Original Article
Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors
N Engl J Med 2011; 364:501-513February 10, 2011
- Abstract
Background
The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials.
Methods
We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors–defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety.
Results
The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue.
Conclusions
Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.)
Media in This Article
Figure 1
Kaplan-Meier Analysis of Progression-free Survival and Overall Survival in the Intention-to-Treat Population and the Maximum Percent Change from Baseline in the Sum of the Longest Diameters of Target Lesions, According to Patient.Figure 2
Cox Proportional-Hazards Analysis of Progression-free Survival in Selected Subgroups, According to Baseline Characteristics in the Intention-to-Treat Population.Article Activity
- Article
Pancreatic neuroendocrine tumors are uncommon tumors arising from endocrine cells of the pancreas.1 Surgery is the mainstay of treatment for resectable disease,2 and therapy directed to the liver may have some palliative benefit for metastases that occur predominantly in the liver.3,4 Somatostatin analogues relieve symptoms resulting from hormone hypersecretion in functioning tumors and may delay disease progression in selected patients.5-7 Streptozocin alone or in combination with doxorubicin remains the only chemotherapeutic agent approved for the treatment of advanced pancreatic neuroendocrine tumors,8-11– though the magnitude of benefit has been challenged. 12,13
Vascular endothelial growth factor (VEGF) is a key driver of angiogenesis in pancreatic neuroendocrine tumors.14,15 Tissue from malignant pancreatic endocrine tumors also shows widespread expression of platelet-derived growth factor receptors (PDGFRs) α and β, stem-cell factor receptor (c-kit), and VEGF receptor (VEGFR)-2 and VEGFR-3.16-18 Sunitinib malate (Sutent, Pfizer) inhibits these kinases19,20 and delays tumor growth in a RIP1-Tag2 transgenic mouse model of pancreatic islet-cell tumors by reducing endothelial-cell density and pericyte coverage of tumor vessels.21,22 In phase 1 and 2 trials, sunitinib showed antitumor activity in patients with pancreatic neuroendocrine tumors.23,24 On the basis of these findings, we conducted a phase 3, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of continuous daily administration of sunitinib at a dose of 37.5 mg per day in patients with advanced pancreatic neuroendocrine tumors.
Methods
Patients
Eligible patients had pathologically confirmed, well-differentiated pancreatic endocrine tumors that were advanced, metastatic, or both,25,26 and they were not candidates for surgery. Additional inclusion criteria were the following: documented disease progression within the previous 12 months as assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST27); one or more measurable target lesions; an Eastern Cooperative Oncology Group performance status of 0 or 1 (with 0 indicating that the patient is fully active and 1 that the patient is restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature [e.g., light housework or office work]); and adequate hematologic, hepatic, and renal function. The Ki-67 index (the percentage of cells that were positive for Ki-67, determined by immunostaining of the primary tumor) was assessed at screening from available pathology reports. Patients with poorly differentiated pancreatic neuroendocrine tumors,25 previous tyrosine kinase or VEGF inhibitor treatment, cardiac events or pulmonary embolism in the previous 12 months, ongoing cardiac dysrhythmias or a prolonged QT interval corrected for heart rate (QTc), symptomatic brain metastases, or a left ventricular ejection fraction of 50% or less were excluded.
The trial was approved by the institutional review board or ethics committee at each center and complied with Good Clinical Practice guidelines, the Declaration of Helsinki, and local laws. All patients provided written informed consent.
Trial Design
This multinational, randomized, double-blind, placebo-controlled, phase 3 trial was funded by Pfizer. Patients were randomly assigned in a 1:1 ratio to receive once-daily oral sunitinib at a dose of 37.5 mg per day or matching placebo. In patients with other types of tumors, continuous administration of sunitinib at a dose of 37.5 mg per day is similar to intermittent administration with respect to the predicted blood level, safety profile, and time to tumor progression.28,29
Treatment interruptions and a dose reduction to 25 mg per day were permitted to manage adverse events, with a subsequent increase in dose if toxicity of grade 2 or higher did not recur. In patients without an objective tumor response who had grade 1 or lower nonhematologic or grade 2 or lower hematologic treatment-related adverse events during the first 8 weeks, the dose could be increased to 50 mg per day. Treatment continued until RECIST-defined progression was documented, unacceptable adverse events occurred, or the patient died. Patients with disease progression while receiving placebo could enter an open-label sunitinib extension protocol (A Treatment Protocol for Patients Continuing from Prior SU11248 Protocol, ClinicalTrials.gov number, NCT00443534, or A Continuation Study Using Sunitinib Malate for Patients Leaving Treatment on a Previous Sunitinib Study, NCT00428220). Before the trial, during the trial, or both, patients could receive somatostatin analogues at the investigator's discretion.
The trial was designed by Pfizer in conjunction with the investigators. Data collection and statistical analyses were performed by the sponsor. The initial draft of the manuscript was prepared by the first author in collaboration with the sponsor and professional medical writers paid by the sponsor. All authors had access to the data and contributed to subsequent drafts. The conduct of the trial was overseen by an independent data and safety monitoring committee that had access to safety and efficacy data. The academic authors vouch for the completeness and accuracy of the data, the data analyses, and the fidelity of this report to the study protocol (available with the full text of this article at NEJM.org).
Assessments and Outcomes
Data and patient-reported outcomes were recorded every 4 weeks (one cycle) during clinic visits. Clinical assessments, biologic measurements, and full tumor imaging were performed at screening; subsequent imaging was performed during week 5 and week 9 and every 8 weeks thereafter, whenever progression was suspected, and at the end of treatment or withdrawal from the study. Compliance and safety were assessed every 4 weeks and at the end of treatment.
The primary end point was progression-free survival, defined as the time from randomization to the first evidence of progression or death from any cause. For patients with inadequate baseline assessments, data on the progression-free survival time were censored on the date of randomization, with a 1-day duration.
Secondary efficacy end points included overall survival, the objective response rate, the time to tumor response, the duration of response, safety, and patient-reported outcomes. Tumor response was assessed by investigators with the use of RECIST. Confirmed responses were those that persisted on repeat imaging 4 weeks or more after initial documentation. Safety assessments included documentation of adverse events with the use of the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf), hematologic and biochemical laboratory tests, physical examination, and vital-sign measurements. The self-administered European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire (QLQ-C30, version 3.0) was used to measure patient-reported outcomes.30
Statistical Analysis
Efficacy was assessed in the intention-to-treat population on the basis of investigator-assessed tumor response. Kaplan-Meier methods were used to obtain estimates of median progression-free survival, with corresponding two-sided 95% confidence intervals. The Cox proportional-hazards model was used to calculate hazard ratios. A target sample of 340 patients was estimated on the basis of a total of 260 events required for 90% power to detect a 50% increase in progression-free survival with sunitinib from an estimated median progression-free survival of 5.1 months with placebo, with the use of a two-sided, unstratified log-rank test adjusted for one interim analysis after the first 130 events. The nominal significance level for the interim and final progression-free survival analyses was determined by means of the Lan-DeMets procedure with an O'Brien-Fleming stopping boundary, with an overall two-sided type I error rate of 5%. Exploratory regression analyses with the use of the Cox proportional-hazards model were performed to test the influence of baseline characteristics on progression-free survival. Fisher's exact test was used to compare the objective response rate between study groups. Overall survival was analyzed with the use of Kaplan-Meier methods. The duration of response and time to tumor response were analyzed with the use of descriptive statistics.
