Clinical Presentation and Management of Carcinoid Tumors

Hematol Oncol Clin N Am 21 (2007) 433–455

HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA

Clinical Presentation and Management of Carcinoid Tumors Matthew H. Kulke, MD Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, D 1220, Boston, MA 02115-0684, USA

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berndorfer [1] first used the term ‘‘Karzinoide’’ in 1907 to describe tumors arising in the gastrointestinal tract that pursued a more indolent clinical course than the more common adenocarcinomas. In addition to their generally slow growth rates, carcinoid tumors have since been characterized by their ability to secrete various hormones and biogenic amines. For patients who have localized disease, surgical resection alone is often curative. Patients who have metastatic disease, on the other hand, often present a therapeutic challenge. Although somatostatin analogs are highly effective in controlling symptoms of hormonal secretion, they are only rarely associated with tumor regression. Selected patients who have hepatic metastases may benefit from surgical debulking, embolization, or other ablative therapies. The clinical benefit associated with the administration of systemic agents, such as alpha interferon or cytotoxic chemotherapy, is less clear, and the widespread use of such regimens has been limited by their modest antitumor activity and concerns regarding their potential toxicity. New treatment approaches for patients who have metastatic carcinoid tumors, including the use of targeted radiotherapy and angiogenesis inhibitors, are being actively explored. INCIDENCE The incidence of carcinoid tumors has been estimated to be 1 to 2 per 100,000 population [2]. Because carcinoids often pursue an indolent clinical course, their true incidence is likely much higher. A Swedish series, in which the incidence of carcinoid tumors was evaluated in surgical specimens and autopsies in a single geographic location, estimated the true incidence of carcinoids to be 8.4 cases per 100,000 population, suggesting that a large proportion of patients who have carcinoid tumors may in fact die of other, non–tumor-related causes [3].

M. H. Kulke is supported in part by NIH grants K23 CA 093401, K30 HL04095, and gifts from Raymond and Beverly Sackler, the Caring for Carcinoid Foundation, and the Caroline Kaufer Fund for Neuroendocrine Tumor Research.

E-mail address: [email protected] 0889-8588/07/$ – see front matter doi:10.1016/j.hoc.2007.04.004

ª 2007 Elsevier Inc. All rights reserved. hemonc.theclinics.com

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A recent analysis of 10,878 carcinoid tumors from the Surveillance, Epidemiology, and End Result Program (SEER) of the National Cancer Institute found that 64% of all carcinoids originate in the gastrointestinal tract and 28% originate in the lungs or bronchi (Table 1). Within the gastrointestinal tract, small intestine carcinoids were most common (29%) and were followed in incidence by tumors of the rectum (14%), stomach (5%), and appendix (5%) [2]. These rates differ from those in earlier tumor registries, including the End Results Group, which collected data in the United States from 1950 to 1969. This study reported that appendiceal carcinoid tumors composed 44% of all carcinoid tumors; similarly, the Third National Cancer Survey (1969–1971) reported that appendiceal carcinoids composed 35.5% of all carcinoids [4]. These vastly differing incidence rates should be interpreted with some caution, and likely do not reflect as dramatic a decrease in the incidence of appendiceal carcinoid tumors as seems initially apparent. A major factor in the apparently decreasing incidence of appendiceal carcinoid tumors is that the SEER database reported only ‘‘malignant’’ carcinoid tumors, whereas the earlier registries reported carcinoids with ‘‘benign’’ and ‘‘malignant’’ features. A decreasing incidence of incidental appendectomy during surgery for other indications may have also influenced the recent decrease in the diagnosis of appendiceal carcinoid tumors. CLINICAL PRESENTATION AND MANAGEMENT OF LOCALIZED DISEASE A commonly used classification scheme groups carcinoid tumors according to their presumed derivation from the embryonic gut: foregut (bronchial and gastric), midgut (small intestine and appendiceal), and hindgut (rectal). The clinical Table 1 Percentage of carcinoid tumors at each site as a proportion of the total number of carcinoid tumors in each study [2]

Carcinoid site Lungs and bronchi Stomach Duodenum Jejunum Ileum Appendix Cecum Colon Rectum

End results study group (1950–1960) N ¼ 1867

Third national cancer survey (1969–1970) N ¼ 970

Surveillance, epidemiology, and end results program (NCI) (1973–1999) N ¼ 10,878

10.2

14.1

27.9

2.2 1.8 1.0 10.8 43.9 2.7 4.7 15.4

1.9 2.3 2.0 13.8 35.5 3.0 3.9 12.3

4.6 2.8 1.8 14.9 4.8 4.1 8.6 13.6

Data from Modlin I, Lye K, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97:934–59.

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presentation and management of these tumors varies, depending on their site of origin (Table 2). Bronchial Carcinoid Tumors Bronchial carcinoids compose approximately 2% of primary lung tumors [5,6]. Typical carcinoids, also classified as well-differentiated pulmonary neuroendocrine tumors, usually present in the fifth decade of life [6–8]. They are most often central in location, causing symptoms of cough, wheezing, hemoptysis, and recurrent postobstructive pneumonia [8,9]. Typical pulmonary carcinoid tumors are only rarely associated with the classic carcinoid syndrome; however, they have been associated with ectopic adrenocorticotropic hormone secretion resulting in Cushing’s syndrome [8,10–12]. Approximately one third of bronchial carcinoids demonstrate atypical histologic features [5,9,11,13]. Atypical carcinoids are characterized by the presence of frequent mitoses or areas of necrosis. They tend to occur in older individuals, most commonly in the sixth decade of life, and unlike typical carcinoid tumors are more common in smokers. They also tend to be larger in size than typical carcinoids and are more commonly peripheral in location [14,15].

