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Activity of Sunitinib in Patients With Advanced Neuroendocrine Tumors

Matthew H. Kulke, Heinz-Josef Lenz, Neal J. Meropol, James Posey, David P. Ryan, Joel Picus, Emily Bergsland, Keith Stuart, Lesley Tye, Xin Huang, Jim Z. Li, Charles M. Baum, Charles S. Fuchs

From the Dana-Farber Cancer Institute; Massachusetts General Hospital; Beth Israel Deaconess Medical Center, Boston, MA; University of Southern California Norris Comprehensive Cancer Center, Los Angeles; University of California, San Francisco Comprehensive Cancer Center, San Francisco; Pfizer Global Research and Development, La Jolla, CA; Fox Chase Cancer Center, Philadelphia, PA; University of Alabama, Birmingham, AL; and Washington University, St Louis, MO

Corresponding author: Matthew Kulke, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, e-mail: Matthew_Kulke{at}dfci.harvard.edu

	ABSTRACT

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Purpose Standard cytotoxic chemotherapy has limited efficacy in metastatic neuroendocrine tumor patients. Neuroendocrine tumors express vascular endothelial growth factor (VEGF) and its receptor (VEGFR). Sunitinib malate, an oral tyrosine kinase inhibitor, has activity against VEGFRs as well as platelet-derived growth factor receptors, stem-cell factor receptor, glial cell line–derived neurotrophic factor, and FMS-like tyrosine kinase-3. We evaluated the efficacy of sunitinib in a two-cohort, phase II study of advanced carcinoid and pancreatic neuroendocrine tumor patients.

Patients and Methods Patients were treated with repeated 6-week cycles of oral sunitinib (50 mg/d for 4 weeks, followed by 2 weeks off treatment). Patients were observed for response, survival, and adverse events. Patient-reported outcomes were assessed.

Results Among 109 enrolled patients, 107 received sunitinib (carcinoid, n = 41; pancreatic endocrine tumor, n = 66). Overall objective response rate (ORR) in pancreatic endocrine tumor patients was 16.7% (11 of 66 patients), and 68% (45 of 66 patients) had stable disease (SD). Among carcinoid patients, ORR was 2.4% (one of 41 patients), and 83% (34 of 41 patients) had SD. Median time to tumor progression was 7.7 months in pancreatic neuroendocrine tumor patients and 10.2 months in carcinoid patients. One-year survival rate was 81.1% in pancreatic neuroendocrine tumor patients and 83.4% in carcinoid patients. No significant differences from baseline in patient-reported quality of life or fatigue were observed during treatment.

Conclusion Sunitinib has antitumor activity in pancreatic neuroendocrine tumors; its activity against carcinoid tumors could not be definitively determined in this nonrandomized study. Randomized trials of sunitinib in patients with neuroendocrine tumors are warranted.

	INTRODUCTION

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Carcinoid and pancreatic neuroendocrine tumors are characterized by indolent behavior, characteristic well-differentiated histologic features, and the ability to secrete neuropeptides resulting in characteristic clinical syndromes.¹ The most common of these is the carcinoid syndrome, which is associated with high serotonin levels, episodic flushing, diarrhea, and right-sided valvular heart disease.^2,3 When neuroendocrine tumors are diagnosed at an early stage, surgical resection is often curative.⁴ Unfortunately, curative surgery is rarely an option for patients with advanced disease.⁵

Palliative options for patients with advanced neuroendocrine tumors are limited. Approximately 90% of neuroendocrine tumors express somatostatin receptors.⁶ Although somatostatin analogs are effective in ameliorating hormonal secretion symptoms, they only rarely result in tumor regression.^7,8 Interferon alfa therapy has been associated with objective tumor responses in up to 10% of patients with advanced neuroendocrine tumors, but may be associated with fatigue, myelosuppression, and depression.⁹ Approximately one third of patients with pancreatic neuroendocrine tumors experience objective responses after therapy with streptozocin- or temozolomide-based combination chemotherapy regimens.^10-13 These regimens are less effective in patients with advanced carcinoid tumors; moreover, their prolonged use is often associated with toxicity.¹⁴

