Durable complete response with a short course of streptozotocin plus doxorubicin combination in malignant metastatic insulinoma.

Due to the cytotoxic effects of old chemotherapy regimens used in the islet cell tumors, capecitabine plus temozolomide combination has now become the first choice in the treatment of malignant insulinoma (MIoma). We present this case to emphasize and remind that a durable complete response in advanced stage MIoma may be achieved with a short course of streptozotocin plus doxorubicin combination.

Attainment of a Long-term Favorable Outcome by Sunitinib Treatment for Pancreatic Neuroendocrine Tumor and Renal Cell Carcinoma Associated with von Hippel-Lindau Disease.

von Hippel-Lindau (VHL) disease, caused by germline mutations in the VHL gene, is a hereditary autosomal-dominant disorder which predisposes the individual to various malignant and benign tumors. VHL acts as a tumor suppressor, mainly through the negative regulation of hypoxia-inducible factors. Molecular-targeted drugs against vascular endothelial growth factor-signaling pathways, a target of hypoxia-inducible factors, have recently been introduced into clinical practice for the treatment of patients with sporadic renal cell carcinoma and pancreatic neuroendocrine tumors. However, whether such treatments are effective in patients with VHL disease remains to be elucidated. We herein report a Japanese patient with VHL disease who was successfully treated with sunitinib for approximately 5 years.

Enalapril and ASS inhibit tumor growth in a transgenic mouse model of islet cell tumors.

Accumulating evidence suggests a role for angiotensin-converting enzymes involving the angiotensin II-receptor 1 (AT1-R) and the cyclooxygenase pathway in carcinogenesis. The effects of ASS and enalapril were assessed in vitro and in a transgenic mouse model of pancreatic neuroendocrine neoplasms (pNENs). The effects of enalapril and ASS on proliferation and expression of the AGTR1A and its target gene vascular endothelial growth factor (Vegfa) were assessed in the neuroendocrine cell line BON1. Rip1-Tag2 mice were treated daily with either 0.6 mg/kg bodyweight of enalapril i.p., 20 mg/kg bodyweight of ASS i.p., or a vehicle in a prevention (weeks 5-12) and a survival group (week 5 till death). Tumor surface, weight of pancreatic glands, immunostaining for AT1-R and nuclear factor kappa beta (NFKB), and mice survival were analyzed. In addition, sections from human specimens of 20 insulinomas, ten gastrinomas, and 12 non-functional pNENs were evaluated for AT1-R and NFKB (NFKB1) expression and grouped according to the current WHO classification. Proliferation was significantly inhibited by enalapril and ASS in BON1 cells, with the combination being the most effective. Treatment with enalapril and ASS led to significant downregulation of known target genes Vegf and Rela at RNA level. Tumor growth was significantly inhibited by enalapril and ASS in the prevention group displayed by a reduction of tumor size (84%/67%) and number (30%/45%). Furthermore, daily treatment with enalapril and ASS prolonged the overall median survival compared with vehicle-treated Rip1-Tag2 (107 days) mice by 9 and 17 days (P=0.016 and P=0.013). The AT1-R and the inflammatory transcription factor NFKB were abolished completely upon enalapril and ASS treatment. AT1-R and NFKB expressions were observed in 80% of human pNENs. Enalapril and ASS may provide an approach for chemoprevention and treatment of pNENs.

In vivo imaging of GLP-1R with a targeted bimodal PET/fluorescence imaging agent.

Accurate visualization and quantification of ß-cell mass is critical for the improved understanding, diagnosis, and treatment of both type 1 diabetes (T1D) and insulinoma. Here, we describe the synthesis of a bimodal imaging probe (PET/fluorescence) for imaging GLP-1R expression in the pancreas and in pancreatic islet cell tumors. The conjugation of a bimodal imaging tag containing a near-infrared fluorescent dye, and the copper chelator sarcophagine to the GLP-1R targeting peptide exendin-4 provided the basis for the bimodal imaging probe. Conjugation was performed via a novel sequential one-pot synthetic procedure including (64)Cu radiolabeling and copper-catalyzed click-conjugation. The bimodal imaging agent (64)Cu-E4-Fl was synthesized in good radiochemical yield and specific activity (RCY = 36%, specific activity: 141 µCi/µg, >98% radiochemical purity). The agent showed good performance in vivo and ex vivo, visualizing small xenografts (<2 mm) with PET and pancreatic ß-cell mass by phosphor autoradiography. Using the fluorescent properties of the probe, we were able to detect individual pancreatic islets, confirming specific binding to GLP-1R and surpassing the sensitivity of the radioactive label. The use of bimodal PET/fluorescent imaging probes is promising for preoperative imaging and fluorescence-assisted analysis of patient tissues. We believe that our procedure could become relevant as a protocol for the development of bimodal imaging agents.

Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor.

Foregut neuroendocrine tumors [NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor (EGFR) by growth factors, gastrointestinal (GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGFα and various GI hormones to stimulate growth of the human foregut carcinoid,BON, the somatostatinoma QGP-1 and the rat islet tumor,Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGFα and the other growth-stimulating GI hormones increased Tyr(1068) EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs.

Hedgehog inhibition with the orally bioavailable Smo antagonist LDE225 represses tumor growth and prolongs survival in a transgenic mouse model of islet cell neoplasms.

BACKGROUND: This study was designed to evaluate the role of the hedgehog pathway in tumor progression of murine islet cell tumors. Blockade of aberrant hedgehog activation has recently been proposed as a therapeutic target, but effects in models of islet cell tumors with a new orally bioavailable Smoothened (Smo) antagonist LDE225 have not been examined. MATERIAL AND METHODS: To assess in vivo effects, transgenic Rip1Tag2 mice, which develop islet cell neoplasms, were treated with vehicle or LDE225 (80 mg/kg/d) from week 5 until death. The resected pancreata were evaluated macroscopically and microscopically by iummohistochemsistry. Quantitative real-time polymerase chain reaction was performed for hedgehog target genes with RNA from islet, isolated from treated and untreated Rip1Tag2 mice. RESULTS: LDE225 significantly reduced tumor volume by 95% compared with untreated control mice. Hedgehog inhibition with LDE225 significantly prolonged median survival in the used transgenic mouse model (105 vs 116 days; P = 0.02). Quantitative real-time polymerase chain reaction for downstream hedgehog target genes demonstrated significant downregulation in the islet cell tumors of Rip1Tag2 mice treated with LDE225, confirming the ability to achieve effective pharmacologic levels of LDE225 within the desired tissue site, in vivo. CONCLUSION: This is the first study to show that the orally bioavailable Smo antagonist LDE225 may provide a new option for therapy of islet cell neoplasms.

VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer.

Angiogenesis inhibitors that block VEGF receptor (VEGFR) signaling slow the growth of many types of tumors, but eventually the disease progresses. Multiple strategies are being explored to improve efficacy by concurrent inhibition of other functionally relevant receptor tyrosine kinases (RTK). XL880 (foretinib, GSK1363089) and XL184 (cabozantinib) are small-molecule inhibitors that potently block multiple RTKs, including VEGFR and the receptor of hepatocyte growth factor c-Met, which can drive tumor invasion and metastasis. This study compared the cellular effects of XL880 and XL184 with those of an RTK inhibitor (XL999) that blocks VEGFR but not c-Met. Treatment of RIP-Tag2 mice with XL999 resulted in 43% reduction in vascularity of spontaneous pancreatic islet tumors over 7 days, but treatment with XL880 or XL184 eliminated approximately 80% of the tumor vasculature, reduced pericytes and empty basement membrane sleeves, caused widespread intratumoral hypoxia and tumor cell apoptosis, and slowed regrowth of the tumor vasculature after drug withdrawal. Importantly, XL880 and XL184 also decreased invasiveness of primary tumors and reduced metastasis. Overall, these findings indicate that inhibition of c-Met and functionally related kinases amplifies the effects of VEGFR blockade and leads to rapid, robust, and progressive regression of tumor vasculature, increased intratumoral hypoxia and apoptosis, and reduced tumor invasiveness and metastasis.

Polymorphic genetic control of tumor invasion in a mouse model of pancreatic neuroendocrine carcinogenesis.

Cancer is a disease subject to both genetic and environmental influences. In this study, we used the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis to identify a genetic locus that influences tumor progression to an invasive growth state. RT2 mice inbred into the C57BL/6 (B6) background develop both noninvasive pancreatic neuroendocrine tumors (PNET) and invasive carcinomas with varying degrees of aggressiveness. In contrast, RT2 mice inbred into the C3HeB/Fe (C3H) background are comparatively resistant to the development of invasive tumors, as are RT2 C3HB6(F1) hybrid mice. Using linkage analysis, we identified a 13-Mb locus on mouse chromosome 17 with significant linkage to the development of highly invasive PNETs. A gene residing in this locus, the anaplastic lymphoma kinase (Alk), was expressed at significantly lower levels in PNETs from invasion-resistant C3H mice compared with invasion-susceptible B6 mice, and pharmacological inhibition of Alk led to reduced tumor invasiveness in RT2 B6 mice. Collectively, our results demonstrate that tumor invasion is subject to polymorphic genetic control and identify Alk as a genetic modifier of invasive tumor growth.