Table 2 Clinical presentation of carcinoid tumors Carcinoid tumors Foregut Bronchial carcinoids

Gastric carcinoids Midgut Small intestine carcinoids

Appendiceal carcinoids

Hindgut Rectal carcinoids

Cough, hemoptysis, postobstructive pneumonia, Cushing’s syndrome. Carcinoid syndrome rare. Usually asymptomatic and found incidentally. Intermittent bowel obstruction or mesenteric ischemia. Carcinoid syndrome common when metastatic. Usually found incidentally. May cause carcinoid syndrome when metastatic. Either found incidentally or discovered because of bleeding, pain, and constipation. Rarely cause hormonal symptoms, even when metastatic.

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Although typical carcinoid tumors are generally indolent, with metastases reported in less than 15% of cases, atypical carcinoids pursue an aggressive clinical course, metastasizing to mediastinal lymph nodes in 30% to 50% of cases [7,8,11,12]. Accordingly, long-term survival rates for patients who have typical carcinoid tumors following surgical resection generally exceed 85% but are significantly less for patients who undergo resection for atypical carcinoids (Table 3) [5,9–13,15–20]. Histology also influences the choice of surgical procedure; conservative resection, consisting of wedge or segmental resection, is currently the preferred form of treatment of localized bronchial carcinoid tumors, whereas more aggressive procedures are often chosen for atypical carcinoids [12,15]. Gastric Carcinoid Tumors Gastric carcinoid tumors compose less than 1% of gastric neoplasms [4,21]. Gastric carcinoid tumors can be subclassifed into three distinct groups: those associated with chronic atrophic gastritis (type 1), those associated with the Zollinger-Ellison syndrome (type 2), and sporadic gastric carcinoids (type 3). Both type 1 and type 2 gastric carcinoids are associated with hypergastrinemia. High levels of gastrin are believed to result in hyperplasia of the enterochromaffin cells in the stomach, ultimately leading to hyperplastic lesions and small, often multiple carcinoid tumors [21]. These tumors generally pursue an indolent course and can be resected endoscopically, with subsequent interval followup. Patients who have larger or recurrent tumors may require more extensive surgical resection. In patients who have chronic atrophic gastritis, antrectomy has been used to eliminate the source of gastric production and has been reported to result in tumor regression [22,23]. In patients who have ZollingerEllison syndrome, the use of somatostatin analogs has resulted in tumor regression [24].

Table 3 Long-term survival for bronchial carcinoid tumor patients following resection

Series

N

Long-term survival: typical carcinoids (%)

Okike et al [8] (1976) McCaughan et al [11] (1985) Paladugu [19] (1985) Rea et al [10] (1989) Attar et al [20] (1985) Harpole et al [5] (1992) Fink et al [9] (2001) Skuladottir et al [13] (2002) Mezzetti et al [16] (2003) Fiala et al [17] (2003) Schrevens et al [18] (2004)

203 124 156 60 51 126 142 297 98 96 67

94 87 83 89 88 92 89 87 92 87 92

Long-term survival: atypical carcinoids (%) 57 52 64 60 59 31 75 44 71 74 56

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Between 15% and 25% of gastric carcinoids are sporadic [25]. In contrast to type I and type II carcinoids, these lesions develop in the absence of hypergastrinemia, are usually greater than 1 cm in size, and tend to pursue an aggressive clinical course [25]. Sporadic carcinoid tumors have been associated with an atypical carcinoid syndrome, which is manifested primarily by flushing and believed to be mediated by histamine [26]. Most sporadic carcinoid tumors are metastatic at the time of presentation, and death attributable to disease is frequent [25]. Because of the aggressive nature of these lesions, most are treated with radical gastrectomy. Small Intestine Carcinoid Tumors Small bowel carcinoid tumors compose approximately one third of small bowel tumors in surgical series [27]. Patients who have small bowel carcinoids generally present in the sixth or seventh decade of life, most commonly with abdominal pain or small bowel obstruction; these symptoms are commonly misdiagnosed as irritable bowel syndrome [27–29]. Approximately 5% to 7% present with the carcinoid syndrome, at which time hepatic metastases are usually also present [30,31]. The difficulty in diagnosing small bowel carcinoids is compounded by the fact that standard imaging techniques, such as CT scan and small bowel barium contrast studies, only rarely identify the primary tumor. When detected and surgically removed, they are most frequently located in the distal ileum and are often multicentric, occasionally appearing as dozens of lesions lining the small bowel [30]. Tumor size is an unreliable predictor of metastatic disease, and metastases have been reported even from tumors measuring less than 0.5 cm [28]. The 5-year survival rate is 60% for patients who have localized disease, 73% for those who have regional metastases, and 21% for patients who have distant metastases [2]. Mesenteric fibrosis and associated ischemia, caused by a characteristic desmoplastic reaction, is often present in association with small bowel carcinoids. These tumors are also frequently associated with buckling or tethering of the intestine caused by extensive mesenteric involvement [30,32]. Resection of the small bowel primary tumor, together with associated mesenteric metastases, leads to significant reduction in tumor-related symptoms of pain and obstruction and is therefore recommended even in patients who have known metastatic disease [29]. Appendiceal Carcinoid Tumors Historically, carcinoid tumors have been considered the most common tumor of the appendix, accounting for more than 50% of all appendiceal malignancies and discovered in up to 7 of every 1000 appendectomy specimens [33–35]. In older surgical series, appendiceal carcinoids were most commonly discovered during incidental appendectomy for other reasons. The most common indication for appendectomy in a 1968 series of 137 appendiceal carcinoid tumors was benign pelvic disease (43%) or gallbladder disease (35%) [2]. In recent series, however, most appendiceal carcinoids are discovered during surgery for acute appendicitis [36]. The carcinoid tumor itself is believed to be the cause