The QLQ-C30 questionnaire was scored with the use of the QLQ-C30 scoring manual31 and interpreted with the use of a minimally-important-difference approach.32 Patient-reported outcomes were analyzed with the use of a repeated-measures, mixed-effects model (which included all 15 QLQ-C30 scales and items). Safety was assessed in patients who received one or more doses of a study drug.
Results
Patients
Between June 2007 and April 2009, a total of 171 patients were randomly assigned to a study group. In February 2009, the data and safety monitoring committee convened for ongoing safety monitoring and assessed data on 154 patients who had undergone randomization up to that point. The committee recommended discontinuation of the trial because of the greater number of deaths and serious adverse events in the placebo group and the difference in progression-free survival favoring sunitinib; as a result of this recommendation, the trial was closed. The last patient received a study drug in April 2009; study-group assignments were revealed at that time, and patients were offered open-label sunitinib treatment in a separate trial (NCT00443534 or NCT00428220). A total of 44 patients in the sunitinib group and 59 patients in the placebo group entered these studies. Because of the early trial closure, 3 patients in the sunitinib group and 2 patients in the placebo group did not receive the study drug; in addition, 1 patient in the placebo group had a protocol violation and did not receive placebo (see Figure 1 in the Supplementary Appendix, available at NEJM.org).
Patients were enrolled at 42 centers in 11 countries. Baseline characteristics were similar between the two study groups (Table 1Table 1
Demographic and Baseline Characteristics of the Patients.).Study Treatment
Patients received sunitinib for a median duration of 4.6 months (range, 0.4 to 17.5), and patients received placebo for a median duration of 3.7 months (range, 0.03 to 20.2). Nineteen patients (22%) who were randomly assigned to sunitinib remained in the study for more than 1 year, as compared with four patients who were randomly assigned to placebo (5%).
The most common reasons for study discontinuation were disease progression (in 19 patients who received sunitinib [22%] and in 47 patients who received placebo [55%]), termination of the trial (in 41 patients who received sunitinib [48%] and in 16 patients who received placebo [19%]), and adverse events (in 15 patients who received sunitinib [17%] and in 7 patients who received placebo [8%]). The most common adverse events leading to discontinuation in the sunitinib group were fatigue (in 4% of patients) and diarrhea and cardiac failure (2% each).
The mean relative dose intensity (the proportion of administered doses relative to the number of planned doses at 37.5 mg daily) was 91.3% in the sunitinib group and 100.6% in the placebo group. One or more dose interruptions were reported in 30% and 12% of patients in the sunitinib and placebo groups, respectively. Adverse events were the primary reason for interruptions. Among patients who received sunitinib, the most commonly reported adverse events were neutropenia (in 12% of patients); diarrhea (10%); asthenia, erythrodysesthesia, and hypertension (7% each); and thrombocytopenia (6%). Among the patients who received placebo, the most commonly reported adverse events were abdominal pain, vomiting, and asthenia (each in 3% of patients). At least one dose reduction to 25 mg per day was reported in 31% and 11% of patients receiving sunitinib and placebo, with dose escalations to 50 mg per day in 10% and 24%, respectively.
Sixty-eight patients (31 patients in the sunitinib group and 37 patients in the placebo group) received treatment with a somatostatin analogue either before enrollment (30 patients who received sunitinib and 32 patients who received placebo) or during the study (23 patients who received sunitinib and 25 patients who received placebo), concomitantly with the study drug. Of the patients who had received treatment with a somatostatin analogue before enrollment, 22 of those in the sunitinib group and 20 of those in the placebo group continued the use of the somatostatin analogue during the study. A single patient in the sunitinib group and 5 patients in the placebo group began to receive a somatostatin analogue after study enrollment while they were already receiving a study drug.
Efficacy
Progression-free Survival
Among the 171 patients enrolled in the study, 81 primary outcome events (disease progression or death) were reported as of April 15, 2009 (Table 2). An improvement in progression-free survival with sunitinib was observed: median, 11.4 months as compared with 5.5 months with placebo (hazard ratio for disease progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001) (Figure 1AFigure 1
Kaplan-Meier Analysis of Progression-free Survival and Overall Survival in the Intention-to-Treat Population and the Maximum Percent Change from Baseline in the Sum of the Longest Diameters of Target Lesions, According to Patient.). The probability of progression-free survival at 6 months was 71.3% in the sunitinib group and 43.2% in the placebo group. The observed test statistic (z value) was 3.85, which did not exceed the z value of 3.88 (which was adjusted for three assessments of the data by the data-monitoring committee) that constituted the Lan-DeMets and O'Brien-Fleming efficacy boundary for statistical significance. Two sensitivity analyses for progression-free survival were performed, and the results provided support for the robustness of the primary analysis (Table 1 in the Supplementary Appendix).An exploratory analysis to determine the potential influence of patient and tumor characteristics on treatment effect showed that in all subgroups analyzed, the hazard ratio for progression or death favored sunitinib (Figure 2Figure 2
Cox Proportional-Hazards Analysis of Progression-free Survival in Selected Subgroups, According to Baseline Characteristics in the Intention-to-Treat Population.). Sunitinib improved progression-free survival as compared with placebo among patients with a Ki-67 index of 5% or less, with a trend toward a benefit among the few patients with a Ki-67 index of more than 5%.In a multivariate analysis, only the interval between diagnosis and randomization (≥3 years vs. <3 years) was a potential independent prognostic variable for progression-free survival (hazard ratio for progression or death, 0.60; 95% CI, 0.38 to 0.95; P=0.03). The progression-free survival advantage with sunitinib treatment versus placebo was greater with adjustment for the interval between diagnosis and randomization (hazard ratio, 0.37; 95% CI, 0.23 to 0.60; P<0.001).
Overall Survival
Nine deaths were reported in the sunitinib group (10%) and 21 deaths were reported in the placebo group (25%), and most patients were still in follow-up at the data cutoff point. The hazard ratio for death was 0.41 (95% CI, 0.19 to 0.89; P=0.02) in favor of sunitinib. Kaplan-Meier estimates are shown in Figure 1B and Table 2Table 2
Summary of Efficacy Measures in the Intention-to-Treat Population.; because of the relatively high number of censored events, median overall survival could not be estimated for either study group.Tumor Response
Eight patients who received sunitinib had a confirmed tumor response (two had complete responses and six had partial responses) (Figure 1C); the objective response rate was 9.3% (95% CI, 3.2 to 15.4). No objective responses were observed with placebo (Figure 1C) (P=0.007 for the between-group difference) (Table 2). Among patients with a tumor response, seven had nonfunctioning tumors and in one, tumor function was unknown; the median time to tumor response was 3.1 months (range, 0.8 to 11.1). The duration of response ranged from 0.9 to more than 15.0 months. Only one of the eight patients with a response had disease progression before trial closure.
Safety
The majority of adverse events in both groups were grade 1 or 2 in severity, with grade 3 or 4 events more common in patients who received sunitinib (Table 3Table 3
Common Adverse Events in the Safety Population.). The most common adverse events associated with sunitinib were diarrhea, nausea, asthenia, vomiting, and fatigue; each occurred in 30% or more of patients. Vomiting, asthenia, and fatigue occurred at similar rates in both groups; abdominal and back pain were more common in patients who received placebo. Palmar-plantar erythrodysesthesia and hypertension of any grade occurred in 23% and 26% of patients receiving sunitinib, respectively. The most common grade 3 or 4 adverse events in patients who received sunitinib were neutropenia (12%) and hypertension (10%). Hyperthyroidism was reported as an adverse event in two patients who received placebo, and hypothyroidism was reported as an adverse event in six patients who received sunitinib and in one patient who received placebo. All but one of these events were considered to be treatment-related, and all were grade 1 or 2 in severity and classified as nonserious. Overall, findings for thyroid function were consistent with those previously reported with the use of sunitinib.