The highly vascular nature of neuroendocrine tumors led to initial interest in angiogenesis inhibition as a treatment modality in this disease.¹⁵ Overexpression of vascular endothelial growth factor (VEGF), together with VEGF receptor (VEGFR) subtypes, has been observed in both carcinoid and pancreatic endocrine tumors, suggesting that autocrine activation of the VEGF pathway may promote tumor growth.^16-18 Inhibition of VEGFR with function-blocking antibodies disrupted tumor growth in a mouse pancreatic neuroendocrine tumor model, providing further support for this hypothesis.¹⁹ A number of other signaling pathways have also been implicated in neuroendocrine tumors, which also express platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), insulin-like growth factor-1, insulin-like growth factor receptor, basic fibroblast growth factor, transforming growth factor and β, epidermal growth factor receptor, and stem-cell factor receptor.^20-28

Sunitinib malate (SUTENT; Pfizer Inc, New York, NY) is a small-molecule kinase inhibitor with activity against a number of tyrosine kinase receptors, including VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-, PDGFR-β, stem-cell factor receptor, glial cell line–derived neurotrophic factor receptor (rearranged during transfection), and FMS-like tyrosine kinase-3 (Pfizer Inc, data on file).^29-32 In a phase I trial of sunitinib, antitumor activity was reported in patients with renal call carcinoma (RCC) and GI stromal tumors (GIST) and in one of four patients with neuroendocrine tumors.³³ Subsequent trials in both RCC and GIST confirmed antitumor activity and safety in these tumor types,^34-37 leading to approval by the US Food and Drug Administration and the European Medicines Agency for use in advanced RCC patients who are treatment naïve or who experience relapse after interleukin-2 or interferon alfa treatment and in GIST patients after disease progression on or intolerance to imatinib therapy.

We performed a phase II, open-label, multicenter study to assess the safety and efficacy of sunitinib in patients with advanced neuroendocrine tumors. Eligible patients with carcinoid and pancreatic endocrine tumors received repeated 6-week treatment cycles of sunitinib administered at an oral dose of 50 mg once daily for 4 weeks, followed by 2 weeks off treatment. In light of the tumor regression observed in the phase I study, radiologic response was chosen as the primary end point of the present study. Patients were also observed for time to response/progression, survival, and toxicity. Patient-reported outcomes and drug exposure levels were assessed.

	PATIENTS AND METHODS

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Patients
Patients were enrolled at eight centers in the United States between March 2003 and November 2005. All patients had histologic evidence of carcinoid or pancreatic endocrine tumor and were not candidates for curative surgery. Patients with small-cell carcinoma were excluded. All patients had measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST)³⁸; an Eastern Cooperative Oncology Group performance status of 0 or 1; adequate hepatic, hematologic, and renal function; and either an echocardiogram or multiple-gated acquisition scan that demonstrated preserved left ventricular ejection fraction. Treatment with prior chemotherapy, embolization, or radiotherapy was permitted. Patients receiving stable doses of somatostatin analogs were allowed to continue receiving these treatments. Patients who had prior treatment with VEGF pathway inhibitors, known brain metastases, a history of cardiac arrhythmias, or evidence of myocardial ischemia or cerebrovascular accident within 12 months were excluded. All patients signed informed consent, and the study was approved by the institutional review boards of the participating institutions. The trial was registered (www.clinicaltrials.gov/ct/gui/show/NCT00056693) and performed in accordance with International Conference on Harmonization Good Clinical Practice guidelines, the Declaration of Helsinki (1996), and applicable local regulatory requirements and laws.

