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Transarterial Liver-Directed Therapies of Neuroendocrine Hepatic Metastases
Transarterial Liver-Directed Therapies of Neuroendocrine Hepatic Metastases Javier Nazario and Sanjay Gupta Neuroendocrine tumors (NETs) comprise a diverse group of slowly growing tumors with an indolent course, characterized by the capacity to synthesize and secrete polypeptide products that are hormonally active. Presence of liver metastases results in significant debilitating hormonal symptoms, and is associated with poor prognosis. Systemic chemotherapy has limited success in the management of patients with NET hepatic metastases. Although somatostatin analogs are effective in controlling symptoms in many of these patients, the disease can become refractory to treatment. For these reasons, interventional radiologic techniques for liver-directed therapy have become an important treatment option in patients with metastatic NETs. Transcatheter arterial procedures such as transarterial embolization (TAE), transarterial chemoembolization (TACE), and selective internal radiation therapy (SIRT) have been shown to reduce hormone levels, palliate symptoms, and reduce the tumor burden in many patients with unresectable and symptomatic NET hepatic metastases. This article summarizes the most recent information on arterial-based liverdirected therapies in the treatment of metastatic NETs. Semin Oncol 37:118-126 © 2010 Elsevier Inc. All rights reserved.
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euroendocrine tumors (NETs) comprise a diverse group of tumors characterized by the capacity to synthesize and secrete polypeptide products that are hormonally active. These tumors can occur in any organ system, including the gastrointestinal and respiratory tracts. The estimated incidence in the United States for this relatively rare group of tumors is 1 to 2 cases per 100,000 persons per year.1 NETs are slowly growing tumors with an indolent course.2 Clinical presentation, which is often late, results from biochemical activity or bulk symptoms, such as local obstruction or invasion of adjacent organs or structures. Unfortunately, by the time NET is diagnosed, 46% to 93% of patients have developed hepatic metastases.3 Presence of hepatic metastatic disease is associated with a poor prognosis, with an established 5-year survival rate of 22%.1,4 The treatment of neuroendocrine hepatic metastases presents a difficult problem for medical and surgical oncologists. Liver metastases result in significant debilitating hormonal symptoms, treated initially with somaDepartment of Diagnostic Radiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Address correspondence to Sanjay Gupta, MD, Department of Diagnostic Radiology, Unit 325, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. E-mail: sgupta@ mdanderson.org. 0270-9295/ - see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2010.03.004
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tostatin analog therapy.5 Systemic chemotherapy has limited success in the management of patients with NET hepatic metastases.6,7 Response rates for advanced carcinoid cancer treated with systemic chemotherapy range in the literature from 0% to 38% and median survival ranges from 5 to 26 months.1,5–7 Islet cell neoplasms are considered generally to be more responsive to systemic chemotherapy, but this is offset by a poorer survival.1,5–7 Curative surgery for hepatic NET metastases should always be considered as a treatment option. Resection of the primary tumor and local lymph nodes is the only potential curative therapy for gastrointestinal (GI) carcinoid tumors.1,5,8 Five-year survival rates of 79% to 80% have been reported for patients with GIrelated neuroendocrine disease after complete surgical resection.9,10 Unfortunately, because of the late presentation of disease, curative resection of identifiable metastatic disease occurs in less than 10% of cases.9,10 Most patients present with extensive bilobar disease or bulky tumor that requires alternative therapy. In addition, although somatostatin analogs have been shown to be effective in controlling symptoms in many of these patients, the disease can become refractory to treatment.5,6 For these reasons, liver-directed therapy has become an important treatment option in patients with metastatic NETs. The generally accepted indications for locoregional therapy for NET liver metastases include symptoms related to hormonal excess or tumor bulk, and rapid progression of liver disease.11 Liver-directed Seminars in Oncology, Vol 37, No 2, April 2010, pp 118-126
Transarterial liver-directed therapies of neuroendocrine tumors
treatment can occasionally be used as an adjuvant therapy to reduce tumor load before hepatic resection, hepatic transplantation, or tumor ablation.12 Interventional radiologists play an important role in the management of refractory, unresectable, or recurrent disease. Specifically, treatment must be individualized according to the therapeutic goal, distribution of disease, magnitude of liver involvement, and patient performance status. The purpose of this review is to summarize the most recent information on arterial based liver-directed therapies in the treatment of metastatic NETs.
TRANSCATHETER ARTERIAL EMBOLIZATION AND CHEMOEMBOLIZATION The rationale for transcatheter arterial embolization (TAE) is based on the observations that liver metastases from NETs are typically hypervascular deriving the majority (80%–90%) of their blood supply from the hepatic artery. Conversely, normal liver tissues derive its blood supply from the portal vein.13,14 Therefore, treatment is achieved by inducing ischemia in the tumor tissue with preservation of normal liver parenchyma. Early attempts at proximal hepatic artery occlusion, either surgically or via embolization, demonstrated response rates exceeding 50%.15 However, these procedures can be associated with high morbidity, and formation of collaterals results in rapid revascularization of tumors resulting in incomplete necrosis.16 More recently, with the development of microcatheter technology, the technique of selective hepatic embolization has evolved, whereby the left or right hepatic arterial branches are embolized separately to minimize nontargeted embolization. Transcatheter arterial chemoembolization (TACE) combines intra-arterial delivery of chemotherapeutic agents with particulate embolization, and has several theoretical advantages over TAE: regional delivery of chemotherapy offers pharmacokinetic advantages compared with systemic administration; it combines local cytotoxic effect of chemotherapeutic agent with selective ischemia induced by embolization; 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 prolong drug retention in the tumor. The TAE or TACE procedure itself involves performing diagnostic superior mesenteric and celiac angiography, usually from a femoral artery access, to identify the hepatic vasculature (including anatomical variants), disease distribution, and ensure patency of the portal vein. After visceral angiography, TAE or TACE is then performed under fluoroscopic guidance using a 3-F microcatheter placed in a selective location to minimize nontargeted embolization. In TAE, the embolic agent of choice is then infused through the microcath-