Five patients who received sunitinib and nine patients who received placebo died during the trial period (from the first study-drug dose until 28 days after the last dose). The deaths were attributed to the disease under study, with the exception of grade 5 cardiac failure (in one patient who received sunitinib) and grade 5 dehydration (in one patient who received placebo), which were both considered to be related to the study drug. Other serious adverse events were less common in the sunitinib group than in the placebo group (26% of patients vs. 41%) (Table 2 in the Supplementary Appendix).
Quality of Life
EORTC QLQ-C30 data were available for 73 of 86 patients in the sunitinib group and 71 of 85 patients in the placebo group, and they were analyzed for the first 10 cycles. No overall difference was noted between study groups in global health-related quality of life; cognitive, emotional, physical, role, and social functioning; or in other symptoms and scales either at baseline or at any other time point (data not shown), with the exception of diarrhea.
In the repeated-measures, mixed-effects model, patients who received sunitinib had overall clinically and statistically significant worsening of diarrhea (difference, 21.4 points; P<0.001), and although statistically significant worsening of insomnia (P=0.04) was noted, the overall difference (7.8 points) was not clinically meaningful, with the use of the minimally-important-difference approach, in which a change or between-group difference of less than 10 points is not considered clinically significant.32
Discussion
In this randomized trial involving patients with advanced, progressive, well-differentiated pancreatic neuroendocrine tumors, median progression-free survival among patients who received sunitinib was more than twice that among patients who received placebo (11.4 vs. 5.5 months). The improvement in progression-free survival observed among patients who received sunitinib provides support for previous preclinical and clinical data suggesting that neuroendocrine tumors may be particularly sensitive to combined inhibition of VEGFRs and PDGFR.21,22,24 The trial was terminated early because of the risk of serious adverse events, disease progression, and death among patients receiving placebo. The objective response rate and overall survival also consistently favored sunitinib. Furthermore, improvement in progression-free survival among patients who received sunitinib, as compared with those who received placebo, was achieved without adversely affecting the quality of life and, per a recently reported post hoc analysis,33 was associated with a delay in the time to deterioration in the quality of life and emotional and physical functioning.
Although early termination of clinical trials may result in overestimation of the true treatment effect and in lower-than-anticipated numbers of enrolled patients, the magnitude of the observed treatment effect, the consistency of the hazard ratio for disease progression or death in the sensitivity analyses, and the favorable survival data in this trial all provide strong evidence of the clinically meaningful benefit of sunitinib. Moreover, results from a retrospective, blinded, independent central review of imaging studies in 49% of patients in this study (84 of 171 patients) provide support for the findings with respect to investigator-assessed progression-free survival (Figure 2 in the Supplementary Appendix).
The trial population was relatively unselected, with demographic characteristics and treatment history that are typical of patients with advanced pancreatic neuroendocrine tumors. When we examined outcomes according to baseline characteristics, previous systemic treatment, and prognostic factors in an exploratory subgroup analysis, the benefit of sunitinib extended across all subgroups, although the numbers of patients were small in some subgroups. The efficacy of sunitinib in our trial appears to be similar regardless of the number of previous treatments or previous exposure to somatostatin analogues. In addition, although numerical between-group differences were observed in some baseline characteristics, a post hoc analysis with the use of Fisher's exact test showed no significant differences in these baseline factors (Table 1); moreover, according to univariate and multivariate analysis, these factors had no effect on the progression-free survival benefit (data not shown).
The most frequent adverse events observed with continuous daily administration of sunitinib, including diarrhea, nausea, vomiting, asthenia, and fatigue, were consistent with those observed in previous trials of sunitinib,24,34 and rates of vomiting, asthenia, and fatigue were similar in the sunitinib and placebo groups in this study. Most sunitinib-related adverse events were manageable through dose interruption or modification.
The incidence of pancreatic neuroendocrine tumors is increasing, and the 5-year survival rate is below 43%.35,36 Our findings, which show the efficacy of sunitinib in pancreatic neuroendocrine tumors, are particularly important because of the limited number of effective treatment options for advanced disease. Somatostatin analogues,6,7 peptide-receptor radionuclide therapy,37,38 and inhibitors of the mammalian target of rapamycin39 have shown antitumor activity in pancreatic neuroendocrine tumors, and results from a phase 3 trial of everolimus are reported elsewhere in this issue of the Journal. 40
Our data show that rationally designed inhibition of VEGFR and PDGFR signaling with the use of sunitinib, given as a continuous daily dose, resulted in clinically meaningful improvements in progression-free survival, the objective-response rate, and overall survival among patients with pancreatic neuroendocrine tumors.
Presented in part at the meeting of the European Cancer Organization and European Society for Medical Oncology, Berlin, September 20–24, 2009, and at the American Society of Clinical Oncology Gastrointestinal Cancer Symposium, Orlando, FL, January 22–24, 2010.
Supported by Pfizer.
Dr. Raymond reports serving as a board member of and receiving grant support and payment for the development of educational presentations from Pfizer and Novartis; Dr. Bang, receiving consulting fees, grant support, and lecture fees from Pfizer; Dr. Borbath, receiving travel fees from Pfizer; Dr. Valle, receiving consulting fees from Pfizer; Dr. Metrakos, receiving consulting fees, lecture fees, and payment for the development of educational presentations from Novartis, and travel fees from Novartis and Pfizer; Dr. Vinik, receiving consulting fees from Ansar, AstraZeneca, Eli Lilly, KV Pharmaceuticals, Merck, Novartis, R.W. Johnson Pharmaceutical Research Institute, Sanofi-Aventis, Takeda, and Tercica, grant support from Abbott, GlaxoSmithKline, Sanofi-Aventis, Arcion Therapeutics, Eli Lilly, and Merck Research, and lecture fees from Abbott, Ansar, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Pfizer, Sanofi-Aventis, and Takeda, owning patents with Eli Lilly, Eisai, FoldRx, Pfizer, Exsulin, and receiving royalties from Eli Lilly, Eisai, FoldRx, Pfizer, and Exsulin, payments for the development of educational presentations from Eli Lilly, Eisai, FoldRx, Pfizer, and Exsulin, and travel fees from Eli Lilly, Eisai, FoldRx, Pfizer, and Exsulin; Dr. Hörsch, serving as a board member of Pfizer, Novartis, and Ipsen, and receiving grant support from Novartis, Covidien, Eckart and Ziegler, and ITG, and lecture fees from Pfizer, Novartis, and Ipsen; Dr. Hammel, receiving consulting fees from Pfizer and Merck Serono; Dr. Wiedenmann, receiving consulting and lecture fees, payment for educational presentations, and travel fees from Pfizer; Dr. Van Cutsem, receiving grant support from Pfizer and Novartis; Dr. Ruszniewski, serving as a board member of and receiving consulting fees from Novartis, Pfizer, and Ipsen, grant support from Novartis and Ipsen, and travel fees from Ferring, AstraZeneca, and Novartis; and Drs. Patyna, Lu, Blanckmeister, and Chao, being full-time employees of and holding stock and stock options in Pfizer.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
No other potential conflict of interest relevant to this article was reported.