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of appendicitis in only a minority of these cases. Approximately two thirds of appendiceal carcinoid tumors arise in the tip of the appendix, where they are unlikely to cause symptoms of obstruction. Less than 10% arise in the base, where they are more prone to obstruct the appendix, giving rise to acute appendicitis [35,37]. Patients who have appendiceal carcinoid tumors generally present at a relatively young age: the mean age at presentation in the recent SEER database analysis was 49 years and in earlier series was even younger [2,35]. Although the early age at presentation may in part reflect the mean age at appendectomy, other explanations have also been proposed. Some investigators have speculated that the pattern of appendiceal carcinoid tumors parallels the biologic behavior of subepithelial neuroendocrine cells, from which appendiceal carcinoid tumors are believed to arise. The density of these cells tends to peak in the third decade of life and subsequently decreases throughout the remainder of life [38–40]. Appendiceal carcinoids are more common in women than in men: in the SEER database, the male to female ratio was 0.82 [2]. The higher incidence of appendiceal carcinoids in women, like the relatively young age at presentation, may be in part attributable to appendectomy patterns. Women are more likely to undergo incidental appendectomy as a result of gynecologic procedures. A female preponderance of appendiceal carcinoids has also been reported in children, however, an observation that cannot be explained by differences in appendectomy rates [41–43]. The clinical behavior of appendiceal carcinoid tumors can be predicted based on the size of the tumor. More than 95% of appendiceal carcinoid tumors are less than 2 cm in diameter [35,44]. The incidence of metastatic disease in such patients is extraordinarily low, although rare cases have been reported in the literature [37,44–48]. In contrast, approximately one third of patients who have appendiceal carcinoid tumors measuring more than 2 cm in diameter have either nodal or distant metastases [49]. Other criteria, such as nodal invasion, perineural invasion, tumor location, and histologic pattern, have not consistently correlated with the presence of metastatic disease. The surgical management of appendiceal carcinoids derives from these historical data, and surgical recommendations are based on tumor size. Based on the low incidence of metastases in patients whose tumors measure less than 2 cm, simple appendectomy is believed to be sufficient in such cases. In contrast, the higher incidence of metastases in patients whose tumors measure more than 2 cm in diameter has led to the recommendation for complete right hemicolectomy in this instance. These recommendations are supported by data from surgical series, one of the largest of which was published by Moertel and colleagues [49]. Among 122 patients undergoing simple appendectomy for tumors measuring less than 2 cm, none developed disease recurrence, whereas 1 of 12 patients undergoing simple appendectomy for a tumor measuring more than 2 cm developed a local recurrence. Whether right colectomy decreases the risk for future distant recurrence has not been formally evaluated,

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and simple appendectomy may at times be appropriate for larger tumors, particularly in older patients or patients who have other comorbidities. Rectal Carcinoid Tumors Rectal carcinoid tumors compose 1% to 2% of all rectal tumors and are most common in the sixth decade of life [50]. Approximately 50% are asymptomatic and found on routine endoscopy [51]. Symptomatic patients usually present with rectal bleeding, pain, or constipation [51,52]. The size of the primary lesion correlates closely with the probability of metastases, which occur in less than 5% of tumors measuring less than 1 cm but in most lesions greater than 2 cm [52,53]. Tumors less than 1 cm compose two thirds of rectal carcinoid tumors and are successfully treated with local excision. The management of tumors measuring 1 to 2 cm is controversial. Although most tumors of this size can be managed with local excision, several authors have suggested that the presence of muscular invasion, symptoms at diagnosis, or ulceration are poor prognostic factors that warrant more extensive surgical procedures [51–53]. Endoscopic ultrasound, particularly in cases in which an endoscopic removal has been performed, may be helpful to ensure that all submucosal tumor has been removed. Tumors measuring greater than 2 cm have traditionally been managed with low anterior resection or abdominoperineal resection. The value of these procedures in the management of rectal carcinoids has been questioned, however, as they do not seem to result in a survival advantage when compared with retrospective series [54–56]. An individualized approach, taking into account patient age and other comorbidities, may therefore be appropriate in deciding on a surgical approach to large rectal carcinoids. MANAGEMENT OF METASTATIC CARCINOID TUMORS Imaging Techniques Patients in whom metastatic disease is suspected are generally first evaluated with an abdominal CT scan to rule out liver metastases. Liver function tests are an unreliable indicator of tumor involvement, and the serum alkaline phosphatase is frequently normal despite extensive liver involvement by carcinoid tumor. Carcinoid liver metastases are often hypervascular, and may become isodense relative to the liver with the administration of intravenous contrast. CT scans should thus be performed both before and after the administration of intravenous contrast agents [57,58]. Magnetic resonance imaging may be helpful in cases in which CT findings are equivocal. More than 90% of carcinoid tumors contain high concentrations of somatostatin receptors and can be imaged with a radiolabeled form of the somatostatin analog octreotide (111-indium pentetreotide) [59–61]. The uptake of radiolabeled octreotide is also predictive of clinical response to therapy with somatostatin analogs. The sensitivity of this technique seems to be higher for extrahepatic than for hepatic lesions, presumably because of heterogeneous octreotide uptake in normal liver [62,63]. In one series, for example, octreotide