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eter until the selected vessel demonstrates complete or near complete stasis of flow. Octreotide is administered before the procedure in patients with the carcinoid syndrome to prevent acute release of serotonin into the circulation. Various embolic agents, including Gelfoam (Pharmacia & Upjohn, Bridgewater, NJ) sponge slurry, Gelfoam powder, lipiodol/Gelfoam slurry, poly vinyl alcohol (PVA) particles, cyanoacrylate, and tris-acryl particles, have been used for TAE or TACE. In TACE, the combination of embolic agent (microparticles or lipiodol) along with the chemotherapeutic drug is administered in a similar fashion. Embolization of the whole liver in a single treatment session is not recommended because of the risk of prolonged postembolization syndrome or liver failure.13,17 Typically, the lobe with the largest tumor burden is treated initially. In the case of extensive bilobar disease, the embolization procedures can be staged and different liver segments are embolized at each treatment session.18 The timing of subsequent embolizations is determined primarily by the patient’s symptoms, biochemical or tumor status, and ability to tolerate the procedure.13,17 Depending on the extent of liver involvement, the entire liver can generally be treated in two to four sessions. Although there is no absolute contraindication to TAE or TACE, complete portal vein occlusion, hepatic insufficiency, and previous biliary-enteric anastomoses are considered relative contraindications to the treatment.17,19 A common side effect associated with patients undergoing TAE or TACE is the postembolization syndrome, characterized by right upper quadrant pain, fever, nausea, leukocytosis, elevation of liver function tests, and malaise. Postembolization syndrome is generally self-limited, improving within 3 to 5 days with conservative management, but can occasionally be severe and require prolonged hospitalization.17,19 Severe complications such as carcinoid crisis, acute liver failure with or without hepatic encephalopathy, emphysematous cholecystitis necessitating surgery, gastric perforation, gastric ulcer and hemorrhage, abscess formation, and tumor lysis syndrome also have been reported but are uncommon.17–19 Many nonrandomized, retrospective reports have shown that TAE and TACE can reduce hormone levels, palliate symptoms, and reduce the tumor burden in many patients with NET hepatic metastases.3,15,17,20 – 44 A summary of the reported TAE and TACE studies is provided in Table 1. Review of the published clinical experience shows that use of TAE and TACE can result in radiologic response in 25% to 95%, and symptomatic response in 53% to 100% of patients with NET liver metastasis (Table 1). The reported 5-year survival rates vary from 13.7% to 75%.3,15,17,20 – 44 This wide range in response rates and survival durations is related to the marked heterogeneity in various studies in terms of patient population; tumor histology and degree of differentiation; regimens of treatment used (TAE v TACE,
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Table 1. Summary of Published Studies Using Hepatic TAE and TACE in Patients with Metastatic NETs Tumor Type and Patients Authors
Year
Tumor Type
Imaging Response (%)
No. of Patients
EHD (%)
6 6 6 22 36
NR NR NR NR NR
8
NR
1983
Ajani et al20 Hanssen et al22
1988 1991
Carcinoid Islet cell Islet cell Islet cell Carcinoid
Hajarizadeh et al29
1992
Carcinoid
Mavligit et al33 Rusznieweski et al61
1993 1993
Therasse et al40 Moertel et al34
1993 1994
Perry et al36 Wangberg et al42 Eriksson et al28
1994 1996 1998
Drougas et al27
1998
Islet cell Carcinoid Gastrinoma Carcinoid Carcinoid Islet cell Carcinoid Islet cell NET Carcinoid Carcinoid Islet cell Carcinoid
5 18 5 23 23 17 42 29 30 40 29 12 15
40 NR NR NR NR NR NR NR NR NR NR NR NR
Diamandidou et al25 Brown et al24 Kim et al62
1998 1999 1999
Dominguez et al26
2000
Chamberlain et al3 Yao et al43 Roche et al37 Loewe et al32 Kress et al31 Gupta et al17
2000 2001 2003 2003 2003 2005
2006 2006
20 35 30 16 14 8 7 33 20 14 23 26 69 54 21 48 59 84 59 20 5
NR NR NR NR NR NR NR 45 NR 7.1 ⱖ48
Osborne et al35 Strosberg et al15
NET NET NET Carcinoid Islet cell Carcinoid Islet cell NET NET NET Carcinoid NET Carcinoid Islet cell Carcinoid Carcinoid NET NET Carcinoid Islet cell Poorly differentiated
Carrasco et
70 57 0 100 26 NR NR NR
Treatment TAE TAE TACE‡ TAE TAE (⫹ systemic interferon) HAI (5FU) ⫹ TACE (cis/mit-C/dox) TACE (cis/vinbl) TACE (dox) TACE (dox) TACE‡ TAE TAE TAE ⫹ IV chemo TAE ⫹ IV chemo TACE (Dox) TAE TAE HAI (5FU) ⫹ TACE (dox/cis/mit-C) TACE (Cis) TAE TACE TACE (cis/dox) TACE (STZ/5FU) TACE (STZ) TACE (STZ) TAE TACE (dox/cis/mit-C) TACE (Dox) TAE TACE (Dox) TAE or TACE‡
TAE TAE
CR ⴙ PR
SD
83 50 100 60 60
20
50
50
PD
20
80 33 33 56 43 75 78 95 42.5 52 50 6.7 33.3
60 50
11
37.5 31 8
66.6
37 25 50 50 57 25 43 73 7.7 66.7 35.2
10 22 53.8 24.6 61.1
48
52
19.2 8.7 3.7
Tumor Marker Response (%)
Median TTP/PFS (months)
Median Survival* (months)
5-Year Survival* (%)
NR NR NR NR 100
NR NR NR NR NR
NR NR NR NR NR
NR NR NR 33.7 NR
NR NR NR NR 75
100
NR
NR
NR
NR
NR 73 NR 100 NR NR NR NR 90 NR NR NR 67
NR 57
8–44 NR NR NR 9.9 4 23.8 21.6 NR NR NR NR NR
NR NR NR 24 27 9 49 35 24 NR 80 20 16
NR NR NR NR NR NR NR NR NR 63 60 NR NR
NR NR NR NR NR NR NR NR NR NR
NR NR 15
NR 54 NR NR NR NR NR 51 40 83† 65.4 48† 26.6 13.7 NR NR NR NR NR NR NR
67 96 NR NR NR 60 75 96 50 90 NR NR NR NR NR NR 91 80
91 82 69 83 87 69 100 38 42 100 73 NR NR 75 90 50 57 NR NR NR 61.5 NR NR NR NR NR NR NR NR NR NR
NR 22.7 16.1 NR NR NR 36 44 31 15
NR NR NR 32 NR 69 NR 33.8 23.2 86.4 33.2 24‡ NR NR NR NR
J. Nazario and S. Gupta
al21
Symptom Response (%)
23 9
6 13 12
32 45
12 38 22
23 18
82 61 82 50 66 1st TACE (cis, dox, mit-C) Repeat TACE (cis, dox, mit-C) TACE‡ TAE TACE (cis, dox, mit-C) TAE or TACE (cis, dox, mit-C) 2007
2007
Bloomston et al23 Ruutiainen et al39
Ho et al30
NET Carcinoid Islet cell
46 31 15
NR NR 28 NR NR 57 NR NR 122 27 122 67 Carcinoid Carcinoid Carcinoid NET 2007 Varker et
Abbreviations: EHD, extrahepatic disease; NET, neuroendocrine tumor; TAE, transcatheter arterial embolization; TACE, transcatheter arterial chemoembolization; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; TTP, time to progression; PFS, progression-free survival; IV, intravenous; NR, not recorded; Dox, doxorubicin; Cis, cisplatin; mit-C, mitomycin-C; 5FU, 5-fluorouracil; STZ, Streptozocin; vinb, vinblastine. *From date of TAE/TACE. †From diagnosis. ‡Multiple chemotherapeutic regimens. §Mean.