We thank the participating patients and their families, as well as the global network of research nurses, trial coordinators, and operations staff for their contributions, and investigators whose patients were enrolled in this trial, including: Australia: G. Van Hazel; Belgium: I. Borbath, E. Van Cutsem, J.-L. Van Laethem; Canada: H. Kennecke, R. Letourneau, P. Metrakos, D. Rayson, L. Siu; France: L. Dahan, F. Duffaud, S. Faivre, F. Goldwasser, P. Hammel, C. Lombard-Bohas, C. Louvet, P. Niccoli, J.-L. Raoul, E. Raymond, P. Ruszniewski, J.-F. Seitz, D. Smith; Germany: N. Begum, T. Gress, D. Hörsch, D. Jaeger, T. Seufferlein, B. Wiedenmann; Italy: N. Fazio, R. Passalacqua, A. Santoro; Korea: Y.-J. Bang, T. W. Kim; Spain: D. Castellano, J. Feliu, P. Garcia-Alfonso, J. Tabernero; Taiwan: J.-S. Chen, C.-H. Hsu; United Kingdom: A. Anthoney, J. Neoptolemos, J. Valle; and United States: D. Berg, M. Kane, R. Kerr, J. Picus, B. Piperdi, and A. Vinik. We thank Mabel Woloj at Pfizer for involvement in the study design and conduct; Deno Klademenos at ExecuPharm for support of the study conduct and data management; Beata Korytowsky at Pfizer for providing assessments of patient-reported outcomes data; Kristen Letrent at Pfizer and Patricia Niccoli at Centre Hospitalier Universitaire Timone, France, for contributions to an earlier version of the manuscript; and Jenni Macdougall and Andy Gannon at Acumed (Tytherington, United Kingdom) for medical-writing support.
Source Information
From the Service Inter-Hospitalier de Cancérologie et Service de Gastroenteropancréatologie, Hôpital Beaujon, Clichy (E.R., P.H., P.R.); Service d'Oncologie Digestive, Hôpital Timone, Marseille, and Réseau National des Tumeurs Endocrines, Provence Alpes Cote d'Azure (L.D.); Eugène Marquis Centre, University of Rennes, Rennes (J.-L.R.); Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon (C.L.-B.); and Hôpital Saint-André, Bordeaux (D.S.) — all in France; Seoul National University Hospital, Seoul, Korea (Y.-J.B.); Cliniques Universitaires Saint-Luc, Brussels (I.B.); Department of Medical Oncology, Christie Hospital National Health Service Foundation Trust, Manchester, United Kingdom (J.V.); McGill University Hospital Centre, Montreal (P.M.); Eastern Virginia Medical School Strelitz Diabetes Center and Neuroendocrine Unit, Norfolk (A.V.); Chang Gung Memorial Hospital and Chang Gung University, Kwei-Shan, Taoyuan, Taiwan (J.-S.C.); Clinic for Internal Medicine, Gastroenterology and Endocrinology, Center for Neuroendocrine Tumors, Bad Berka Central Clinic, Bad Berka, Germany (D.H.); the Department of Hepatology and Gastroenterology, Charité Medical School, Humboldt-Universität zu Berlin, Berlin (B.W.); University Hospital Gasthuisberg Leuven, Leuven, Belgium (E.V.C.); Pfizer Oncology, Development, La Jolla, CA (S.P., D.R.L., R.C.); and Pfizer Oncology, Emerging Markets, New York (C.B.).
Address reprint requests to Dr. Raymond at Service Inter-Hospitalier de Cancérologie Beaujon–Bichat, University Paris 7 Diderot (INSERM Unité 728) and Assistance Publique–Hôpitaux de Paris, Hôpital Beaujon, 100 Blvd. du Général Leclerc, 92118 Clichy CEDEX, France, or at eric.raymond@bjn.aphp.fr.
- References
References
1
Halfdanarson TR ,Rabe KG ,Rubin J ,Petersen GM . Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol 2008;19:1727-1733
CrossRef | Web of Science | Medline2
Ballian N ,Loeffler AG ,Rajamanickam V ,Norstedt PA ,Weber SM ,Cho CS . A simplified prognostic system for resected pancreatic neuroendocrine neoplasms. HPB (Oxford) 2009;11:422-428
CrossRef | Medline3
Knigge U ,Hansen CP ,Stadil F . Interventional treatment of neuroendocrine liver metastases. Surgeon 2008;6:232-239
CrossRef | Web of Science | Medline4
Yao KA ,Talamonti MS ,Nemcek A , et al. Indications and results of liver resection and hepatic chemoembolization for metastatic gastrointestinal neuroendocrine tumors. Surgery 2001;130:677-682
CrossRef | Web of Science | Medline5
Modlin IM ,Pavel M ,Kidd M ,Gustafsson BI . Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther 2010;31:169-188
Web of Science | Medline6
Oberg K ,Kvols L ,Caplin M , et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol 2004;15:966-973
CrossRef | Web of Science | Medline7
Rinke A ,Muller HH ,Schade-Brittinger C , et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009;27:4656-4663
CrossRef | Web of Science | Medline8
Bukowski RM ,Tangen C ,Lee R , et al. Phase II trial of chlorozotocin and fluorouracil in islet cell carcinoma: a Southwest Oncology Group study. J Clin Oncol 1992;10:1914-1918
Web of Science | Medline9
Moertel CG ,Hanley JA ,Johnson LA . Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med 1980;303:1189-1194
Full Text | Web of Science | Medline10
Kouvaraki MA ,Ajani JA ,Hoff P , et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 2004;22:4762-4771[Erratum, J Clin Oncol 2005;23:248.]
CrossRef | Web of Science | Medline11
Moertel CG ,Lefkopoulo M ,Lipsitz S ,Hahn RG ,Klaassen D . Streptozocin-doxorubicin, streptozocin-fluorouracil, or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992;326:519-523
Full Text | Web of Science | Medline12
Cheng PN ,Saltz LB . Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma. Cancer 1999;86:944-948
CrossRef | Web of Science | Medline13
McCollum AD ,Kulke MH ,Ryan DP , et al. Lack of efficacy of streptozocin and doxorubicin in patients with advanced pancreatic endocrine tumors. Am J Clin Oncol 2004;27:485-488
CrossRef | Web of Science | Medline14
Casanovas O ,Hicklin DJ ,Bergers G ,Hanahan D . Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005;8:299-309
CrossRef | Web of Science | Medline15
Inoue M ,Hager JH ,Ferrara N ,Gerber HP ,Hanahan D . VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell 2002;1:193-202
CrossRef | Web of Science | Medline16
Fjallskog ML ,Lejonklou MH ,Oberg KE ,Eriksson BK ,Janson ET . Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumors. Clin Cancer Res 2003;9:1469-1473
Web of Science | Medline17
Fjallskog ML ,Hessman O ,Eriksson B ,Janson ET . Upregulated expression of PDGF receptor beta in endocrine pancreatic tumors and metastases compared to normal endocrine pancreas. Acta Oncol 2007;46:741-746
CrossRef | Web of Science | Medline18
Hansel DE ,Rahman A ,Hermans J , et al. Liver metastases arising from well-differentiated pancreatic endocrine neoplasms demonstrate increased VEGF-C expression. Mod Pathol 2003;16:652-659
CrossRef | Web of Science | Medline19
Faivre S ,Demetri G ,Sargent W ,Raymond E . Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 2007;6:734-745
CrossRef | Web of Science | Medline20
Mendel DB ,Laird AD ,Xin X , et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003;9:327-337
Web of Science | Medline21
Pietras K ,Hanahan D . A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 2005;23:939-952
CrossRef | Web of Science | Medline22
Yao VJ ,Sennino B ,Davis RB , et al. Combined anti-VEGFR and anti-PDGFR actions of sunitinib on blood vessels in preclinical tumor models. Eur J Cancer 2006;4:Suppl:27-2823
Faivre S ,Delbaldo C ,Vera K , et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006;24:25-35
CrossRef | Web of Science | Medline24
Kulke MH ,Lenz HJ ,Meropol NJ , et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008;26:3403-3410
CrossRef | Web of Science | Medline25
Solcia E, Klöppel G, Sobin LH. Histological typing of endocrine tumours. 2nd ed. Berlin: Springer, 2000.