Study Treatment
Patients self-administered sunitinib at a starting dose of 50 mg by mouth daily for 4 weeks followed by 2 weeks off treatment in repeated 6-week cycles. In patients without significant toxicity, dose escalation to 62.5 mg and 75 mg was permitted (but not required) at the discretion of the investigator and after discussion with the study sponsor. Patients with significant grade 3 or 4 toxicities underwent dose reduction to 37.5 mg and 25 mg. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Concomitant treatment with drugs having dysrhythmic potential (terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, and indapamide) was not allowed.

Study Evaluations
Biochemical and hematologic parameters were assessed at baseline and every 2 weeks during the first cycle; thereafter, hematologic parameters were measured every 2 weeks, and biochemical parameters were measured on the first and last treatment days of each cycle. Multiple-gated acquisition or echocardiogram measurement of left ventricular ejection fraction was performed at screening and at the end of odd-numbered cycles.

Computed tomography or magnetic resonance imaging was performed at screening, at the end of cycle 1 and each odd-numbered cycle, if disease progression was suspected, and at study end or patient withdrawal, if a scan had not been performed within the previous 6 weeks. All responses were confirmed at least 4 to 6 weeks after initial documentation of response. Objective tumor response was assessed using RECIST.³⁸ Patients were observed after treatment discontinuation for survival status.

Blood samples for determination of predose (day 1) and trough (day > 1) concentrations of sunitinib and its active metabolite (SU12662) were collected on treatment days 1, 14, and 28 of cycles 1, 2, and 3, respectively; on day 1 of cycles 4; and at end of treatment.

General health-related quality of life was assessed using the EuroQol Group's EQ-5D self-report questionnaire,³⁹ and self-reported fatigue was assessed using the Functional Assessment of Chronic Illness Therapy (FACIT) –Fatigue scale.⁴⁰ Patients completed the EQ-5D assessment on days 1 and 28 of treatment cycles 1 to 6 and at end of treatment/withdrawal visit. Patients completed the FACIT-Fatigue assessment at baseline (cycle 1, day 1), weekly through cycle 4, and at the end of treatment.

Statistical Methods
This study used an open-label, two-cohort, Simon two-stage design⁴¹ to test the null hypothesis that the true objective response rate (ORR) was 5% versus the alternative hypothesis that the true response rate was 15%. Sixty-three patients were required in each cohort (carcinoid and pancreatic neuroendocrine tumor) to detect the response difference with 85% power and a significance level of 5%. In each cohort, 38 patients were treated in stage 1. If one objective tumor response was observed in the first 38 treated patients in either cohort, then enrollment in that cohort was to be terminated. However, if two objective tumor responses were observed in the first 38 treated patients, then the cohort was to be expanded to enroll 63 treated patients.

Secondary end points included time to objective tumor response (time from the first sunitinib dose to the first documentation of objective tumor response), time to tumor progression (TTP; time from the first sunitinib dose to the first documentation of objective tumor progression, initiation of other/additional anticancer therapy, or patient withdrawal as a result of unknown reasons), and overall survival (time from the first sunitinib dose to the date of death as a result of any cause). All time-to-event data (time to objective tumor response, TTP, and overall survival) were described using the Kaplan-Meier method.

	RESULTS

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Patient Characteristics and Treatment
Of the 109 enrolled patients, 107 (41 carcinoid patients and 66 pancreatic neuroendocrine tumor patients) were treated with sunitinib. Characteristics of treated patients are listed in Table 1. The median sunitinib doses administered in the carcinoid and pancreatic neuroendocrine cohorts were 50.0 mg (range, 28.0 to 53.9 mg) and 49.6 mg (range, 28.3 to 58.3 mg), respectively. Sixty-seven patients (62.6%) had at least one dosing interruption, 51 patients (47.7%) had a dose reduction, and three patients had dose increases to 62.5 mg daily. Of the 107 patients who began treatment, 94 (37 with carcinoid tumors and 57 with pancreatic tumors) received more than one treatment cycle, and 65 patients (24 with carcinoid tumors and 41 with pancreatic tumors) began five cycles of treatment (approximately 6 months). The median time on treatment was 7.2 months (range, 0.9 to 19.4 months). The median follow-up duration was 13.4 months, with a median duration of 15.1 months for patients with carcinoid tumors and 12.5 months for patients with pancreatic tumors. The most common reasons for treatment discontinuation were disease progression (n = 45), completion of therapy (n = 30; all 30 patients completed six cycles of therapy and continued therapy on a continuation protocol), withdrawal of consent (n = 20), and adverse events (AEs; n = 11). Of the patients who withdrew consent, 11 withdrew consent before initiation of their fifth treatment cycle, and nine withdrew consent after initiation of cycle 5.