NR NR NR 33 50 29 32 35 33.3 28.1 33.3 39 44 42§ 41.8§ 43.7§ 11.8 NR NR 6 12 18.5§ 22.7§ 16.1§ NR NR 80 NR NR NR NR NR 92 77 92 93 92 78 78 75
PD SD CR ⴙ PR Year
al41
Tumor Type
No. of Patients Authors
Table 1. Continued
Tumor Type and Patients
EHD (%)
Treatment
Imaging Response (%)
Symptom Response (%)
Tumor Marker Response (%)
Median TTP/PFS (months)
Median Survival* (months)
5-Year Survival* (%)
Transarterial liver-directed therapies of neuroendocrine tumors
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number of sessions performed, type of chemotherapeutic agent, and embolization material); the time when embolization was performed (ie, early or late in the clinical course); previous, concurrent, or subsequent use of octreotide and systemic chemotherapy; extent of liver involvement by metastatic disease; frequency and timing of follow-up imaging; criteria used for measuring response; and different methods used to report survival. Some studies had suggested that patients with more than 50% liver involvement by metastatic disease should not be subjected to TAE or TACE due to the high risk of inducing liver failure. Carrasco et al reported a high mortality rate for patients with a tumor burden of more than 50% of the liver.21,45 In another report, by Kress et al,31 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. However, our own results suggest that although the median survival durations and response rates are lower in patients with more than 75% liver disease than in those with lesser liver involvement, many of these patients can benefit from selective embolizations, if small portions of the liver are embolized in each session and the sessions are well separated in time.17,18 In a recent study involving patients with hepatic NET metastases and more than 75% liver involvement, selective segmental sequential TAE or TACE procedures resulted in radiologic response or disease stabilization in 82% of patients, symptomatic response in 65%, a median progression-free survival of 9.2 months, and a median survival of 17.9 months.18 However, the study also showed that patients with massive liver tumor burden, who have additional risk factors such as carcinoid heart disease, sepsis, rapidly worsening performance status, or anasarca should not be subjected to TAE/TACE because of the high risk of procedure-related mortality.18 The therapeutic benefit of TACE over TAE remains unclear. Review of results of various studies in literature shows that there is no difference in the response rates for the two treatment methods (Table 1). In a recent study, Gupta et al17 showed that, although TACE did not show any therapeutic advantage over TAE in patients with carcinoid tumors, patients with islet cell carcinoma treated with TACE had a tendency toward prolonged survival (31.5 months v 18.2 months) and an improved radiologic response rate (50% v 25%) when compared with those treated with TAE alone. However, these differences did not reach statistical significance. This was not an unexpected result since carcinoid tumors classically have a lower response rate to systemic chemotherapy when compared to islet cell carcinomas. Another retrospective multi-institutional review comparing TACE with TAE showed that patients undergoing TACE demonstrated a trend towards improvement in time to progression, symptom control,
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and overall survival.39 Again, statistical significance was not achieved due to the small cohort, warranting the necessity for further prospective randomized trials. The question of the timing of embolization therapy, whether early or late in disease, is unresolved. Although some investigators advocate early embolization, other studies suggest that late embolization can also be equally effective. Hanssen et al22 observed a higher response rate in patients with carcinoid tumors treated at the time of diagnosis with TAE followed by interferon therapy than in patients who received interferon only (86% v 42%), suggesting that embolization early in the course of disease can benefit these patients. However, in another study, in which TAE or TACE was performed at a median of 37 months after diagnosis, Erickson et al28 reported a median survival of 80 months and a 5-year survival rate of 60%, indicating that “late” embolization is also very effective. This is similar to our own experience at M.D. Anderson Cancer Center (MDACC); we found that the response rates or survival durations after TAE or TACE were not affected by the duration of liver disease before embolization.17 In keeping with the results reported in medical and surgical oncology literature, patients with pancreatic islet cell tumors treated with TAE or TACE have poorer survival rates than those with carcinoid tumors treated in a similar fashion (Table 1). In the study by Eriksson et al,28 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 al34 also reported a longer median survival (27 months v 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. This is similar to our experience at MDACC;17 we found that patients with carcinoid tumors had better outcomes than patients with islet cell tumors, as evidenced by significantly higher radiologic response rates (66.7% v 35.2%) and longer median progressionfree survival (22.7 months v 16.1 months) and overall survival durations (33.8 months v 23.2 months). Despite the large number of studies reporting the use of TAE or TACE in patients with metastatic NETs, a number of issues remain unresolved. Due to lack of controlled randomized trials, unequivocal survival benefit has not been established. Although a myriad of chemotherapeutic drugs and embolic agents have been used, no studies to date have addressed the questions of which chemoembolic regimen is best. There is a lack of consensus among interventional radiologists on procedure end points and on the degree of vascular stasis to be achieved. Hepatic tumor burden that can be safely treated, the quantity of liver to be embolized per session, and the ideal time interval between treatment sessions, are other issues that require more investigation. Additionally, the role of concomitant systemic octreotide therapy warrants further investigation.
J. Nazario and S. Gupta
SELECTIVE INTERNAL RADIATION THERAPY Selective internal radiation therapy (SIRT) is an emerging treatment modality for NETs. The rationale behind the use of SIRT is that radiation, if delivered in sufficient doses, is lethal to neoplastic tissue. However, normal hepatocytes have an even lower tolerance of the effects of radiation than does neoplastic tissue, limiting the use of external-beam radiation for liver metastases.46 When delivered intra-arterially as radioactive microspheres (radioembolization) or target specific radiolabeled somatostatin analogue constructs, this theoretically results in a more selective point source of radiation with higher tumor kill specificity. Both of these approaches will be briefly discussed.
Yttrium-90 Microsphere Radioembolization Intra-arterial radioembolization with yttrium-90 microspheres is an emerging technique that is being increasingly used in patients with unresectable primary and metastatic liver malignancies.46 – 48 Yttrium 90 is a pure -emitter with a mean soft tissue penetration of 2.5 mm, and a maximal depth of 1.1 cm. Two US Food and Drug Administration (FDA)-approved 90Y microsphere products are in clinical use at present: TheraSphere (MDS Nordion Inc, Kanata, Ontario, Canada), which are glass microspheres, and the resin-based SIRSpheres (SIRTeX Medical Ltd, Sydney, New South Wales, Australia). Both technologies range in size from 20 to 40 m, with a typical dose consisting of millions of microspheres. The 90Y microspheres, when selectively injected via the hepatic artery, are preferentially distributed into the tumoral and peritumoral vasculature, allowing the delivery of high doses of radiation to the tumor, resulting in tumor necrosis while sparing the surrounding normal liver parenchyma.47,48 Diagnostic angiography is performed, usually in a separate setting, to scrutinize the hepatic arterial anatomy and to determine the pulmonary shunt fraction via technetium-99m macroaggregated albumin infusion as surrogate to therapy.46 Nontargeted embolization to the pulmonary parenchyma could result in significant radiation-induced injury. To avoid nontarget delivery of radioactive microspheres to organs such as the stomach, duodenum, and pancreas, it is essential to perform an angiogram with selective embolization of all extrahepatic arteries before the treatment. The acute and subacute toxicities associated with radioembolization appear to be more tolerable that those associated with other hepatic embolization procedures. Complications include abdominal pain, nausea, fever, and lethargy. Radiation gastritis, duodenal ulcers, and liver dysfunction have been reported. The significantly lower incidence of post-embolization syndrome associated with radioembolization allows for treatment planning in an outpatient setting.46
33.3 66.7
93.8*
NR
NR
SIR-Spheres or TheraSphere SIR-Spheres
12 62.5
9
2008
2009
Rhee et al52
Kalinowski et al53
NR
27
2008 Murthy et al47
NR
2008 King et al51
8
34
1st or ⱕ 2nd line Salvage†
2008 Kennedy et al49
Abbreviations: EHD, extrahepatic disease; NETs, neuroendocrine tumors; TAE, transcatheter arterial embolization; TACE, transcatheter arterial chemoembolization; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; TTP, time to progression; NR, not recorded; 5FU, 5-fluorouracil. *PR⫹SD. †All failed previous TAE/TACE.