Successful control of intractable hypoglycemia using rapamycin in an 86-year-old man with a pancreatic insulin-secreting islet cell tumor and metastases.

CONTEXT: Insulinomas are rare tumors of the pancreatic islet cells that produce insulin. Approximately 5 to 10% of these tumors are cancerous, and control of insulin secretion and hypoglycemia may be difficult in these patients. Malignant insulinomas generally respond poorly to traditional chemotherapeutic agent regimens. At present, streptozotocin is the only approved drug for the treatment of pancreatic islet cell tumors. SETTING AND PATIENT: This report describes a case of an elderly gentleman with a metastatic pancreatic insulinoma and severe hypoglycemia. A continuous infusion of octreotide lowered the blood glucose levels further. He required diazoxide, a thiazide diuretic, phenytoin, and a constant infusion of glucose to control the hypoglycemia and elevated insulin levels. INTERVENTION: Rapamycin was administered at an oral dose of 2 mg/d. RESULTS: On the mTOR (mammalian target of rapamycin) agent rapamycin, he was weaned off all drugs except for the thiazide diuretic and maintained euglycemia with a reduction of circulating insulin levels. He remained euglycemic for the past year with no evidence of tumor progression based on Octreoscan. His quality of life is excellent, and he remains active having recently completed a triathlon. CONCLUSIONS: Rapamycin may provide a useful means of abrogating tumor growth and controlling hypoglycemia in malignant insulinomas by reducing the malignant beta-cell growth and proliferation as well as inhibiting insulin production.

Hepatic artery chemoinfusion with chemoembolization for neuroendocrine cancer with progressive hepatic metastases despite octreotide therapy.

BACKGROUND: Hepatic metastases from neuroendocrine cancer dramatically reduce survival, introducing an important opportunity for intervention. Several treatment modalities have been examined, but an optimal treatment approach has been difficult to define. We evaluated a regimen combining hepatic artery chemoinfusion with chemoembolization. METHODS: Patients with neuroendocrine cancer and diffuse hepatic metastases were treated with hepatic artery chemoinfusion and chemoembolization when they demonstrated disease progression despite octreotide therapy. Four monthly cycles of 5-fluorouracil were administered via hepatic artery infusion with chemoembolization after the final 2 cycles. Response was defined by radiologic response or symptomatic improvement. RESULTS: Seventy-seven patients were treated; 18 received chemoinfusion only. The treatment-related mortality rate was 7%. The overall response rate was 80% for patients with carcinoid or islet cell neoplasms. Median progression-free survival was 19 months. Median disease-specific survival was 39 months from the first treatment; 1- and 5-year survival rates were 78% and 27%, respectively. CONCLUSION: Survival after initiating this regimen was over 3 years for the majority of patients exhibiting progression of extensive, unresectable hepatic disease despite octreotide therapy. The addition of hepatic artery chemoinfusion to chemoembolization offers a high probability of clinical benefit to patients who, otherwise, have severely limited therapeutic options and a dismal survival.

Phase II study of thalidomide in patients with metastatic carcinoid and islet cell tumors.

PURPOSE: Carcinoid and islet cell tumors are known to be highly vascular. There is no effective systemic therapy currently available for metastatic disease. We conducted a phase II trial to evaluate the efficacy of the anti-antiangiogenic agent thalidomide in metastatic neuroendocrine tumors. PATIENTS AND METHODS: Eighteen patients with measurable, histologically proven metastatic carcinoid neuroendocrine carcinomas (well-differentiated, n = 13; moderately-differentiated, n = 5) were enrolled on this study. The majority of the patients had gastrointestinal primaries (small bowel, 8; pancreas, 5; colon, 1). All but one patient had hepatic metastases, and 12 patients (67%) had carcinoid syndrome. All patients had Eastern Cooperative Oncology Group performance status of zero or one. Eight patients (44%) had received previous hepatic artery chemoembolization and 11 (61%) had undergone surgical resection. Patients were started on oral thalidomide at a daily dose of 200 mg that was escalated to the target dose of 400 mg daily after 2 weeks. Tumor response was assessed at 12-week intervals using RECIST criteria. Planned treatment duration was 24 weeks unless unacceptable toxicity or disease progression was observed. RESULTS: No patient achieved a partial remission or a complete remission. Best response was stable disease (SD) in 11 of 16 response-evaluable patients (69%). Serum pancreastatin results did not correlate with clinical response. Grade 3 toxicities included dizziness with orthostatic hypotension (n = 5), sensory neuropathy (n = 2), fatigue (n = 2), hemorrhagic cystitis (n = 1), and deep venous thrombosis (n = 1). Frequent Grade 1-2 toxicities were: fatigue (n = 13), constipation (n = 13), dry mouth (n = 12), somnolence (n = 12), dizziness/syncope (n = 10), weight gain (n = 5), and peripheral neuropathy (n = 5). CONCLUSIONS: Thalidomide was fairly well tolerated in patients with metastatic carcinoid/islet cell tumors, but failed to reveal any objective responses. The single stage design of the trial makes it difficult to determine whether observed SD in a subset of patients was attributable to the indolent nature of these tumors, or to beneficial effect of thalidomide.