AEs
Fatigue was the most common treatment-related AE and developed in 95 patients (88.8%) overall (Table 2). In most patients, fatigue was mild; 26 patients experienced grade 3 fatigue, and none experienced grade 4 fatigue. Other common AEs included diarrhea, nausea, dysgeusia, glossodynia, and skin discoloration. Hypertension, a toxicity also observed with other VEGF pathway inhibitors, was observed in 15.9% of the patient population and was more common among carcinoid patients (19.7%) than among patients with pancreatic neuroendocrine tumors (9.8%). Grade 3 hypertension was reported in 10.3% of patients; no incidents of grade 4 hypertension were reported. Treatment-related grade 4 AEs were reported infrequently and included GI hemorrhage (1.9%), pulmonary embolism (0.9%), increased lipase (0.9%), cardiac congestive failure (0.9%), cerebrovascular accident (0.9%), and hyponatremia (0.9%; Table 2). A single treatment-related death was caused by GI hemorrhage. Grade 3 or 4 neutropenia and thrombocytopenia developed in 33.7% and 8.4% of patients, respectively (Table 2). A higher incidence of grade 3 leukopenia was observed in patients with pancreatic tumors versus carcinoid cancers (18.2% v 7.3%, respectively; no grade 4 leukopenia was reported).

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Investigator-assessed maximum percent reduction in tumor lesions in patients with (A) carcinoid and (B) pancreatic neuroendocrine tumors. Patients delineated in gold (wider bars) were classified as having partial responses by Response Evaluation Criteria in Solid Tumors.

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Time to progression and (B) overall survival of patients receiving sunitinib.

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Quality of life of sunitinib-treated patients. (A) EQ-5D index, ranging from 0 (death) to 1 (perfect health). (B) EQ-5D visual analog scale (EQ-VAS), ranging from 0 (worst) to 100 (best imaginable self-assessed health state). (C) Functional Assessment of Chronic Illness Therapy (FACIT) –Fatigue scores, ranging from 0 (highly fatigued state) to 52 (no fatigue). C, cycle; D, day.

	DISCUSSION

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Our observation that sunitinib seems to be more active in pancreatic neuroendocrine tumors than in carcinoid tumors mirrors similar observations with more traditional cytotoxic agents. Streptozocin-based combination chemotherapy regimens, as well as regimens incorporating the alkylating agent dacarbazine or the oral analog temozolomide, have been associated with ORRs of 33% to 45% in pancreatic endocrine tumors.^10,11,42 ORRs with similar regimens in carcinoid tumors range from 7% to 16%.^11,14,43 In light of the often indolent nature of both carcinoid and pancreatic neuroendocrine tumors, the cumulative toxicities of these regimens (which include effects on renal, cardiac, and hematologic function) have limited their widespread acceptance in these patient populations.

The toxicity profile of sunitinib in our study was similar to that observed in trials of sunitinib in other disease types. The most common treatment-related toxicities were constitutional (fatigue and anorexia) or GI (diarrhea and nausea). Hypertension, a toxicity also observed with other inhibitors of the VEGF pathway, was observed in 15.9% of the patient population. Hypertension was more common in carcinoid patients than in patients with pancreatic neuroendocrine tumors (19.7% v 9.8%, respectively), a finding possibly related to concurrent secretion of vasoactive neuropeptides in some carcinoid patients. A higher incidence of grade 3 leukopenia in pancreatic neuroendocrine tumor patients than in patients with carcinoid cancers (18.2% v 7.3%, respectively) may be attributable to the greater number of pancreatic neuroendocrine tumor patients who had received prior systemic therapy, including cytoxic chemotherapy (Table 1).