3-yr, 57% 11.1 mo NR
18 mo NR NR
14 mo NR NR 37.5 50
24.2 mo NR 55 32.4 14.7 50
SIR-Spheres ⫹ 5FU infusion SIR-Spheres 59
70 mo NR NR 4.9 22.7 63.2 SIR-Spheres NR
82% carcinoid, 18% other NETs 68% carcinoid, 32% other NETs 75% islet cell, 25% carcinoid 67% carcinoid, 33% islet cell NR 148 1st to salvage
Median TTP Symptom Response (%) PD SD CR ⴙ PR Treatment
Imaging/Tumor Marker Response (%)
EHD (%) Histology No. of Patients Line Year Authors
More recently, radiolabeled somatostatin analogues have been developed based on the knowledge of the somatostatin receptor properties of these tumors. For many years, imaging techniques have taken advantage of this property for diagnosing, localizing, and monitoring treatment response of these tumors. The peptides that have been used include octreotide, octreotate, and lanreotide, all modified with the addition of the metal chelator tetraazacyclododecanetetra-acetic acid (DOTA).19 This has allowed the use of a variety of radionuclides, although 90Y, indium 111, and lutetium 177 are the most commonly used. To determine whether a patient may benefit from treatment with radiolabeled-somatostatin analogs, a diagnostic 111Inpentetreotide scan is performed to assess receptor positivity. For example, in carcinoids, nearly 90% of all tumors are receptor-positive. However, this percentage can drop to 50% in NETs of pancreatic origin, especially insulinomas.19,54 For a patient to be eligible for treatment, activity at known tumor sites must be more intense than in the normal liver.55 Two recent studies have been reported in which the intra-arterial administration of these somatostatin analogs labeled with therapeutic radioactive agents has resulted in modest treatment responses. McStay et al,50 in their study involving 23 patients with NET hepatic metastases treated with intra-arterial 90Y-DOTA-lanreotide, reported a response rate of 16% and 1-year survival rate of 63%. More recently, Limouris et al56 observed a complete or partial response in 53% of patients and a survival of 32 months in 70.5%, in their
Patients and Presentation
Hepatic Arterial Infusion of Radiolabeled Somatostatin Analogs
Table 2. Summary of Published Studies Using Radioembolization in Patients With Metastatic NETs
There is limited literature on the use of radioembolization for the treatment of patients with neuroendocrine liver metastases47,49 –53 (Table 2). In a retrospective review of 148 patients with liver metastases from neuroendocrine tumors treated with 185 separate radioembolization procedures using resin 90Y microspheres, Kennedy et al49 observed a complete response in 3%, partial response in 66.7%, stable disease in 25%, and progressive disease in 5.3% of patients. The median survival was 70 months. In a recent prospective study that involved nine patients with unresectable liver metastases from NETs treated with 90Y radioembolization, partial response was seen in six patients (66%), and survival rates were 100% and 57% at 1 and 3 years, respectively.53 No major complications occurred. These initial results suggest that 90Y radioembolization represents a viable alternative therapy for patients with hepatic NETs, especially in patients who have failed to respond to traditional therapies. Further investigation, long-term follow-up, and prospective clinical trials are warranted to determine the exact role of this treatment method in the management of NET hepatic metastases.
123
Median Survival
Transarterial liver-directed therapies of neuroendocrine tumors
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series of 17 patients treated with hepatic arterial infusion (HAI) of 111In-DTPA-D-Phe1-octreotide.
J. Nazario and S. Gupta
directed therapies may lead to further improvements in the management of neuroendocrine carcinomas, specifically low-grade NETs.
HEPATIC ARTERIAL INFUSION HAI of chemotherapeutic agents offers pharmacokinetic advantage over systemic administration. Enhanced first-pass extraction of chemotherapy by neoplastic cells permits relatively higher doses of chemotherapy to be delivered when compared with the systemic route for the same agent.57 Unfortunately, studies documenting the use of hepatic arterial chemotherapy infusion without embolotherapy for patients with metastatic NETs are sparse and restricted to small case series and case reports. In a case report by Takeuchi et al,58 a patient with metastatic carcinoid tumor treated with 40 cycles of intra-arterial methotrexate and 5-flouoruracil (5FU) achieved a partial response that was maintained for 40 months. Tumor remission was also reported with intraarterial continuous infusion of somatostatin analog in a patient with metastatic carcinoid.59 Unfortunately treatment with intra-arterial infusion has not resulted in significant benefit in patients with liver metastases from NETs and this has largely been superseded by TAE and TACE. Few studies have evaluated the combination of HAI followed by TAE/TACE. In a study by Christante et al,60 77 patients with NET hepatic metastases received 4-month cycles of 5-fluorouracil (5FU) via HAI. The last two HAI cycles were combined with TACE using a combination of cisplatin, doxorubicin, and mitocycin mixed with lipiodol. The authors reported a response rate of 80%, a median progression-free survival of 19 months, and a 5-year survival of 27%.
CONCLUSIONS Interventional radiologic techniques for liver-directed therapies play an integral role in the management of patients with metastasis from neuroendocrine tumors. Transcatheter arterial procedures such as TAE, TACE, and radioembolization have been shown to reduce hormone levels, palliate symptoms, and reduce the tumor burden in many patients with unresectable and symptomatic NET hepatic metastases. Furthermore, liver-directed therapies may allow downstaging of disease, allowing for potential resection or ablation. While several modalities exist using liver-directed therapy for treating unresectable disease, there is lack of consensus regarding the ideal approach for treating such patients. A multidisciplinary approach must be implemented to prospectively develop and study protocols for treatment. Recent studies of systemic agents that target angiogenesis or the epidermal growth factor receptor have shown promising results. Combining novel molecular targeted therapy strategies with liver-
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Transarterial liver-directed therapies of neuroendocrine tumors
18. Kamat PP, Gupta S, Ensor JE, et al. Hepatic arterial embolization and chemoembolization in the management of patients with large-volume liver metastases. Cardiovasc Intervent Radiol. 2008;31:299 –307. 19. Steward MJ, Warbey VS, Malhotra A, Caplin ME, Buscombe JR, Yu D. Neuroendocrine tumors: role of interventional radiology in therapy. Radiographics. 2008;28: 1131– 45. 20. Ajani JA, Carrasco CH, Charnsangavej C, Samaan NA, Levin B, Wallace S. Islet cell tumors metastatic to the liver: effective palliation by sequential hepatic artery embolization. Ann Intern Med. 1988;108:340 – 4. 21. Carrasco CH, Chuang VP, Wallace S. Apudomas metastatic to the liver: treatment by hepatic artery embolization. Radiology. 1983;149:79 – 83. 22. Hanssen LE, Schrumpf E, Jacobsen MB, et al. Extended experience with recombinant alpha-2b interferon with or without hepatic artery embolization in the treatment of midgut carcinoid tumours. A preliminary report. Acta Oncol. 1991;30:523–7. 23. Bloomston M, Al-Saif O, Klemanski D, et al. Hepatic artery chemoembolization in 122 patients with metastatic carcinoid tumor: lessons learned. J Gastrointest Surg. 2007;11:264 –71. 24. Brown KT, Koh BY, Brody LA, et al. Particle embolization of hepatic neuroendocrine metastases for control of pain and hormonal symptoms. J Vasc Interv Radiol. 1999;10:397– 403. 25. Diamandidou E, Ajani JA, Yang DJ, et al. Two-phase study of hepatic artery vascular occlusion with microencapsulated cisplatin in patients with liver metastases from neuroendocrine tumors. AJR Am J Roentgenol. 