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scintigraphy detected 12 of 12 known extrahepatic lesions but only 12 of 24 hepatic lesions [62]. Greater sensitivity for hepatic lesions may be achieved by the use of single photon emission computed tomography imaging [64,65]. Tumor Markers Because of the often indolent nature of carcinoid tumors, patients who have metastatic disease who are asymptomatic can sometimes be closely monitored without treatment. The serial measurement of tumor markers may be helpful in these cases to monitor disease progression and also to subsequently monitor treatment response. The serial measurement of the serotonin metabolite 5-hydroxyindoleacetic acid (HIAA) in 24-hour urine collections has been commonly used for monitoring patients who have metastatic carcinoid tumors. Although elevated urinary 5-HIAA levels are highly specific for carcinoid tumors, they are not particularly sensitive; in one study, only 73% of patients who had metastatic carcinoid tumors had elevated levels [66]. Furthermore, 5-HIAA levels are generally elevated in patients who have primary midgut carcinoid tumors but are not useful in patients who have either foregut (bronchial, gastric) or hindgut (rectal) carcinoid tumors, which do not secrete serotonin. The use of urinary 5-HIAA levels can also be limited by false positives. The normal rate of 5-HIAA excretion ranges from 2 to 8 mg/d (10 to 42 lmol/d). Values of up to 30 mg/d (157 lmol/d) may be found in patients who have malabsorption syndromes, such as celiac and Whipple9s disease, and after the ingestion of large amounts of tryptophan-rich foods. Although some patients who have the carcinoid syndrome have similar modest elevations, most have values for urinary 5-HIAA excretion greater than 100 mg/d (523 lmol/d) [67]. Another tumor marker, chromogranin A (CgA) is a 49-kD protein that is contained in the neurosecretory vesicles of neuroendocrine tumor cells and is detectable in the plasma of patients who have endocrine neoplasms. Because it does not rely on serotonin secretion, serum chromogranin A is a more sensitive and broadly applicable marker than urinary 5-HIAA and may be used not only in patients who have metastatic small bowel and appendiceal carcinoid tumors but also in patients who have bronchial and rectal carcinoid tumors in whom urinary 5-HIAA levels are less likely to be elevated [68,69]. Plasma CgA levels have also been shown to correlate with treatment response and may also have prognostic value; in one series of 71 patients who had metastatic carcinoid tumors, CgA levels of more than 5000 lg/mL were independently associated with poor prognosis [69]. Somatostatin Analogs and Alpha Interferon Often, patients first become symptomatic with symptoms of hormonal hypersecretion rather than symptoms related to tumor bulk. This is especially true for patients who have small bowel or appendiceal carcinoid tumors, in whom symptoms are typically absent until hepatic metastases supervene, and the secretion of serotonin and other vasoactive substances into the systemic circulation results in the carcinoid syndrome. This syndrome is characterized by