Effective treatment of locally advanced endocrine tumors of the pancreas with chemoradiotherapy.

BACKGROUND/AIMS: The use of chemoradiation in the management of locally advanced pancreatic endocrine tumors has not been reported in the medical literature. Patients with unresectable tumors are often included in trials of systemic chemotherapy, and use of external beam radiation has been only described in few case reports. Given the sensitivity of pancreatic endocrine tumors to cytotoxic agents including streptozocin, doxorubicin and 5-FU, we have hypothesized that the combination of concurrent and sequential chemotherapy and radiation will yield higher response rates than acheivable with chemotherapy alone. METHODS: Six patients with locally advanced pancreatic endocrine tumors were treated with a protocol consisting of radiation concurrent with infusional 5-FU (or capecitabine) along with induction and consolidation chemotherapy (streptozocin and doxorubicin). We retrospectively determined the objective radiographic response rate. RESULTS: The objective response rate was 80%. With a median follow-up of 29 months, all six patients in the study have had continued reduction in tumor size from the time of the first posttreatment scan to the most recent scan. None of the patients have experienced local or metastatic disease progression. Treatment was well tolerated with minimal toxicity. CONCLUSION: The combination of concurrent and sequential chemoradiotherapy appears to be a highly effective treatment for locally advanced pancreatic endocrine tumors.

Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors.

PURPOSE: There are few treatment options for patients with metastasized or inoperable endocrine gastroenteropancreatic (GEP) tumors. Chemotherapy can be effective, but the response is usually less than 1 year. Here, we present the results of treatment with a radiolabeled somatostatin analog, [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate). PATIENTS AND METHODS: One hundred thirty-one patients with somatostatin receptor-positive tumors were treated with up to a cumulative dose of 600 to 800 mCi (22.2 to 29.6 GBq) of 177Lu-octreotate. RESULTS: One patient developed renal insufficiency, and another patient developed hepatorenal syndrome. Creatinine clearance did not change significantly in the other patients. WHO hematologic toxicity grade 3 or 4 occurred after less than 2% of the administrations. We observed complete remission in three patients (2%), partial remission in 32 patients (26%), minor response (tumor diameter decrease of 25% to 50%) in 24 patients (19%), stable disease (SD) in 44 patients (35%), and progressive disease (PD) in 22 patients (18%). Higher remission rates were positively correlated with high uptake on pretherapy somatostatin receptor imaging and a limited number of liver metastases, whereas PD was significantly more frequent in patients with a low performance score and extensive disease. Median time to progression in 103 patients who either had SD or tumor regression was more than 36 months. CONCLUSION: Treatment with 177Lu-octreotate results in tumor remission in a high percentage of patients with GEP tumors. Serious side effects are rare. The median time to progression compares favorably with chemotherapy. Results are better in patients with a limited tumor load. Therefore, early treatment, even in patients who have no PD, may be better.

A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer.