1998; 170:339 – 44. 26. Dominguez S, Denys A, Madeira I, et al. Hepatic arterial chemoembolization with streptozotocin in patients with metastatic digestive endocrine tumours. Eur J Gastroenterol Hepatol. 2000;12:151–7. 27. Drougas JG, Anthony LB, Blair TK, et al. Hepatic artery chemoembolization for management of patients with advanced metastatic carcinoid tumors. Am J Surg. 1998; 175:408 –12. 28. Eriksson BK, Larsson EG, Skogseid BM, Lofberg AM, Lorelius LE, Oberg KE. Liver embolizations of patients with malignant neuroendocrine gastrointestinal tumors. Cancer. 1998;83:2293–301. 29. Hajarizadeh H, Ivancev K, Mueller CR, Fletcher WS, Woltering EA. Effective palliative treatment of metastatic carcinoid tumors with intra-arterial chemotherapy/chemoembolization combined with octreotide acetate. Am J Surg. 1992;163:479 – 83. 30. Ho AS, Picus J, Darcy MD, et al. Long-term outcome after chemoembolization and embolization of hepatic metastatic lesions from neuroendocrine tumors. AJR Am J Roentgenol. 2007;188:1201–7. 31. Kress O, Wagner HJ, Wied M, Klose KJ, Arnold R, Alfke H. Transarterial chemoembolization of advanced liver metastases of neuroendocrine tumors--a retrospective single-center analysis. Digestion. 2003;68:94 –101. 32. Loewe C, Schindl M, Cejna M, Niederle B, Lammer J, Thurnher S. Permanent transarterial embolization of neuroendocrine metastases of the liver using cyanoacrylate
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48. Salem R, Thurston KG. Radioembolization with 90 yttrium microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies. Part 1: technical and methodologic considerations. J Vasc Interv Radiol. 2006;17:1251–78. 49. Kennedy AS, Dezarn WA, McNeillie P, et al. Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in 148 patients. Am J Clin Oncol. 2008;31:271–9. 50. McStay MK, Maudgil D, Williams M, et al. Large-volume liver metastases from neuroendocrine tumors: hepatic intraarterial 90Y-DOTA-lanreotide as effective palliative therapy. Radiology. 2005;237:718 –26. 51. King J, Quinn R, Glenn DM, et al. Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases. Cancer. 2008;113:921–9. 52. Rhee TK, Lewandowski RJ, Liu DM, et al. 90Y radioembolization for metastatic neuroendocrine liver tumors: preliminary results from a multi-institutional experience. Ann Surg. 2008;247:1029 –35. 53. Kalinowski M, Dressler M, Konig A, et al. Selective internal radiotherapy with yttrium-90 microspheres for hepatic metastatic neuroendocrine tumors: a prospective single center study. Digestion. 2009;79:137– 42. 54. Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med. 1993;20: 716 –31. 55. Krenning EP, Teunissen JJ, Valkema R, deHerder WW, deJong M, Kwekkeboom DJ. Molecular radiotherapy
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with somatostatin analogs for (neuro-)endocrine tumors. J Endocrinol Invest. 2005;28:146 –50. Limouris GS, Chatziioannou A, Kontogeorgakos D, et al. Selective hepatic arterial infusion of In-111-DTPA-Phe1octreotide in neuroendocrine liver metastases. Eur J Nucl Med Mol Imaging. 2008;35:1827–37. Ensminger WD. Intrahepatic arterial infusion of chemotherapy: pharmacologic principles. Semin Oncol. 2002; 29:119 –25. Takeuchi I, Ishida H, Suzuki T, Nakada H, Tada M, Idezuki Y. [A case of liver metastases of rectal carcinoid successfully treated with hepatic arterial infusion of methotrexate and 5-fluorouracil]. Gan To Kagaku Ryoho. 1999;26:1929 –32. Wadamori K, Oka M, Shimizu R, et al. [A case of multiple liver metastasis from ileac carcinoid effectively treated with continuous intraarterial infusion of somatostatin analog]. Gan To Kagaku Ryoho. 1995;22:1669 –72. Christante D, Pommier S, Givi B, Pommier R. Hepatic artery chemoinfusion with chemoembolization for neuroendocrine cancer with progressive hepatic metastases despite octreotide therapy. Surgery. 2008;144:885–93. Ruszniewski P, Rougier P, Roche A, et al. Hepatic arterial chemoembolization in patients with liver metastases of endocrine tumors. A prospective phase II study in 24 patients. Cancer. 1993;71:2624 –30. Kim YH, Ajani JA, Carrasco CH, et al. Selective hepatic arterial chemoembolization for liver metastases in patients with carcinoid tumor or islet cell carcinoma. Cancer Invest. 1999;17:474 – 8.
N
euroendocrine tumors (NETs) comprise a diverse group of tumors characterized by the capacity to synthesize and secrete polypeptide products that are hormonally active. These tumors can occur in any organ system, including the gastrointestinal and respiratory tracts. The estimated incidence in the United States for this relatively rare group of tumors is 1 to 2 cases per 100,000 persons per year.1 NETs are slowly growing tumors with an indolent course.2 Clinical presentation, which is often late, results from biochemical activity or bulk symptoms, such as local obstruction or invasion of adjacent organs or structures. Unfortunately, by the time NET is diagnosed, 46% to 93% of patients have developed hepatic metastases.3 Presence of hepatic metastatic disease is associated with a poor prognosis, with an established 5-year survival rate of 22%.1,4 The treatment of neuroendocrine hepatic metastases presents a difficult problem for medical and surgical oncologists. Liver metastases result in significant debilitating hormonal symptoms, treated initially with somaDepartment of Diagnostic Radiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Address correspondence to Sanjay Gupta, MD, Department of Diagnostic Radiology, Unit 325, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. E-mail: sgupta@ mdanderson.org. 0270-9295/ - see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2010.03.004
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tostatin analog therapy.5 Systemic chemotherapy has limited success in the management of patients with NET hepatic metastases.6,7 Response rates for advanced carcinoid cancer treated with systemic chemotherapy range in the literature from 0% to 38% and median survival ranges from 5 to 26 months.1,5–7 Islet cell neoplasms are considered generally to be more responsive to systemic chemotherapy, but this is offset by a poorer survival.1,5–7 Curative surgery for hepatic NET metastases should always be considered as a treatment option. Resection of the primary tumor and local lymph nodes is the only potential curative therapy for gastrointestinal (GI) carcinoid tumors.1,5,8 Five-year survival rates of 79% to 80% have been reported for patients with GIrelated neuroendocrine disease after complete surgical resection.9,10 Unfortunately, because of the late presentation of disease, curative resection of identifiable metastatic disease occurs in less than 10% of cases.9,10 Most patients present with extensive bilobar disease or bulky tumor that requires alternative therapy. In addition, although somatostatin analogs have been shown to be effective in controlling symptoms in many of these patients, the disease can become refractory to treatment.5,6 For these reasons, liver-directed therapy has become an important treatment option in patients with metastatic NETs. The generally accepted indications for locoregional therapy for NET liver metastases include symptoms related to hormonal excess or tumor bulk, and rapid progression of liver disease.11 Liver-directed Seminars in Oncology, Vol 37, No 2, April 2010, pp 118-126
Transarterial liver-directed therapies of neuroendocrine tumors
treatment can occasionally be used as an adjuvant therapy to reduce tumor load before hepatic resection, hepatic transplantation, or tumor ablation.12 Interventional radiologists play an important role in the management of refractory, unresectable, or recurrent disease. Specifically, treatment must be individualized according to the therapeutic goal, distribution of disease, magnitude of liver involvement, and patient performance status. The purpose of this review is to summarize the most recent information on arterial based liver-directed therapies in the treatment of metastatic NETs.