The modest ORRs observed in our trial highlight the challenge of assessing the efficacy of an agent that may be largely cytostatic, particularly in a disease that is naturally indolent. In a randomized trial of sunitinib versus placebo in patients with imatinib-refractory GIST, for example, the ORR associated with sunitinib treatment was only 7%, yet treatment with sunitinib was associated with a significant improvement in TTP.³⁴ Our observation that the majority of patients with both carcinoid and pancreatic neuroendocrine tumors seemed to experience minor responses to therapy, classified as SD by RECIST, suggests that sunitinib may also delay TTP in neuroendocrine tumors. The median TTP in our trial exceeds 7 months in both patient cohorts, compared with values ranging from 3.2 to 7.6 months reported in other recent therapeutic trials in neuroendocrine tumor patients.^14,44,45 However, differences in patient selection and inherent variability in the natural history of neuroendocrine tumors make direct comparisons between these different trials difficult. The uncertainty surrounding the interpretation of tumor stability in this setting highlights the need for appropriately stratified randomized trials or, alternatively, validated surrogate markers of antitumor activity in this disease.

The mechanism of action of sunitinib in neuroendocrine tumors remains unclear. Inhibitors of the VEGF pathway are generally thought to exert their antitumor effects indirectly by targeting endothelial cells and inhibiting tumor angiogenesis.⁴⁶ In preclinical studies, VEGF inhibition alone has been associated with inhibition of tumor growth and metastases, although not necessarily tumor shrinkage.⁴⁷ For this reason, VEGF pathway inhibitors have generally been combined with standard cytotoxic chemotherapy in clinical trials.⁴⁸

In RCC, treatment with sunitinib was associated with an ORR of 40%, suggesting that direct inhibition of VEGF signaling in tumor cells may be an alternative mechanism of action in specific tumor type.^35,49 Like RCC, neuroendocrine tumors are both highly vascular and associated with high levels of VEGF and VEGFR expression. Additional mechanisms, including inhibition of PDGFR or other cell signaling pathways, may also have contributed to the antitumor activity in neuroendocrine tumors observed in this study.

Secondary end points in our study included quality-of-life assessment and assessment of fatigue using the EQ-5D and FACIT-Fatigue questionnaires, respectively. The relatively high number of patients who withdrew consent to participate in the study raises the possibility that treatment may have been associated with undue toxicity. However, the formal assessments suggest that treatment with sunitinib did not seem to cause significant changes from baseline in either quality-of-life or fatigue scores during the treatment period. These findings are consistent with a high incidence of SD but are also intriguing in light of the high incidence of fatigue reported as an AE. A similarly high incidence of fatigue was reported in a randomized trial of sunitinib versus placebo in patients with GIST.³⁴ In this study, the incidence of fatigue was similar in both the treatment and placebo groups, suggesting that a large proportion of reported fatigue may be attributable to tumor burden. It is possible that, in our study, tumor burden also accounted for the high incidence of reported fatigue. Alternatively, drug toxicities may have been, to some extent, balanced by treatment-related clinical benefit.