26
Falconi M ,Plockinger U ,Kwekkeboom DJ , et al. Well-differentiated pancreatic nonfunctioning tumors/carcinoma. Neuroendocrinology 2006;84:196-211
CrossRef | Web of Science | Medline27
Therasse P ,Arbuck SG ,Eisenhauer EA , et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205-216
CrossRef | Web of Science | Medline28
George S ,Blay JY ,Casali PG , et al. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer 2009;45:1959-1968
CrossRef | Web of Science | Medline29
Escudier B ,Roigas J ,Gillessen S , et al. Phase II study of sunitinib administered in a continuous once-daily dosing regimen in patients with cytokine-refractory metastatic renal cell carcinoma. J Clin Oncol 2009;27:4068-4075
CrossRef | Web of Science | Medline30
Aaronson NK ,Ahmedzai S ,Bergman B , et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365-376
CrossRef | Web of Science | Medline31
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A. EORTC QLQ-C30 scoring manual. 3rd ed. Brussels: EORTC Quality of Life Group, 2001.
32
Osoba D ,Rodrigues G ,Myles J ,Zee B ,Pater J . Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 1998;16:139-144
Web of Science | Medline33
Vinik A, Bang Y-J, Raoul J-L, et al. Patient-reported outcomes in patients with pancreatic neuroendocrine tumors (NET) receiving sunitinib in a phase III trial. Presented at the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago, June 4–8, 2010.
34
Theou-Anton N ,Faivre S ,Dreyer C ,Raymond E . Benefit-risk assessment of sunitinib in gastrointestinal stromal tumours and renal cancer. Drug Saf 2009;32:717-734
CrossRef | Web of Science | Medline35
Vinik AI, Perry RR. Neoplasms of the gastroenteropancreatic endocrine system. In: Holland JF, Bast RC Jr, Morton DL, Frei E III, Kufe DW, Wichselbaum RR, eds. Cancer medicine. 4th ed. Baltimore: Williams & Wilkins, 1997:1605-41.
36
Pape UF ,Bohmig M ,Berndt U ,Tiling N ,Wiedenmann B ,Plockinger U . Survival and clinical outcome of patients with neuroendocrine tumors of the gastroenteropancreatic tract in a German referral center. Ann N Y Acad Sci 2004;1014:222-233
CrossRef | Web of Science | Medline37
Kwekkeboom DJ ,Teunissen JJ ,Bakker WH , et al. Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol 2005;23:2754-2762
CrossRef | Web of Science | Medline38
Valkema R ,Pauwels S ,Kvols LK , et al. Survival and response after peptide receptor radionuclide therapy with [90Y-DOTA0,Tyr3]octreotide in patients with advanced gastroenteropancreatic neuroendocrine tumors. Semin Nucl Med 2006;36:147-156
CrossRef | Web of Science | Medline39
Yao JC ,Lombard-Bohas C ,Baudin E , et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 2010;28:69-76
CrossRef | Web of Science | Medline40
Yao JC ,Shah MH ,Ito T , et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011;364:514-523
Full Text | Web of Science | Medline
- Citing Articles (100)
Citing Articles
1
2013. Z. , 1178-1180.
CrossRef2
Diane Reidy-Lagunes, Raymond Thornton. (2012) Pancreatic Neuroendocrine and Carcinoid Tumors: What’s New, What’s Old, and What’s Different?. Current Oncology Reports 14:3, 249-256
CrossRef3
Giordano Savelli, Francesco Bertagna, Fabio Franco, Ludovica Dognini, Giovanni Bosio, Elena Migliorati, Carlo Rodella, Giorgio Biasiotto, Giovanni Bettinsoli, Chiara Minari, Alberto Zaniboni, Chiara Ferrari, Paola Tomassetti, Vittorio Ferrari, Raffaele Giubbini. (2012) Final results of a phase 2A study for the treatment of metastatic neuroendocrine tumors with a fixed activity of 90Y-DOTA-D-Phe1-Tyr3 octreotide. Cancer 118:11, 2915-2924
CrossRef4
Alexandre Teulé, Oriol Casanovas. (2012) Relevance of angiogenesis in neuroendocrine tumors. Targeted Oncology
CrossRef5
Sandrine Faivre, Maxime Ronot, Chantal Dreyer, Camille Serrate, Olivia Hentic, Mohamed Bouattour, Onorina Bruno, Anne Couvelard, Valérie Vilgrain, Eric Raymond. (2012) Imaging response in neuroendocrine tumors treated with targeted therapies: the experience of sunitinib. Targeted Oncology
CrossRef6
Marta Benavent, Maria Jose Miguel, Rocio Garcia-Carbonero. (2012) New targeted agents in gastroenteropancreatic neuroendocrine tumors. Targeted Oncology
CrossRef7
Peter P. Rainer, Bernhard Doleschal, Jonathan A. Kirk, Vidhya Sivakumaran, Zora Saad, Klaus Groschner, Heinrich Maechler, Gerald Hoefler, Thomas Bauernhofer, Hellmut Samonigg, Georg Hutterer, David A. Kass, Burkert Pieske, Dirk von Lewinski, Martin Pichler. (2012) Sunitinib causes dose-dependent negative functional effects on myocardium and cardiomyocytes. BJU Internationalno-no
CrossRef8
Jaume Capdevila, Guillem Argilés, Nuria Mulet-Margalef, Josep Tabernero. (2012) Tumores neuroendocrinos: la era de las terapias dirigidas. Endocrinología y Nutrición
CrossRef9
Dik J. Kwekkeboom. (2012) Therapy: Neuroendocrine cancer—are two radionuclides better than one?. Nature Reviews Endocrinology
CrossRef10
Annamaria Rapisarda, Giovanni Melillo. (2012) Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nature Reviews Clinical Oncology
CrossRef11
A. Naganuma, H. Mayahara, C. Morizane, Y. Ito, A. Hagihara, S. Kondo, H. Ueno, J. Itami, T. Okusaka. (2012) Successful Control of Intractable Hypoglycemia Using Radiopharmaceutical Therapy with Strontium-89 in a Case with Malignant Insulinoma and Bone Metastases. Japanese Journal of Clinical Oncology
CrossRef12
Federica Maione, Stefania Capano, Donatella Regano, Lorena Zentilin, Mauro Giacca, Oriol Casanovas, Federico Bussolino, Guido Serini, Enrico Giraudo. (2012) Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice. Journal of Clinical Investigation
CrossRef13
M. Troch, B. Kiesewetter, Markus Raderer. (2012) Pancreatic neuroendocrine tumours – new therapeutic concepts. memo - Magazine of European Medical Oncology 5:1, 63-65
CrossRef14
J H Yi, J Lee, J Lee, S H Park, J O Park, D-S Yim, Y S Park, H Y Lim, W K Kang. (2012) Randomised phase II trial of docetaxel and sunitinib in patients with metastatic gastric cancer who were previously treated with fluoropyrimidine and platinum. British Journal of Cancer
CrossRef15
Daniel M. Halperin, Matthew H. Kulke. (2012) Management of Pancreatic Neuroendocrine Tumors. Gastroenterology Clinics of North America 41:1, 119-131
CrossRef16
Kristen P. Massimino, Esther Han, SuEllen J. Pommier, Rodney F. Pommier. (2012) Laparoscopic surgical exploration is an effective strategy for locating occult primary neuroendocrine tumors. The American Journal of Surgery
CrossRef17