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episodic flushing, secretory diarrhea, and the development of wheezing and right-sided valvular heart disease. The carcinoid syndrome, and other hormonal syndromes associated with neuroendocrine tumors, can often be well controlled with somatostatin analogs. Somatostatin is a 14–amino acid peptide that inhibits the secretion of a broad range of hormones and acts by binding to somatostatin receptors, which are expressed on most neuroendocrine tumors [70]. In an initial study, the subcutaneous administration of the somatostatin analog octreotide, administered at a dosage of 150 lg three times a day, improved the symptoms of carcinoid syndrome in 88% of patients [71]. More recently, the use of a long-acting depot form of octreotide, which can be administered monthly, has largely obviated the need for patients to inject themselves daily. Long-acting octreotide is typically initiated at a dose of 20 mg IM after a brief trial of the short-acting formulation, with gradual escalation of the dose as needed for optimal control of symptoms [72]. Patients may, in addition, use additional short-acting octreotide for breakthrough symptoms. Lanreotide is another somatostatin analog that has been used for the management of carcinoid syndrome [73–77]. A randomized study of lanreotide SR versus octreotide in 33 patients who had carcinoid syndrome demonstrated equivalent efficacy for symptom control and reduction in tumor cell markers [75]. The addition of alpha interferon to therapy with somatostatin analogs has also been reported to be effective in controlling symptoms in patients who have the carcinoid syndrome who may be resistant to somatostatin analogs alone [78,79]. The ability of interferon alfa (IFNa) to stimulate T-cell function and to control the secretion of tumor products led to its initial use in patients who had the carcinoid syndrome [80]. Therapy with low-dose alpha interferon has been reported to result in biochemical responses in approximately 40% of patients who have metastatic neuroendocrine tumors [81]. In clinical trials, doses of alpha interferon have ranged from 3 to 9 MU subcutaneously, administered from three to seven times per week. IFNa is somewhat myelosuppressive, and the dose is often titrated in individual patients to achieve a total leukocyte count of 3000/lL. The more widespread acceptance of alpha interferon in the treatment of metastatic neuroendocrine tumors has been limited by studies challenging its efficacy and the potential for side effects, which may include myelosuppression, fatigue, and depression [82]. The direct antineoplastic effects of somatostatin analogs either with or without interferon remain uncertain, and the use of these agents in patients who are not symptomatic of hormonal hypersecretion remains controversial [83]. The comparable efficacy of lanreotide, alpha interferon, or combined therapy was evaluated in a prospective randomized trial involving 80 therapy-naive patients who had documented progressive metastatic neuroendocrine tumors [77]. The rates of objective partial response (4%, 4%, and 7% for lanreotide, IFN, and combined therapy, respectively) were low in all three groups; however, treatment resulted in apparent disease stabilization in a higher proportion of patients (28%, 26%, and 18%, respectively). At 3, 6, and 12 months, rates of objective

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partial response were low (3%, 2%, and 6%), but several patients had stable disease (45%, 28%, and 16%, respectively). Randomized trials of these agents with nontreatment control arms have not yet been performed. Surgical Management of Carcinoid Disease Carcinoid heart disease Carcinoid heart disease occurs in approximately two thirds of patients who have the carcinoid syndrome [84]. Carcinoid heart lesions are characterized by plaquelike, fibrous endocardial thickening that classically involves the right side of the heart and often causes retraction and fixation of the leaflets of the tricuspid and pulmonary valves. Tricuspid regurgitation is a nearly universal finding; tricuspid stenosis, pulmonary regurgitation, and pulmonary stenosis may also occur [85]. Left-sided heart disease occurs in less than 10% of patients [86,87]. The preponderance of lesions in the right heart suggests that carcinoid heart disease is related to factors secreted by liver metastases into the hepatic vein. Among patients who have carcinoid syndrome, patients who have heart disease exhibit higher levels of serum serotonin and urinary 5-HIAA excretion than patients who do not have heart disease [84,86–89]. Other investigators have suggested that high atrial natriuretic peptide may also contribute to the pathogenesis of this disease. Whether these factors are directly responsible for the cardiac lesions, however, is unclear. Treatment with somatostatin analogs resulting in decreased serotonin secretion may not prevent the development of carcinoid heart disease and does not result in regression of cardiac lesions [87,88]. The indolent nature of metastatic carcinoid, combined with the availability of effective treatments for carcinoid syndrome, has led to interest in valve replacement surgery for selected patients. Right-sided heart failure in such patients may lead to significant morbidity and mortality. In early series, valvular replacement in patients who had symptomatic carcinoid heart disease has been associated with relatively high perioperative morbidity [90,91]. Surviving patients, however, seem to achieve significant symptomatic improvement, and more advanced techniques may facilitate the future use of valve replacement surgery in carcinoid patients [92]. Surgical resection of hepatic metastases The predominant site of metastatic spread in patients who have neuroendocrine tumors involving the GI tract is the liver. In patients who have a limited number of hepatic metastases, surgical resection has resulted in long-term survival and significant palliation of symptoms [93–95]. In one series of 74 patients undergoing hepatic resection for metastatic disease, more than 90% experienced symptomatic relief and the 4-year survival rate exceeded 70% [93]. Liver transplantation The number of patients who had liver-isolated metastatic disease in whom liver transplantation (OLT) has been attempted is small, and its role in such patients remains unclear [96–98]. Most series have reported high rates of perioperative