In conclusion, treatment with sunitinib resulted in objective tumor responses in patients with pancreatic neuroendocrine tumors. Whether sunitinib may also be associated with an antitumor effect in carcinoid tumors could not be clearly determined in this nonrandomized study. Further investigation of sunitinib in the randomized setting or in combination with other agents is warranted in these diseases.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Lesley Tye, Pfizer Inc (C); Xin Huang, Pfizer Inc (C); Charles M. Baum, Pfizer Inc (C) Consultant or Advisory Role: Matthew H. Kulke, Novartis (C); Heinz-Josef Lenz, Pfizer Inc (C); Neal J. Meropol, Pfizer Inc (C); Emily Bergsland, Genentech (C); Charles S. Fuchs, Roche (C), Sanofi-aventis (C), Pfizer Inc (C), AstraZeneca (C), Bristol-Meyers Squibb Co (C), Amgen Inc (C), Genentech (C) Stock Ownership: None Honoraria: None Research Funding: Heinz-Josef Lenz, Pfizer Inc Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Matthew H. Kulke, Charles M. Baum, Charles S. Fuchs

Provision of study materials or patients: Matthew H. Kulke, Heinz-Josef Lenz, Neal J. Meropol, James Posey, David P. Ryan, Joel Picus Picus, Emily Bergsland, Keith Stuart, Charles S. Fuchs

Collection and assembly of data: Lesley Tye, Xin Huang, Jim Z. Li, Charles M. Baum

Data analysis and interpretation: Matthew H. Kulke, Heinz-Josef Lenz, Neal J. Meropol, James Posey, David P. Ryan, Joel Picus Picus, Keith Stuart, Lesley Tye, Xin Huang, Jim Z. Li, Charles M. Baum, Charles S. Fuchs

Manuscript writing: Matthew H. Kulke

Final approval of manuscript: Matthew H. Kulke, Heinz-Josef Lenz, Neal J. Meropol, James Posey, David P. Ryan, Joel Picus Picus, Emily Bergsland, Keith Stuart, Lesley Tye, Xin Huang, Jim Z. Li, Charles M. Baum, Charles S. Fuchs

	Appendix

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Preliminary data from this study have previously been presented, as follows: Kulke M, Lenz HJ, Meropol NJ, et al: A phase 2 study to evaluate the efficacy and safety of SU11248 in patients (pts) with unresectable neuroendocrine tumors (NETs). J Clin Oncol 23:310, 2005 (suppl 16s; abstr 4008); Kulke M, Lenz H, Meropol N, et al: Results of a phase II study with sunitinib malate (SU11248) in patients (pts) with advanced neuroendocrine tumours (NETs). Eur J Cancer Supp 3:204, 2005 (abstr 718); Kulke MH, Lenz HJ, Meropol NJ, et al: Sunitinib malate (SU11248) is associated with clinical activity in patients with advanced neuroendocrine tumors. World Congress of Gastroenterology (Greenspan), Montreal, Canada, September 10-14, 2005 (abstr 331); Kulke MH, Lenz HJ, Meropol NJ, et al: Sunitinib malate (SU11248) in patients with advanced neuroendocrine tumors: A multicenter phase II study. Presented at the 23rd Annual Chemotherapy Foundation Symposium, New York, NY, November 2-5, 2005; Bello C, DePrimo SE, Friece C, et al: Analysis of circulating biomarkers of sunitinib malate in patients with unresectable neuroendocrine tumors (NET): VEGF, IL-8, and soluble VEGF receptors 2 and 3. J Clin Oncol 24:189s, 2006 (suppl; abstr 4045); and Kulke MH, Lenz HJ, Meropol NJ, et al: Clinical activity of SU11248 (sunitinib malate) in patients with advanced neuroendocrine tumors (NETs): Results of a phase II study. Presented at the 17th International Congress of Anti-Cancer Treatment, Paris, France, January 30-February 2, 2006.

	ACKNOWLEDGMENTS

 
We thank ACUMED (Tytherington, United Kingdom) and Taylor S. Spear for editorial assistance in the preparation of the manuscript and figures.

	NOTES

 
Supported by Pfizer Inc. M.H.K. acknowledges additional support from the Caring for Carcinoid Foundation, Dr Raymond and Beverly Sackler, and the Stephen and Caroline Kaufer fund for neuroendocrine tumor research.

Sources of preliminary data are listed in the Appendix available online.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted December 20, 2007; accepted April 7, 2008.

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