Manel Puig Domingo, Justo Castaño, Cristina Álvarez-Escolá, Eugenia Resmini, Eva Venegas, Juan García Arnés, Elena Torres, Beatriz Lecumberri, María José Barahona, Cristina Lamas, Carmen Fajardo, Rosa Cámara, Almudena Vicente, Concepción Blanco, Carles Villabona, Carlos del Pozo, Irene Halperin, Isabel Salinas, Gemma Sesmilo, Javier Aller, Mónica Marazuela, Susan M. Webb, Ignacio Bernabeu. (2012) El año 2011 en Neuroendocrinología. Endocrinología y Nutrición
CrossRef18
Andrea Weiss, Hubert van den Bergh, Arjan W. Griffioen, Patrycja Nowak-Sliwinska. (2012) Angiogenesis inhibition for the improvement of photodynamic therapy: The revival of a promising idea. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
CrossRef19
Ferdinando Riccardi, Mimma Rizzo, Lucia Festino, Francesca Ambrosio, Carlo Molino, Generoso Uomo, Giacomo Cartenì. (2012) Therapy innovation for the treatment of pancreatic neuroendocrine tumors. Expert Opinion on Therapeutic Targets1-12
CrossRef20
Gordon C. Jayson, Daniel J. Hicklin, Lee M. Ellis. (2012) Antiangiogenic therapy—evolving view based on clinical trial results. Nature Reviews Clinical Oncology
CrossRef21
Timothy A. Yap, Paul Workman. (2012) Exploiting the Cancer Genome: Strategies for the Discovery and Clinical Development of Targeted Molecular Therapeutics. Annual Review of Pharmacology and Toxicology 52:1, 549-573
CrossRef22
J. R. Strosberg, J. M. Weber, J. Choi, T. L. Campos, T. L. Valone, G. Han, M. J. Schell, L. K. Kvols. (2012) A phase II clinical trial of sunitinib following hepatic transarterial embolization for metastatic neuroendocrine tumors. Annals of Oncology
CrossRef23
Roeland F. de Wilde, Barish H. Edil, Ralph H. Hruban, Anirban Maitra. (2012) Well-differentiated pancreatic neuroendocrine tumors: from genetics to therapy. Nature Reviews Gastroenterology & Hepatology
CrossRef24
Krystallenia I. Alexandraki, Gregory Kaltsas. (2012) Gastroenteropancreatic neuroendocrine tumors: new insights in the diagnosis and therapy. Endocrine 41:1, 40-52
CrossRef25
Laleh Amiri-Kordestani, Antoinette R Tan, Sandra M Swain. (2012) Pazopanib for the treatment of breast cancer. Expert Opinion on Investigational Drugs 21:2, 217-225
CrossRef26
Constantin A Dasanu, Shounak Majumder, Srila Gopal, Elena Stoica-Mustafa, Guru Trikudanathan. (2012) Emerging therapeutic options for advanced enteropancreatic neuroendocrine tumors. Expert Opinion on Pharmacotherapy1-11
CrossRef27
Natalie Cook, Duncan I. Jodrell, David A. Tuveson. (2012) Predictive in vivo animal models and translation to clinical trials. Drug Discovery Today
CrossRef28
Thomas Walter, Hedia Brixi-Benmansour, Catherine Lombard-Bohas, Guillaume Cadiot. (2012) New treatment strategies in advanced neuroendocrine tumours. Digestive and Liver Disease 44:2, 95-105
CrossRef29
Nancy M. Gardner-Roehnelt. (2012) Update on the Management of Neuroendocrine Tumors: Focus on Somatostatin Antitumor Effects. Clinical Journal of Oncology Nursing 16:1, 56-64
CrossRef30
Krastan B. Blagoev, Julia Wilkerson, Tito Fojo. (2012) Hazard ratios in cancer clinical trials—a primer. Nature Reviews Clinical Oncology
CrossRef31
Laura Horsley, Kalena Marti, GC Jayson. (2012) Is the toxicity of anti-angiogenic drugs predictive of outcome? A review of hypertension and proteinuria as biomarkers of response to anti-angiogenic therapy. Expert Opinion on Drug Metabolism & Toxicology1-11
CrossRef32
Jun Ho Yi, Sumitra Thongprasert, Jeeyun Lee, D.C. Doval, Se Hoon Park, Joon Oh Park, Young Suk Park, Won Ki Kang, Ho Yeong Lim. (2012) A phase II study of sunitinib as a second-line treatment in advanced biliary tract carcinoma: A multicentre, multinational study. European Journal of Cancer 48:2, 196-201
CrossRef33
Richard A. Feelders, Leo J. Hofland, Dik J. Kwekkeboom, StevenW. Lamberts, Wouter W. de Herder. 2012. Neuroendocrine Tumors. , 761-778.
CrossRef34
S A Holstein, R J Hohl. (2012) Therapeutic Additions and Possible Deletions in Oncology in 2011. Clinical Pharmacology & Therapeutics 91:1, 15-17
CrossRef35
N. Starling, F. Vazquez-Mazon, D. Cunningham, I. Chau, J. Tabernero, F. J. Ramos, T. J. Iveson, M. P. Saunders, E. Aranda, A. M. Countouriotis, A. Ruiz-Garcia, G. Wei, J. M. Tursi, C. Guillen-Ponce, A. Carrato. (2012) A phase I study of sunitinib in combination with FOLFIRI in patients with untreated metastatic colorectal cancer. Annals of Oncology 23:1, 119-127
CrossRef36
Stacey A. Milan, Charles J. Yeo. (2012) Neuroendocrine tumors of the pancreas. Current Opinion in Oncology 24:1, 46-55
CrossRef37
Michael J. Levy, Geoffrey B. Thompson, Mark D. Topazian, Matthew R. Callstrom, Clive S. Grant, Adrian Vella. (2012) US-guided ethanol ablation of insulinomas: a new treatment option. Gastrointestinal Endoscopy 75:1, 200-206
CrossRef38
K.Y. Gulenchyn, X. Yao, S.L. Asa, S. Singh, C. Law. (2012) Radionuclide Therapy in Neuroendocrine Tumours: A Systematic Review. Clinical Oncology
CrossRef39
Ron Basuroy, Rajaventhan Srirajaskanthan, John K. Ramage. (2012) A Multimodal Approach to the Management of Neuroendocrine Tumour Liver Metastases. International Journal of Hepatology 2012, 1-13
CrossRef40
Massimo Falconi, Detlef Klaus Bartsch, Barbro Eriksson, Günter Klöppel, José M. Lopes, Juan M. O'Connor, Ramón Salazar, Babs G. Taal, Marie Pierre Vullierme, Dermot O'Toole. (2012) ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms of the Digestive System: Well-Differentiated Pancreatic Non-Functioning Tumors. Neuroendocrinology 95:2, 120-134
CrossRef41
Marianne Pavel, Eric Baudin, Anne Couvelard, Eric Krenning, Kjell Öberg, Thomas Steinmüller, Martin Anlauf, Bertram Wiedenmann, Ramon Salazar. (2012) ENETS Consensus Guidelines for the Management of Patients with Liver and Other Distant Metastases from Neuroendocrine Neoplasms of Foregut, Midgut, Hindgut, and Unknown Primary. Neuroendocrinology 95:2, 157-176
CrossRef42
Robert T. Jensen, Guillaume Cadiot, Maria L. Brandi, Wouter W. de Herder, Gregory Kaltsas, Paul Komminoth, Jean-Yves Scoazec, Ramon Salazar, Alain Sauvanet, Reza Kianmanesh. (2012) ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms: Functional Pancreatic Endocrine Tumor Syndromes. Neuroendocrinology 95:2, 98-119
CrossRef43
Ramon Salazar, Bertram Wiedenmann, Guido Rindi, Philippe Ruszniewski. (2012) ENETS 2011 Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors: An Update. Neuroendocrinology 95:2, 71-73
CrossRef44
Ping Gu, Jennifer Wu, Elliot Newman, Franco Muggia. (2012) Treatment of Liver Metastases in Patients with Neuroendocrine Tumors of Gastroesophageal and Pancreatic Origin. International Journal of Hepatology 2012, 1-8
CrossRef45
Saboor Khan, David M. Nagorney, Florencia G. Que. 2012. Metastatic malignant liver tumors. , 1305-1318.