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mortality and early tumor recurrence. One multicenter European study reported a 5-year survival rate of 36% among highly selected patients who had metastatic carcinoid tumors [97]. Because many patients who have metastatic carcinoid may have indolent disease and encouraging 5-year survival rates without treatment, however, it is difficult to assess the impact of hepatic transplantation in this population. Hepatic artery chemoembolization Hepatic arterial embolization may be used as a palliative technique in patients who have hepatic metastases who are not candidates for surgical resection. Hepatic artery embolization is based on the principle that tumors in the liver derive most of their blood supply from the hepatic artery, whereas healthy hepatocytes derive most of their blood supply from the portal vein. Embolization of the hepatic arterial blood supply can be performed with or without the concurrent injection of chemotherapy. The response rates associated with embolization, as measured either by decrease in hormonal secretion or by radiographic regression, are generally greater than 50% [99–108]. The duration of response can be brief, however, ranging from 4 to 24 months in uncontrolled series [100,103]. In one of the largest series of 81 patients undergoing embolization or chemoembolization for carcinoid tumor, the median duration of response was 17 months and the probability of progression-free survival at 1, 2, and 3 years was 75%, 35%, and 11%, respectively [103]. Early studies reported a significant incidence of postembolization complications, which included renal failure, hepatic necrosis, and sepsis. Improved techniques have, in recent years, reduced the incidence of such complications, making embolization an important and generally safe treatment option for patients who have neuroendocrine tumors [103]. Radiofrequency ablation and cryoablation Other approaches to the treatment of hepatic metastases have included the use of radiofrequency ablation (RFA) and cryoablation, either alone or in conjunction with surgical debulking. These approaches can be performed using a percutaneous or laparoscopic approach. Although they seem to be less morbid than either resection or hepatic artery embolization, their long-term efficacy, particularly in patients who have large-volume hepatic disease, is not clearly established. Most published reports are small case studies of fewer than 40 patients [109]. In one series, 31 symptomatic patients who had metastatic carcinoid, islet cell tumor, or medullary thyroid cancer, underwent resection, cryosurgery, or RFA [110]. Symptoms were eliminated in 27 (87%), and 16 had progressive or recurrence disease with a median follow-up of 26 months. Cytotoxic Chemotherapy Cytotoxic chemotherapy has contributed in only a limited fashion to the treatment of patients who have metastatic carcinoid tumors (Table 4) [111–119]. Studies of single-agent therapy with 5-fluorouracil, streptozocin, or doxorubicin

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Table 4 Selected trials of cytotoxic chemotherapy regimens in patients who have advanced carcinoid tumors Regimen

Patients, n

Response rate, %

Streptozocin/ cyclophosphamidea Streptozocin/5FUa Dacarbazine

47

26

42 15

33 13

81 80 7 17 56

21 22 14 12 30

24 10 15 56 9 24 21 19 88 88 70

8 0 14 16 11 8 0 0 15.9 16 8.2

Doxorubicina Streptozocin/5FUa Streptozocin Etoposide Streptozocin/5FU/ doxorubicin/ cyclophosphamide Streptozocin/5FU Streptozocin/5FU 5FU/doxorubicin/cisplatin Dacarbazine Dacarbazine/5FU/leucovorin Paclitaxel Docetaxel Gemcitabinb 5FU/doxorubicina 5FU/streptozocina Dacarbazinea a b

Study Moertel and Hanley [121] (1979) Moertel et al [111,112,120] (1983) Engstrom et al [122] (1984) Oberg et al [113] (1987) Kelsen et al [152] (1987) Bukowski et al [123] (1987)

Oberg et al [113] (1987) Oberg et al [114] (1989) Rougier et al [115] (1991) Bukowski et al [124] (1994) Ollivier et al [116] (1998) Ansell et al [128] (2001) Kulke et al [117] (2004) Kulke et al [118] (2004) Sun et al [119] (2005)

Denotes a randomized trial. Included patients who have both carcinoid and pancreatic endocrine tumors.

have shown that these agents are associated with response rates of approximately 20% [120]. Combination chemotherapy does not seem to be significantly superior to single-agent therapy in the treatment of patients who have metastatic carcinoid tumors. In an initial trial, the Eastern Oncology Cooperative Group (ECOG) randomized 118 patients to receive streptozocin combined with either 5-flurouracil or cyclophosphamide [121]. Response rates, as measured either by tumor regression or a decrease in urinary 5-HIAA levels, were 33% for strepotozicin/ 5-fluorouracil and 26% for streptozocin/cyclophosphamide. There was no difference in survival between the two groups, and both regimens were associated with significant toxicity. In an attempt to decrease the toxicity associated with 5fluorouracil and streptozocin, the ECOG in a subsequent trial increased the dosing interval between cycles of streptocin/5-fluorouracil and compared this regimen to doxorubicin alone [122]. Although these regimens were better tolerated, the response rate for streptozocin and 5-fluorouracil dropped to 22%, as compared with only 21% for doxorubicin alone. The median survival