TRANSCATHETER ARTERIAL EMBOLIZATION AND CHEMOEMBOLIZATION The rationale for transcatheter arterial embolization (TAE) is based on the observations that liver metastases from NETs are typically hypervascular deriving the majority (80%–90%) of their blood supply from the hepatic artery. Conversely, normal liver tissues derive its blood supply from the portal vein.13,14 Therefore, treatment is achieved by inducing ischemia in the tumor tissue with preservation of normal liver parenchyma. Early attempts at proximal hepatic artery occlusion, either surgically or via embolization, demonstrated response rates exceeding 50%.15 However, these procedures can be associated with high morbidity, and formation of collaterals results in rapid revascularization of tumors resulting in incomplete necrosis.16 More recently, with the development of microcatheter technology, the technique of selective hepatic embolization has evolved, whereby the left or right hepatic arterial branches are embolized separately to minimize nontargeted embolization. Transcatheter arterial chemoembolization (TACE) combines intra-arterial delivery of chemotherapeutic agents with particulate embolization, and has several theoretical advantages over TAE: regional delivery of chemotherapy offers pharmacokinetic advantages compared with systemic administration; it combines local cytotoxic effect of chemotherapeutic agent with selective ischemia induced by embolization; 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 prolong drug retention in the tumor. The TAE or TACE procedure itself involves performing diagnostic superior mesenteric and celiac angiography, usually from a femoral artery access, to identify the hepatic vasculature (including anatomical variants), disease distribution, and ensure patency of the portal vein. After visceral angiography, TAE or TACE is then performed under fluoroscopic guidance using a 3-F microcatheter placed in a selective location to minimize nontargeted embolization. In TAE, the embolic agent of choice is then infused through the microcath-
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eter until the selected vessel demonstrates complete or near complete stasis of flow. Octreotide is administered before the procedure in patients with the carcinoid syndrome to prevent acute release of serotonin into the circulation. Various embolic agents, including Gelfoam (Pharmacia & Upjohn, Bridgewater, NJ) sponge slurry, Gelfoam powder, lipiodol/Gelfoam slurry, poly vinyl alcohol (PVA) particles, cyanoacrylate, and tris-acryl particles, have been used for TAE or TACE. In TACE, the combination of embolic agent (microparticles or lipiodol) along with the chemotherapeutic drug is administered in a similar fashion. Embolization of the whole liver in a single treatment session is not recommended because of the risk of prolonged postembolization syndrome or liver failure.13,17 Typically, the lobe with the largest tumor burden is treated initially. In the case of extensive bilobar disease, the embolization procedures can be staged and different liver segments are embolized at each treatment session.18 The timing of subsequent embolizations is determined primarily by the patient’s symptoms, biochemical or tumor status, and ability to tolerate the procedure.13,17 Depending on the extent of liver involvement, the entire liver can generally be treated in two to four sessions. Although there is no absolute contraindication to TAE or TACE, complete portal vein occlusion, hepatic insufficiency, and previous biliary-enteric anastomoses are considered relative contraindications to the treatment.17,19 A common side effect associated with patients undergoing TAE or TACE is the postembolization syndrome, characterized by right upper quadrant pain, fever, nausea, leukocytosis, elevation of liver function tests, and malaise. Postembolization syndrome is generally self-limited, improving within 3 to 5 days with conservative management, but can occasionally be severe and require prolonged hospitalization.17,19 Severe complications such as carcinoid crisis, acute liver failure with or without hepatic encephalopathy, emphysematous cholecystitis necessitating surgery, gastric perforation, gastric ulcer and hemorrhage, abscess formation, and tumor lysis syndrome also have been reported but are uncommon.17–19 Many nonrandomized, retrospective reports have shown that TAE and TACE can reduce hormone levels, palliate symptoms, and reduce the tumor burden in many patients with NET hepatic metastases.3,15,17,20 – 44 A summary of the reported TAE and TACE studies is provided in Table 1. Review of the published clinical experience shows that use of TAE and TACE can result in radiologic response in 25% to 95%, and symptomatic response in 53% to 100% of patients with NET liver metastasis (Table 1). The reported 5-year survival rates vary from 13.7% to 75%.3,15,17,20 – 44 This wide range in response rates and survival durations is related to the marked heterogeneity in various studies in terms of patient population; tumor histology and degree of differentiation; regimens of treatment used (TAE v TACE,
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Table 1. Summary of Published Studies Using Hepatic TAE and TACE in Patients with Metastatic NETs Tumor Type and Patients Authors
Year
Tumor Type
Imaging Response (%)
No. of Patients
EHD (%)
6 6 6 22 36
NR NR NR NR NR
8
NR
1983
Ajani et al20 Hanssen et al22
1988 1991
Carcinoid Islet cell Islet cell Islet cell Carcinoid
Hajarizadeh et al29
1992
Carcinoid
Mavligit et al33 Rusznieweski et al61
1993 1993
Therasse et al40 Moertel et al34
1993 1994
Perry et al36 Wangberg et al42 Eriksson et al28
1994 1996 1998
Drougas et al27
1998
Islet cell Carcinoid Gastrinoma Carcinoid Carcinoid Islet cell Carcinoid Islet cell NET Carcinoid Carcinoid Islet cell Carcinoid
5 18 5 23 23 17 42 29 30 40 29 12 15
40 NR NR NR NR NR NR NR NR NR NR NR NR
Diamandidou et al25 Brown et al24 Kim et al62
1998 1999 1999
Dominguez et al26
2000
Chamberlain et al3 Yao et al43 Roche et al37 Loewe et al32 Kress et al31 Gupta et al17
2000 2001 2003 2003 2003 2005
2006 2006
20 35 30 16 14 8 7 33 20 14 23 26 69 54 21 48 59 84 59 20 5
NR NR NR NR NR NR NR 45 NR 7.1 ⱖ48
Osborne et al35 Strosberg et al15
NET NET NET Carcinoid Islet cell Carcinoid Islet cell NET NET NET Carcinoid NET Carcinoid Islet cell Carcinoid Carcinoid NET NET Carcinoid Islet cell Poorly differentiated
Carrasco et
70 57 0 100 26 NR NR NR
Treatment TAE TAE TACE‡ TAE TAE (⫹ systemic interferon) HAI (5FU) ⫹ TACE (cis/mit-C/dox) TACE (cis/vinbl) TACE (dox) TACE (dox) TACE‡ TAE TAE TAE ⫹ IV chemo TAE ⫹ IV chemo TACE (Dox) TAE TAE HAI (5FU) ⫹ TACE (dox/cis/mit-C) TACE (Cis) TAE TACE TACE (cis/dox) TACE (STZ/5FU) TACE (STZ) TACE (STZ) TAE TACE (dox/cis/mit-C) TACE (Dox) TAE TACE (Dox) TAE or TACE‡
TAE TAE
CR ⴙ PR
SD
83 50 100 60 60
20
50
50
PD
20
80 33 33 56 43 75 78 95 42.5 52 50 6.7 33.3
60 50
11
37.5 31 8
66.6
37 25 50 50 57 25 43 73 7.7 66.7 35.2
10 22 53.8 24.6 61.1
48
52
19.2 8.7 3.7
Tumor Marker Response (%)
Median TTP/PFS (months)
Median Survival* (months)
5-Year Survival* (%)
NR NR NR NR 100
NR NR NR NR NR
NR NR NR NR NR
NR NR NR 33.7 NR
NR NR NR NR 75
100
NR
NR
NR
NR
NR 73 NR 100 NR NR NR NR 90 NR NR NR 67
NR 57
8–44 NR NR NR 9.9 4 23.8 21.6 NR NR NR NR NR
NR NR NR 24 27 9 49 35 24 NR 80 20 16
NR NR NR NR NR NR NR NR NR 63 60 NR NR
NR NR NR NR NR NR NR NR NR NR
NR NR 15
NR 54 NR NR NR NR NR 51 40 83† 65.4 48† 26.6 13.7 NR NR NR NR NR NR NR
67 96 NR NR NR 60 75 96 50 90 NR NR NR NR NR NR 91 80
91 82 69 83 87 69 100 38 42 100 73 NR NR 75 90 50 57 NR NR NR 61.5 NR NR NR NR NR NR NR NR NR NR
NR 22.7 16.1 NR NR NR 36 44 31 15
NR NR NR 32 NR 69 NR 33.8 23.2 86.4 33.2 24‡ NR NR NR NR
J. Nazario and S. Gupta
al21
Symptom Response (%)
23 9
6 13 12
32 45
12 38 22
23 18
82 61 82 50 66 1st TACE (cis, dox, mit-C) Repeat TACE (cis, dox, mit-C) TACE‡ TAE TACE (cis, dox, mit-C) TAE or TACE (cis, dox, mit-C) 2007
2007
Bloomston et al23 Ruutiainen et al39
Ho et al30
NET Carcinoid Islet cell
46 31 15
NR NR 28 NR NR 57 NR NR 122 27 122 67 Carcinoid Carcinoid Carcinoid NET 2007 Varker et
Abbreviations: EHD, extrahepatic disease; NET, neuroendocrine tumor; TAE, transcatheter arterial embolization; TACE, transcatheter arterial chemoembolization; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; TTP, time to progression; PFS, progression-free survival; IV, intravenous; NR, not recorded; Dox, doxorubicin; Cis, cisplatin; mit-C, mitomycin-C; 5FU, 5-fluorouracil; STZ, Streptozocin; vinb, vinblastine. *From date of TAE/TACE. †From diagnosis. ‡Multiple chemotherapeutic regimens. §Mean.