CrossRef46
Chenfei Zhou, Jun Zhang, Ying Zheng, Zhenggang Zhu. (2012) Pancreatic neuroendocrine tumors: A comprehensive review. International Journal of Cancern/a-n/a
CrossRef47
J.A. Stockman. (2012) Everolimus for Advanced Pancreatic Neuroendocrine Tumors. Yearbook of Pediatrics 2012, 488-490
CrossRef48
Louis de Mestier, Cindy Neuzillet, Olivia Hentic, Reza Kianmanesh, Pascal Hammel, Philippe Ruszniewski. (2012) Prolonged Survival in a Patient with Neuroendocrine Tumor of the Cecum and Diffuse Peritoneal Carcinomatosis. Case Reports in Gastroenterology 6:1, 205-210
CrossRef49
Robert T. Jensen. 2012. Pancreatic Endocrine Tumors. , 1292-1297.
CrossRef50
William R. Burns, Barish H. Edil. (2011) Neuroendocrine Pancreatic Tumors: Guidelines for Management and Update. Current Treatment Options in Oncology
CrossRef51
P. Olson, G. C. Chu, S. R. Perry, O. Nolan-Stevaux, D. Hanahan. (2011) PNAS Plus: Imaging guided trials of the angiogenesis inhibitor sunitinib in mouse models predict efficacy in pancreatic neuroendocrine but not ductal carcinoma. Proceedings of the National Academy of Sciences 108:49, E1275-E1284
CrossRef52
Irvin M. Modlin, Steven F. Moss, Bjorn I. Gustafsson, Ben Lawrence, Simon Schimmack, Mark Kidd. (2011) The archaic distinction between functioning and nonfunctioning neuroendocrine neoplasms is no longer clinically relevant. Langenbeck's Archives of Surgery 396:8, 1145-1156
CrossRef53
Khairuddin Memon, Robert J. Lewandowski, Mary F. Mulcahy, Ahsun Riaz, Robert K. Ryu, Kent T. Sato, Ramona Gupta, Paul Nikolaidis, Frank H. Miller, Vahid Yaghmai, Vanessa L. Gates, Bassel Atassi, Steven Newman, Reed A. Omary, Al B. Benson, Riad Salem. (2011) Radioembolization for Neuroendocrine Liver Metastases: Safety, Imaging, and Long-term Outcomes. International Journal of Radiation Oncology*Biology*Physics
CrossRef54
Rajesh Gupta, Michael L. Maitland. (2011) Sunitinib, Hypertension, and Heart Failure: A Model for Kinase Inhibitor-Mediated Cardiotoxicity. Current Hypertension Reports 13:6, 430-435
CrossRef55
Richard A Hubner, Juan W Valle. (2011) Sunitinib for advanced pancreatic neuroendocrine tumors. Expert Review of Anticancer Therapy 11:12, 1817-1827
CrossRef56
J. Naidoo, D. O’Toole, M. J. Kennedy, J. V. Reynolds, M. O’Connor, K. O’Byrne. (2011) A single institution experience of streptozocin/fluorouracil combination chemotherapy: a case series. Irish Journal of Medical Science
CrossRef57
Hedia Brixi-Benmansour, Jean-Louis Jouve, Emmanuel Mitry, Franck Bonnetain, Bruno Landi, Olivia Hentic, Laurent Bedenne, Guillaume Cadiot. (2011) Phase II study of first-line FOLFIRI for progressive metastatic well-differentiated pancreatic endocrine carcinoma. Digestive and Liver Disease 43:11, 912-916
CrossRef58
Robert Goldstein, Tim Meyer. (2011) Role of everolimus in pancreatic neuroendocrine tumors. Expert Review of Anticancer Therapy 11:11, 1653-1665
CrossRef59
Rebecca M. Minter, Diane M. Simeone. (2011) Contemporary Management of Nonfunctioning Pancreatic Neuroendocrine Tumors. Journal of Gastrointestinal Surgery
CrossRef60
M. S. Khan, M. E. Caplin. (2011) Therapeutic management of patients with gastroenteropancreatic neuroendocrine tumours. Endocrine Related Cancer 18:S1, S53-S74
CrossRef61
L. Q. M. Chow, N. Blais, D. J. Jonker, S. A. Laurie, S. G. Diab, C. Canil, M. McWilliam, A. Thall, A. Ruiz-Garcia, K. Zhang, L. Tye, R. C. Chao, D. R. Camidge. (2011) A phase I dose-escalation and pharmacokinetic study of sunitinib in combination with pemetrexed in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer. Cancer Chemotherapy and Pharmacology
CrossRef62
Kein-Leong Yim. (2011) Role of biological targeted therapies in gastroenteropancreatic neuroendocrine tumours. Endocrine 40:2, 181-186
CrossRef63
Emma D. Deeks, Eric Raymond. (2011) Sunitinib. BioDrugs 25:5, 307-316
CrossRef64
EC Feliberti, RR Perry, AI Vinik. (2011) Advances in the management and treatment of gastroenteropancreatic neuroendocrine tumors. Clinical Investigation 1:10, 1455-1468
CrossRef65
C. Kratochwil, R. Lopez-Benitez, W. Mier, S. Haufe, B. Isermann, H.-U. Kauczor, P. L. Choyke, U. Haberkorn, F. L. Giesel. (2011) Hepatic arterial infusion enhances DOTATOC radiopeptide therapy in patients with neuroendocrine liver metastases. Endocrine Related Cancer 18:5, 595-602
CrossRef66
K.E. Öberg. (2011) The Management of Neuroendocrine Tumours: Current and Future Medical Therapy Options. Clinical Oncology
CrossRef67
Wouter W. de Herder, Ellen van Schaik, Dik Kwekkeboom, Richard A. Feelders. (2011) New therapeutic options for metastatic malignant insulinomas. Clinical Endocrinology 75:3, 277-284
CrossRef68
Chaitanya Divgi. (2011) Targeted Systemic Radiotherapy of Pheochromocytoma and Medullary Thyroid Cancer. Seminars in Nuclear Medicine 41:5, 369-373
CrossRef69
Georgios Baltogiannis, Christos Katsios, Dimitrios H Roukos. (2011) New target therapies for patients with neuroendocrine tumors of the pancreas. Expert Review of Gastroenterology & Hepatology 5:5, 563-566
CrossRef70
Theodore Liakakos, Dimitrios H Roukos. (2011) Everolimus and sunitinib: from mouse models to treatment of pancreatic neuroendocrine tumors. Future Oncology 7:9, 1025-1029
CrossRef71
S M Pyonteck, B B Gadea, H-W Wang, V Gocheva, K E Hunter, L H Tang, J A Joyce. (2011) Deficiency of the macrophage growth factor CSF-1 disrupts pancreatic neuroendocrine tumor development. Oncogene