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duration for patients randomized to streptozocin and 5-fluourouracil was 14 months as compared with 11 months for patients randomized to doxorubicin. This survival difference was not statistically significant. Most recently, streptozocin/5-fluorouracil was compared with streptozocin/doxorubicin in a randomized trial of 73 patients. The response rate associated with the two regimens were similar (16% versus 15.9%), although there was a slight survival benefit associated with streptozocin/5- fluorouracil. A four-drug combination of 5-fluorouracil, doxorubicin, cyclophosphamide, and streptozotocin was evaluated by the Southwest Oncology Group in 56 patients [123]. This regimen resulted in a response rate of 31% and was therefore not believed to be superior to the previously tested regimen of streptozotocin/5-fluorouracil (Table 4). Dacarbazine (DTIC) has been evaluated as a potential alternative to streptozocin-based therapy in carcinoid and pancreatic endocrine tumors. A Southwest Oncology Group study reported that treatment with DTIC was associated with an objective radiologic response rate of 16% in 56 patients who had metastatic carcinoid tumors [124]. In an ECOG study evaluating the efficacy of DTIC in patients who had failed either streptozocin/5- fluorouracil or streptozocin/doxorubicin, the overall response rate was 8%. The addition to 5-fluorouracil and epirubicin to DTIC (FDE) does not seem to further enhance antitumor activity beyond that seen with DTIC alone and has been associated with an objective response rate of 25% in a heterogeneous group of patients who had advanced neuroendocrine tumors [125]. Patients who have poorly differentiated neuroendocrine tumors have been previously reported to be more responsive to cytotoxic chemotherapy than patients who have well-differentiated tumors. In an initial study, a combination of cisplatin and etoposide commonly used for small cell lung cancer was associated with an overall tumor response rate of 67% in 18 patients who had ‘‘anaplastic’’ neuroendocrine tumors (presumably analogous to poorly differentiated neuroendocrine tumors), but had little activity in more well-differentiated tumor subtypes [126]. In a subsequent study of 36 patients who had advanced neuroendocrine tumors, treatment with cisplatin and etoposide was associated with an overall radiologic response rate of 36% and a median survival time of 19 months. All patients enrolled in this study had either poorly differentiated histology or a rapidly progressing clinical course, suggesting that few if any of these patients had more classic, indolent carcinoid or pancreatic endocrine tumors [127]. Newer chemotherapeutic agents have, to date, proved relatively inactive in neuroendocrine tumors. High dose paclitaxel, administered with granulocytecolony stimulating factor, was evaluated in 24 patients who had metastatic carcinoid and islet cell tumors [128]. Significant hematologic toxicity was observed, and the objective radiologic response rate was only 8%. Treatment with docetaxel was associated with biochemical responses but no radiologic responses in a recent phase II trial of 21 patients who had carcinoid tumors [129]. No responses were observed in 19 neuroendocrine tumor patients treated with gemcitabine [130].

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Novel Treatment Approaches for Metastatic Carcinoid Tumors The modest efficacy of current systemic treatment regimens has led to interest in the development of novel therapeutic approaches for patients who have advanced neuroendocrine tumors. Such approaches include the use of radiolabeled somatostatin analogs and regimens incorporating angiogenesis inhibitors and small molecule tyrosine kinase inhibitors. Radiolabeled somatostatin analogs One novel strategy includes the therapeutic use of radiolabeled somatostatin analogs [131–139]. Scintigraphy with indium-111labeledd octreotide has been commonly used to localize previously undetected primary or metastatic neuroendocrine tumor lesions. At higher doses, indium-111–labeled octreotide has also been evaluated as a potential novel therapeutic; unfortunately, objective response rates with this agent have been low [140]. More encouraging results have been obtained with octreotide coupled to yttrium-90, a high-energy beta particle emitter. In early phase II trials, objective radiologic responses have been noted in up to 23% of patients who have metastatic neuroendocrine tumors [136,141]. The longer-term usefulness of this agent, however, seems to be limited by renal and hematologic toxicity [142]. Most recently, octreotide labeled with Lu-177, a low-energy beta particle emitter, has been evaluated in a phase I study with encouraging results. In one series, 131 patients who had somatostatin receptor–positive advanced neuroendocrine tumors received 177Lu-octreotate administered every 6 to 10 weeks, to a final intended dose of 600 to 800 mCi [139]. There were 35 objective responses (27%), three of which were complete. Benefit has also been suggested for local tumor irradiation with 131I-metaiodobenzylguanidine (131I-MIBG) [143,144]. MIBG is a compound resembling norepinephrine that can be accumulated by neuroendocrine cells. One limitation of this strategy is that not all patients who have metastatic carcinoid have evidence of MIBG uptake, limiting the number of patients potentially eligible for treatment. In one retrospective series, biochemical (5-HIAA) responses were observed in 37% of carcinoid patients treated with MIBG, and 15% had radiographic responses to therapy [144]. Radiographic response did not, however, correlate with improved survival. Recombinant human endostatin Carcinoid tumors are characterized by abundant vasculature and high levels of plasma vascular endothelial growth factor (VEGF) [145]. Recombinant human endostatin (rhEndostatin), a 20-kD protein derived from collagen XVIII, has been shown to inhibit endothelial cell proliferation and inhibit tumor growth in preclinical models. In one study, performed in a mouse model, treatment with the angiogenesis inhibitors angiostatin and endostatin reduced the tumor burden of pancreatic islet cell tumors by 60% [146]. These early observations were confirmed in a phase I human safety study, in which treatment with rhEndostatin resulted in a 17% decrease in tumor size in a patient who had metastatic pancreatic endocrine tumor [147]. In a subsequent phase II study

