outcomes in terms of symptom control and objective tumor response (100 104), cryoablation has shown two disadvantages: higher rates of complications for large liver tumors and a large-diameter probe that has led to an increased risk of hemorrhage. More recently, the introduction of smaller-caliber probes has enabled the use of cryotherapy by interventional radiologists as an alternative percutaneous technique to RF ablation for the treatment of NET hepatic metastases. complications (12%), four of which were major. In a smaller series (95), seven patients with 38 tumors were treated with percutaneous RF ablation. The number of tumors treated in each patient varied between one and 13. Individual tumors ranged in size from 1 cm to 12 cm. All patients were symptomatic at the time of RF ablation. Symptom relief was achieved in five of seven patients (71%) for 17 35 months (mean, 27 months). There were four minor complications. As with embolotherapy, RF ablation of liver metastases from neuroendocrine primary tumors is associated with the release of hormones during the procedure (96). Therefore, even in asymptomatic patients, prophylactic treatment with somatostatin analogues and careful observation of vital signs during the procedure may be warranted. Although surgery remains the treatment of choice for patients with limited and resectable liver metastases, RF ablation is an excellent alternative for palliative treatment of hormone-related symptoms in selected Percutaneous Ethanol Injection Percutaneous ethanol injection (PEI) can be incorporated into the treatment of NET hepatic metastases. In one study (105), complete responses were achieved in all four neuroendocrine hepatic metastases treated with alcohol. Others have performed PEI of metastases located adjacent to vital structures (such as the hepatic flexure of the colon), large vessels vulnerable to the heat-sink effect, and central bile ducts, where subsequent biliary stricture may occur (106). Very small metastases can also be successfully ab-

1246 Update on the Management of Neuroendocrine Hepatic Metastases August 2006 JVIR Figure 8. Images from a 53-year-old man who underwent resection of a small bowel carcinoid tumor and was found to have a solitary liver metastasis on follow-up CT images. The lesion doubled in size over a 6-month period of observation. (a) Contrast agent enhanced axial CT image of the abdomen shows an enhancing mass in segment VII of the liver. The tumor measures 1.9 cm in diameter. (b) Contrast agent enhanced CT images in the portal venous phase 1 month after CT-guided RF ablation of the tumor demonstrate successful treatment of the lesion. The ablation zone (nonenhancing lesion) is larger than the treated tumor. (c) Contrast agent enhanced axial CT images in the portal venous phase 3 years after percutaneous RF ablation demonstrate no evidence of recurrence. As expected, the zone of ablation has decreased in size. lated with alcohol with limited collateral injury to the adjacent liver. Despite the successful use of PEI for NET hepatic metastases, it should be emphasized that PEI has been shown to be less effective in metastatic liver disease, such as from a colorectal primary tumor, than in hepatocellular carcinoma. In fact, PEI has been essentially replaced by RF ablation because RF ablation can achieve necrosis in fewer sessions and is associated with lower rates of recurrence (107,108). Therefore, although there may be a role for PEI in the setting of metastatic NET, it is more likely to be reserved for difficult cases. FOLLOW-UP AFTER TREATMENT Given the diversity of NET types and clinical features, presently there is no consensus as to how these patients are monitored after therapy. A resource used by clinicians is the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology updated for 2006 (109), which presents management algorithms for various types of NETs. Follow-up for patients with NET hepatic metastases is individualized on the basis of the patient s clinical status (including symptoms), laboratory and tumor marker analysis (including chromogranin A), imaging findings (anatomic and functional), and tumor histology. At M.D. Anderson Cancer Center, patients who have undergone imageguided intervention or palliative cytoreduction are initially followed up with imaging and chromogranin A level measurement every 3 4 months. If patients have stable disease for more than 1 year, they are then routinely seen for imaging and tumor marker analysis every 6 months. In patients who underwent essentially curative hepatic resection, they are followed up 3 4 months after surgery. Subse-