NR NR NR 33 50 29 32 35 33.3 28.1 33.3 39 44 42§ 41.8§ 43.7§ 11.8 NR NR 6 12 18.5§ 22.7§ 16.1§ NR NR 80 NR NR NR NR NR 92 77 92 93 92 78 78 75
PD SD CR ⴙ PR Year
al41
Tumor Type
No. of Patients Authors
Table 1. Continued
Tumor Type and Patients
EHD (%)
Treatment
Imaging Response (%)
Symptom Response (%)
Tumor Marker Response (%)
Median TTP/PFS (months)
Median Survival* (months)
5-Year Survival* (%)
Transarterial liver-directed therapies of neuroendocrine tumors
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number of sessions performed, type of chemotherapeutic agent, and embolization material); the time when embolization was performed (ie, early or late in the clinical course); previous, concurrent, or subsequent use of octreotide and systemic chemotherapy; extent of liver involvement by metastatic disease; frequency and timing of follow-up imaging; criteria used for measuring response; and different methods used to report survival. Some studies had suggested that patients with more than 50% liver involvement by metastatic disease should not be subjected to TAE or TACE due to the high risk of inducing liver failure. Carrasco et al reported a high mortality rate for patients with a tumor burden of more than 50% of the liver.21,45 In another report, by Kress et al,31 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. However, our own results suggest that although the median survival durations and response rates are lower in patients with more than 75% liver disease than in those with lesser liver involvement, many of these patients can benefit from selective embolizations, if small portions of the liver are embolized in each session and the sessions are well separated in time.17,18 In a recent study involving patients with hepatic NET metastases and more than 75% liver involvement, selective segmental sequential TAE or TACE procedures resulted in radiologic response or disease stabilization in 82% of patients, symptomatic response in 65%, a median progression-free survival of 9.2 months, and a median survival of 17.9 months.18 However, the study also showed that patients with massive liver tumor burden, who have additional risk factors such as carcinoid heart disease, sepsis, rapidly worsening performance status, or anasarca should not be subjected to TAE/TACE because of the high risk of procedure-related mortality.18 The therapeutic benefit of TACE over TAE remains unclear. Review of results of various studies in literature shows that there is no difference in the response rates for the two treatment methods (Table 1). In a recent study, Gupta et al17 showed that, although TACE did not show any therapeutic advantage over TAE in patients with carcinoid tumors, patients with islet cell carcinoma treated with TACE had a tendency toward prolonged survival (31.5 months v 18.2 months) and an improved radiologic response rate (50% v 25%) when compared with those treated with TAE alone. However, these differences did not reach statistical significance. This was not an unexpected result since carcinoid tumors classically have a lower response rate to systemic chemotherapy when compared to islet cell carcinomas. Another retrospective multi-institutional review comparing TACE with TAE showed that patients undergoing TACE demonstrated a trend towards improvement in time to progression, symptom control,
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and overall survival.39 Again, statistical significance was not achieved due to the small cohort, warranting the necessity for further prospective randomized trials. The question of the timing of embolization therapy, whether early or late in disease, is unresolved. Although some investigators advocate early embolization, other studies suggest that late embolization can also be equally effective. Hanssen et al22 observed a higher response rate in patients with carcinoid tumors treated at the time of diagnosis with TAE followed by interferon therapy than in patients who received interferon only (86% v 42%), suggesting that embolization early in the course of disease can benefit these patients. However, in another study, in which TAE or TACE was performed at a median of 37 months after diagnosis, Erickson et al28 reported a median survival of 80 months and a 5-year survival rate of 60%, indicating that “late” embolization is also very effective. This is similar to our own experience at M.D. Anderson Cancer Center (MDACC); we found that the response rates or survival durations after TAE or TACE were not affected by the duration of liver disease before embolization.17 In keeping with the results reported in medical and surgical oncology literature, patients with pancreatic islet cell tumors treated with TAE or TACE have poorer survival rates than those with carcinoid tumors treated in a similar fashion (Table 1). In the study by Eriksson et al,28 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 al34 also reported a longer median survival (27 months v 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. This is similar to our experience at MDACC;17 we found that patients with carcinoid tumors had better outcomes than patients with islet cell tumors, as evidenced by significantly higher radiologic response rates (66.7% v 35.2%) and longer median progressionfree survival (22.7 months v 16.1 months) and overall survival durations (33.8 months v 23.2 months). Despite the large number of studies reporting the use of TAE or TACE in patients with metastatic NETs, a number of issues remain unresolved. Due to lack of controlled randomized trials, unequivocal survival benefit has not been established. Although a myriad of chemotherapeutic drugs and embolic agents have been used, no studies to date have addressed the questions of which chemoembolic regimen is best. There is a lack of consensus among interventional radiologists on procedure end points and on the degree of vascular stasis to be achieved. Hepatic tumor burden that can be safely treated, the quantity of liver to be embolized per session, and the ideal time interval between treatment sessions, are other issues that require more investigation. Additionally, the role of concomitant systemic octreotide therapy warrants further investigation.
J. Nazario and S. Gupta
SELECTIVE INTERNAL RADIATION THERAPY Selective internal radiation therapy (SIRT) is an emerging treatment modality for NETs. The rationale behind the use of SIRT is that radiation, if delivered in sufficient doses, is lethal to neoplastic tissue. However, normal hepatocytes have an even lower tolerance of the effects of radiation than does neoplastic tissue, limiting the use of external-beam radiation for liver metastases.46 When delivered intra-arterially as radioactive microspheres (radioembolization) or target specific radiolabeled somatostatin analogue constructs, this theoretically results in a more selective point source of radiation with higher tumor kill specificity. Both of these approaches will be briefly discussed.