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involving patients who had advanced pancreatic endocrine tumors and carcinoid tumors, rhEndostatin was administered by subcutaneous injection twice a day. In a preliminary analysis of the results from this study, 2 of 36 evaluable patients had experienced minor radiologic responses and 23 (64%) patients experienced stable disease as their best response to therapy [148]. Thalidomide Thalidomide is postulated to have antiangiogenic activity through its ability to interfere with the VEGF and bFGF pathways, and was associated with apparent disease stabilization in a small phase II study of patients who had metastatic neuroendocrine tumors. Thalidomide was combined with temozolomide, an oral analog of DTIC, in a phase II study of 30 patients who had metastatic neuroendocrine tumors. In a preliminary analysis of 25 evaluable patients, 36% had experienced decreases in chromogranin A levels of more than 50% and 20% had experienced objective radiologic tumor responses [149]. The relative contributions of thalidomide and temozolomide to the antitumor activity observed in this study, however, are uncertain. Bevacizumab Bevacizumab is a humanized monoclonal antibody targeting VEGF. In a phase II trial, 44 patients who had advanced or metastatic carcinoid tumors on a stable dose of octreotide were randomly assigned to bevacizumab or pegylated IFN alfa 2b [150]. In a preliminary report of 35 patients completing 18 weeks of therapy, treatment with bevacizumab was associated with a sustained decrease in tumor perfusion by functional CT; furthermore, 3 of 18 patients treated with bevacizumab experienced radiographic partial responses. After 18 weeks, 95% of patients treated with bevacizumab remained progression free compared with only 67% of patients treated with IFN. Sunitinib (SU11248) Sunitinib (SU11248, Sutent) is an orally active, multitargeted tyrosine kinase inhibitor that specifically inhibits the VEGF receptor (VEGFR), the platelet-derived growth factor receptor, and c-kit. Antitumor efficacy associated with sunitinib was suggested in a preliminary report of a phase II study in which patients who had unresectable neuroendocrine tumors received sunitinib administered daily for 4 of every 6 weeks). Among 39 patients who had carcinoid tumors, there were 2 partial responses (5%), and prolonged periods of stable disease in 36 (92%) [151]. SUMMARY The generally indolent nature of neuroendocrine tumors is an advantage in the management of patients who have localized disease, and surgery alone is often curative in such cases. This same property presents a challenge in the treatment of patients who have metastatic disease, in whom standard cytotoxic chemotherapy has only limited benefit. In such patients, the use of somatostatin analogs, interferon, and the treatment of hepatic metastases may provide effective

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palliation. The highly vascular nature of carcinoid tumors has recently led to the investigation of antiangiogenic agents in this setting. Preliminary reports of activity associated with agents targeting the VEGF pathway in patients who have metastatic carcinoid tumors suggest that such strategies may play a role in the future treatment of patients who have this disease. Acknowledgments The author would like to thank Taylor S. Spear for invaluable assistance in the preparation and editing of the manuscript. References [1] Oberndorfer S. Karzinoide Tumoren des Dunndarms. Frankfurter Zeitschrift fur Pathologie 1907;1:425–9 [in German]. [2] Modlin I, Lye K, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003;97:934–59. [3] Berge T, Linnell F. Carcinoid tumors: frequency in a defined population during a 12-year period. Acta Pathol Microbiol Scand [A] 1976;84:322–30. [4] Godwin J. Carcinoid tumors: an analysis of 2837 cases. Cancer 1975;36:560–9. [5] Harpole D, Feldman J, Buchanan S, et al. Bronchial carcinoid tumors: a retrospective analysis of 126 patients. Ann Thorac Surg 1992;54:50–5. [6] Vadasz P, Palffy G, Egervary M, et al. Diagnosis and treatment of bronchial carcinoid tumors: clinical and pathological review of 120 operated patients. Eur J Cardiothorac Surg 1993;7:8–11. [7] Torre M, Barberis M, Barbieri B, et al. Typical and atypical bronchial carcinoids. Respir Med 1989;83:305–8. [8] Okike N, Bernatz P, Woolner L. Carcinoid tumors of the lung. Ann Thorac Surg 1976;22: 270–7. [9] Fink G, Krelbaum T, Yellin A, et al. Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from literature. Chest 2001;119(6): 1647–51. [10] Rea F, Binda R, Spreafico G, et al. Bronchial carcinoids: a review of 60 patients. Ann Thorac Surg 1989;47:412–4. [11] McCaughan B, Martini N, Bains M. Bronchial carcinoids: review of 124 cases. J Thorac Cardiovasc Surg 1985;89:8–17. [12] Chughtai T, Morin J, Sheiner N, et al. Bronchial carcinoid—twenty years’ experience defines a selective surgical approach. Surgery 1997;122:801–8. [13] Skuladottir H, Hirsch F, Hansen H, et al. Pulmonary neuroendocrine tumors: incidence and prognosis of hislogical subtypes. A population-based study in Denmark. Lung Cancer 2002;37(2):127–35. [14] Smolle-Juttner F, Popper H, Klemen H, et al. Clinical features and therapy of ‘‘typical’’ and ‘‘atypical’’ bronchial carcinoid tumors (grade 1 and grade 2 neuroendocrine carcinoma). Eur J Cardiothorac Surg 1993;7:121–5. [15] Marty-Ane C, Costes V, Pujol J, et al. Carcinoid tumors of the lung: do atypical features require aggressive management? Ann Thorac Surg 1995;59:78–83. [16] Mezzetti M, Raveglia F, Panigalli T, et al. Assessment of outcomes in typical and atypical carcinoids according to latest WHO classification. Ann Thorac Surg 2003;76(6): 1838–42. [17] Fiala P, Petraskova K, Cernohorsky S, et al. Bronchial carcinoid tumors: long-term outcome after surgery. Neoplasma 2003;50(1):60–5. [18] Schrevens L, Vansteenkiste J, Deneffe G, et al. Clinical-radiological presentation and outcome of surgically treated pulmonary carcinoid tumours: a long-term single institution expierence. Lung Cancer 2004;43(1):39–45.

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