CrossRef72
Guido Rindi, Bertram Wiedenmann. (2011) Neuroendocrine neoplasms of the gut and pancreas: new insights. Nature Reviews Endocrinology 8:1, 54-64
CrossRef73
De-shen Wang, Dong-sheng Zhang, Miao-zhen Qiu, Zhi-qiang Wang, Hui-yan Luo, Feng-hua Wang, Yu-hong Li, Rui-hua Xu. (2011) Prognostic factors and survival in patients with neuroendocrine tumors of the pancreas. Tumor Biology 32:4, 697-705
CrossRef74
Gareth Rees. (2011) Industry Update: The latest developments in therapeutic delivery. Therapeutic Delivery 2:8, 975-985
CrossRef75
Ginger J. Gardner, Diane Reidy-Lagunes, Paola A. Gehrig. (2011) Neuroendocrine tumors of the gynecologic tract: A Society of Gynecologic Oncology (SGO) clinical document. Gynecologic Oncology 122:1, 190-198
CrossRef76
M. Pavel. (2011) Medizinische Therapie und Chemotherapie von neuroendokrinen Tumoren. Der Onkologe 17:7, 592-601
CrossRef77
P. La Rosée. (2011) Tyrosinkinaseinhibitoren. Der Onkologe 17:7, 641-650
CrossRef78
M. Pavel. (2011) Metastasierte neuroendokrine Neoplasien. Der Chirurg 82:7, 612-617
CrossRef79
Robert T. Jensen. (2011) Cancer: A roadmap for the land of small tumors. Nature Reviews Endocrinology 7:6, 319-321
CrossRef80
Catherine Delbaldo, Sébastien Albert, Chantal Dreyer, Marie-Paule Sablin, Maria Serova, Eric Raymond, Sandrine Faivre. (2011) Predictive biomarkers for the activity of mammalian target of rapamycin (mTOR) inhibitors. Targeted Oncology 6:2, 119-124
CrossRef81
Thomas Walter, Jean-Yves Scoazec, Christophe Couderc, Julien Forestier, Colette Roche, Jean-Alain Chayvialle, Catherine Lombard-Bohas. (2011) Well-differentiated pancreatic islet cell carcinoma: Is there reversibility in mTOR inhibitor resistance?. Acta Oncologica 50:5, 731-732
CrossRef82
(2011) Advances in Pancreatic Neuroendocrine Tumor Treatment. New England Journal of Medicine 364:19, 1871-1875
Full Text83
Allen M. Spiegel, Steven K. Libutti. (2011) Targeted therapies: Good news for advanced-stage pancreatic neuroendocrine tumors. Nature Reviews Clinical Oncology 8:5, 258-259
CrossRef84
Ramon Salazar, Diane Reidy-Lagunes, James Yao. (2011) Potential Synergies for Combined Targeted Therapy in the Treatment of Neuroendocrine Cancer. Drugs 71:7, 841-852
CrossRef85
Natalie J. Wood. (2011) Cancer: Optimism surrounds new targeted therapies for pancreatic neuroendocrine tumors. Nature Reviews Gastroenterology & Hepatology 8:4, 179-179
CrossRef86
Sònia Tugues, Sina Koch, Laura Gualandi, Xiujuan Li, Lena Claesson-Welsh. (2011) Vascular endothelial growth factors and receptors: Anti-angiogenic therapy in the treatment of cancer. Molecular Aspects of Medicine 32:2, 88-111
CrossRef87
David Tuveson, Douglas Hanahan. (2011) Translational medicine: Cancer lessons from mice to humans. Nature 471:7338, 316-317
CrossRef88
Rebecca Kirk. (2011) Targeted therapies: Hope for pancreatic neuroendocrine tumors. Nature Reviews Clinical Oncology 8:4, 191-191
CrossRef89
John M. L. Ebos, Robert S. Kerbel. (2011) Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nature Reviews Clinical Oncology 8:4, 210-221
CrossRef90
Yao, James C., Shah, Manisha H., Ito, Tetsuhide, Bohas, Catherine Lombard, Wolin, Edward M., Van Cutsem, Eric, Hobday, Timothy J., Okusaka, Takuji, Capdevila, Jaume, de Vries, Elisabeth G.E., Tomassetti, Paola, Pavel, Marianne E., Hoosen, Sakina, Haas, Tomas, Lincy, Jeremie, Lebwohl, David, Öberg, Kjell, . (2011) Everolimus for Advanced Pancreatic Neuroendocrine Tumors. New England Journal of Medicine 364:6, 514-523
Full Text91
Jensen, Robert T., Delle Fave, Gianfranco , . (2011) Promising Advances in the Treatment of Malignant Pancreatic Endocrine Tumors. New England Journal of Medicine 364:6, 564-565
Full Text92
Matthew H Kulke, Johanna Bendell, Larry Kvols, Joel Picus, Rodney Pommier, James Yao. (2011) Evolving Diagnostic and Treatment Strategies for Pancreatic Neuroendocrine Tumors. Journal of Hematology & Oncology 4:1, 29
CrossRef93
Theresa R. Harring, N. Thao N. Nguyen, John A. Goss, Christine A. O'Mahony. (2011) Treatment of Liver Metastases in Patients with Neuroendocrine Tumors: A Comprehensive Review. International Journal of Hepatology 2011, 1-11
CrossRef94
Bertram Wiedenmann, Marianne Pavel, Beata Kos-Kudla. (2011) From Targets to Treatments: A Review of Molecular Targets in Pancreatic Neuroendocrine Tumors. Neuroendocrinology 94:3, 177-190
CrossRef95
Justin S Gundara, Raul Alvarado-Bachmann, Nicholas Williams, Sivakumar Gananadha, Anthony Gill, Thomas J Hugh, Jaswinder S Samra. (2011) Multivisceral resection of pancreatic neuroendocrine tumours: a report of two cases. World Journal of Surgical Oncology 9:1, 93
CrossRef96
Martin Vyleta, Douglas Coldwell. (2011) Radioembolization in the Treatment of Neuroendocrine Tumor Metastases to the Liver. International Journal of Hepatology 2011, 1-5
CrossRef97
R.K. Pearson. (2011) Everolimus for Advanced Pancreatic Neuroendocrine Tumors. Yearbook of Gastroenterology 2011, 138-139
CrossRef98
R.K. Pearson. (2011) Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors. Yearbook of Gastroenterology 2011, 143-144
CrossRef99
Stephen J. Marx, Samuel A. Wells. 2011. Multiple Endocrine Neoplasia. , 1728-1767.
CrossRef100
Raman Sreedharan, Chris A. Liacouras. 2011. Functional Abdominal Pain (Nonorganic Chronic Abdominal Pain). , 1346-1349.
CrossRef
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