Yttrium-90 Microsphere Radioembolization Intra-arterial radioembolization with yttrium-90 microspheres is an emerging technique that is being increasingly used in patients with unresectable primary and metastatic liver malignancies.46 – 48 Yttrium 90 is a pure -emitter with a mean soft tissue penetration of 2.5 mm, and a maximal depth of 1.1 cm. Two US Food and Drug Administration (FDA)-approved 90Y microsphere products are in clinical use at present: TheraSphere (MDS Nordion Inc, Kanata, Ontario, Canada), which are glass microspheres, and the resin-based SIRSpheres (SIRTeX Medical Ltd, Sydney, New South Wales, Australia). Both technologies range in size from 20 to 40 m, with a typical dose consisting of millions of microspheres. The 90Y microspheres, when selectively injected via the hepatic artery, are preferentially distributed into the tumoral and peritumoral vasculature, allowing the delivery of high doses of radiation to the tumor, resulting in tumor necrosis while sparing the surrounding normal liver parenchyma.47,48 Diagnostic angiography is performed, usually in a separate setting, to scrutinize the hepatic arterial anatomy and to determine the pulmonary shunt fraction via technetium-99m macroaggregated albumin infusion as surrogate to therapy.46 Nontargeted embolization to the pulmonary parenchyma could result in significant radiation-induced injury. To avoid nontarget delivery of radioactive microspheres to organs such as the stomach, duodenum, and pancreas, it is essential to perform an angiogram with selective embolization of all extrahepatic arteries before the treatment. The acute and subacute toxicities associated with radioembolization appear to be more tolerable that those associated with other hepatic embolization procedures. Complications include abdominal pain, nausea, fever, and lethargy. Radiation gastritis, duodenal ulcers, and liver dysfunction have been reported. The significantly lower incidence of post-embolization syndrome associated with radioembolization allows for treatment planning in an outpatient setting.46
33.3 66.7
93.8*
NR
NR
SIR-Spheres or TheraSphere SIR-Spheres
12 62.5
9
2008
2009
Rhee et al52
Kalinowski et al53
NR
27
2008 Murthy et al47
NR
2008 King et al51
8
34
1st or ⱕ 2nd line Salvage†
2008 Kennedy et al49
Abbreviations: EHD, extrahepatic disease; NETs, neuroendocrine tumors; TAE, transcatheter arterial embolization; TACE, transcatheter arterial chemoembolization; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; TTP, time to progression; NR, not recorded; 5FU, 5-fluorouracil. *PR⫹SD. †All failed previous TAE/TACE.
3-yr, 57% 11.1 mo NR
18 mo NR NR
14 mo NR NR 37.5 50
24.2 mo NR 55 32.4 14.7 50
SIR-Spheres ⫹ 5FU infusion SIR-Spheres 59
70 mo NR NR 4.9 22.7 63.2 SIR-Spheres NR
82% carcinoid, 18% other NETs 68% carcinoid, 32% other NETs 75% islet cell, 25% carcinoid 67% carcinoid, 33% islet cell NR 148 1st to salvage
Median TTP Symptom Response (%) PD SD CR ⴙ PR Treatment
Imaging/Tumor Marker Response (%)
EHD (%) Histology No. of Patients Line Year Authors
More recently, radiolabeled somatostatin analogues have been developed based on the knowledge of the somatostatin receptor properties of these tumors. For many years, imaging techniques have taken advantage of this property for diagnosing, localizing, and monitoring treatment response of these tumors. The peptides that have been used include octreotide, octreotate, and lanreotide, all modified with the addition of the metal chelator tetraazacyclododecanetetra-acetic acid (DOTA).19 This has allowed the use of a variety of radionuclides, although 90Y, indium 111, and lutetium 177 are the most commonly used. To determine whether a patient may benefit from treatment with radiolabeled-somatostatin analogs, a diagnostic 111Inpentetreotide scan is performed to assess receptor positivity. For example, in carcinoids, nearly 90% of all tumors are receptor-positive. However, this percentage can drop to 50% in NETs of pancreatic origin, especially insulinomas.19,54 For a patient to be eligible for treatment, activity at known tumor sites must be more intense than in the normal liver.55 Two recent studies have been reported in which the intra-arterial administration of these somatostatin analogs labeled with therapeutic radioactive agents has resulted in modest treatment responses. McStay et al,50 in their study involving 23 patients with NET hepatic metastases treated with intra-arterial 90Y-DOTA-lanreotide, reported a response rate of 16% and 1-year survival rate of 63%. More recently, Limouris et al56 observed a complete or partial response in 53% of patients and a survival of 32 months in 70.5%, in their
Patients and Presentation
Hepatic Arterial Infusion of Radiolabeled Somatostatin Analogs
Table 2. Summary of Published Studies Using Radioembolization in Patients With Metastatic NETs
There is limited literature on the use of radioembolization for the treatment of patients with neuroendocrine liver metastases47,49 –53 (Table 2). In a retrospective review of 148 patients with liver metastases from neuroendocrine tumors treated with 185 separate radioembolization procedures using resin 90Y microspheres, Kennedy et al49 observed a complete response in 3%, partial response in 66.7%, stable disease in 25%, and progressive disease in 5.3% of patients. The median survival was 70 months. In a recent prospective study that involved nine patients with unresectable liver metastases from NETs treated with 90Y radioembolization, partial response was seen in six patients (66%), and survival rates were 100% and 57% at 1 and 3 years, respectively.53 No major complications occurred. These initial results suggest that 90Y radioembolization represents a viable alternative therapy for patients with hepatic NETs, especially in patients who have failed to respond to traditional therapies. Further investigation, long-term follow-up, and prospective clinical trials are warranted to determine the exact role of this treatment method in the management of NET hepatic metastases.
123
Median Survival
Transarterial liver-directed therapies of neuroendocrine tumors
124
series of 17 patients treated with hepatic arterial infusion (HAI) of 111In-DTPA-D-Phe1-octreotide.
J. Nazario and S. Gupta
directed therapies may lead to further improvements in the management of neuroendocrine carcinomas, specifically low-grade NETs.
HEPATIC ARTERIAL INFUSION HAI of chemotherapeutic agents offers pharmacokinetic advantage over systemic administration. Enhanced first-pass extraction of chemotherapy by neoplastic cells permits relatively higher doses of chemotherapy to be delivered when compared with the systemic route for the same agent.57 Unfortunately, studies documenting the use of hepatic arterial chemotherapy infusion without embolotherapy for patients with metastatic NETs are sparse and restricted to small case series and case reports. In a case report by Takeuchi et al,58 a patient with metastatic carcinoid tumor treated with 40 cycles of intra-arterial methotrexate and 5-flouoruracil (5FU) achieved a partial response that was maintained for 40 months. Tumor remission was also reported with intraarterial continuous infusion of somatostatin analog in a patient with metastatic carcinoid.59 Unfortunately treatment with intra-arterial infusion has not resulted in significant benefit in patients with liver metastases from NETs and this has largely been superseded by TAE and TACE. Few studies have evaluated the combination of HAI followed by TAE/TACE. In a study by Christante et al,60 77 patients with NET hepatic metastases received 4-month cycles of 5-fluorouracil (5FU) via HAI. The last two HAI cycles were combined with TACE using a combination of cisplatin, doxorubicin, and mitocycin mixed with lipiodol. The authors reported a response rate of 80%, a median progression-free survival of 19 months, and a 5-year survival of 27%.
CONCLUSIONS Interventional radiologic techniques for liver-directed therapies play an integral role in the management of patients with metastasis from neuroendocrine tumors. Transcatheter arterial procedures such as TAE, TACE, and radioembolization have been shown to reduce hormone levels, palliate symptoms, and reduce the tumor burden in many patients with unresectable and symptomatic NET hepatic metastases. Furthermore, liver-directed therapies may allow downstaging of disease, allowing for potential resection or ablation. While several modalities exist using liver-directed therapy for treating unresectable disease, there is lack of consensus regarding the ideal approach for treating such patients. A multidisciplinary approach must be implemented to prospectively develop and study protocols for treatment. Recent studies of systemic agents that target angiogenesis or the epidermal growth factor receptor have shown promising results. Combining novel molecular targeted therapy strategies with liver-
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