PURPOSE: A transgenic mouse model has revealed parameters of the angiogenic switch during multistep tumorigenesis of pancreatic islets, and demonstrated efficacy of antiangiogenic therapies. Pericytes have been revealed as functionally important for tumor neovasculature, using kinase inhibitors targeting their platelet-derived growth factor receptors (PDGFRs). Additionally, vascular endothelial growth factor receptor (VEGFR) inhibitors and metronomic chemotherapy show modest benefit against early- but not late-stage disease. MATERIALS AND METHODS: Seeking to improve efficacy against otherwise intractable end-stage pancreatic islet tumors, two receptor tyrosine kinase inhibitors, imatinib and SU11248, were used to disrupt PDGFR-mediated pericyte support of tumor endothelial cells in concert with maximum-tolerated dose (MTD) or metronomic chemotherapy and/or VEGFR inhibition. RESULTS: Imatinib, despite equivocal efficacy as monotherapy, reduced pericyte coverage of tumor vessels and enhanced efficacy in combination with metronomic chemotherapy or VEGFR inhibition. A regimen involving all three was even better. MTD using cyclophosphamide caused transitory regression, but then rapid regrowth, in contrast to metronomic cyclophosphamide plus imatinib, which produced stable disease. The MTD regimen elicited apoptosis of tumor cells but not endothelial cells, whereas the other regimens increased endothelial cell apoptosis concordant with efficacy. A "chemo-switch" protocol, involving sequential MTD and then metronomic chemotherapy, overlaid with multitargeted inhibition of PDGFR and VEGFR, gave complete responses and unprecedented survival advantage in this model. CONCLUSION: This study demonstrates a potentially tractable clinical strategy in a stringent preclinical model, wherein standard-of-care chemotherapy is followed by a novel maintenance regimen: PDFGR is targeted to disrupt pericyte support, while metronomic chemotherapy and/or VEGFR inhibitors target consequently sensitized endothelial cells, collectively destabilizing pre-existing tumor vasculature and inhibiting ongoing angiogenesis.

A case of dopamine agonists inhibiting pancreatic polypeptide secretion from an islet cell tumor.

A patient with a large prolactinoma developed a metastatic islet cell tumor secreting pancreatic polypeptide. Dopamine agonist drugs reduced the prolactin levels to normal, caused a 7-fold decrease in the pancreatic polypeptide levels, and inhibited the liver metastases. Elevated chromogranin A levels also normalized on the higher doses of bromocriptine. Dopamine receptors are found in many endocrine tissues, and the expression of dopamine-2 receptor on endocrine tumors establishes the potential for response to dopamine agonist treatment. The relatively benign risk profile of dopaminergic agents makes further testing of these drugs to treat neuroendocrine tumors a worthwhile endeavor.

Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282.

BACKGROUND: A phase II study of dacarbazine (DTIC), was conducted to determine the response rate, duration of response, toxicity and overall survival of patients with advanced pancreatic islet cell tumors. PATIENTS AND METHODS: Fifty patients with advanced pancreatic islet cell tumors, having progressive symptoms or evidence of rapidly advancing disease were entered on this study. DTIC was given by IV infusion at a dose of 850 mg/m2, over 60-90 minutes, repeated every four weeks. RESULTS: The response rate was 33% in 42 patients who had measurable tumor, and 34% in the 50 patients (90% confidence interval (90% CI): 23%-47%). The majority of the responses were seen in patients without prior chemotherapy. Median overall survival was 19.3 months. There were two lethal toxicities on the study, one septic shock and one myocardial infarction. Grade 4 toxicities were, hematological (5 patients), sepsis, neurological (depression and paranoid behavior) and bleeding (1 patient each). The most common toxicity was vomiting, grade 3 in 13% of patients. CONCLUSIONS: DTIC has activity in advanced previously untreated pancreatic islet cell tumors.

Islet cell tumors of the pancreas: the medical oncologist's perspective.

Islet cell tumors of the pancreas are rare, indolent, neuroendocrine tumors. Approximately 50% of the patients diagnosed with these tumors present with symptoms related to various biologically active hormones that are secreted by these neoplasms. Currently, the only curative treatment for islet cell tumors is complete surgical resection. Management of metastatic disease is conservative. Initial treatment of these tumors includes expectant observation and medical management of symptoms with clinical monitoring and serial CT scans to assess tumor growth. Patients with rapidly progressive disease, with local symptoms caused by tumor bulk, or with uncontrolled symptoms related to hormone secretion require more aggressive medical or surgical intervention. The somatostatin analogue octreotide may help control hormone secretion and stabilize tumor growth. Patients refractory to octreotide with tumor predominantly in the liver are potential candidates for mechanical ablative techniques, such as hepatic arterial embolization. Radiofrequency ablation and cryosurgical techniques may also be useful, although specific data are limited. Surgical resection of metastatic disease may offer palliative relief of symptoms related to hormone secretion in carefully selected patients. Chemotherapy may be used for palliation when ablative techniques have failed or when significant extrahepatic disease is present. Streptozicin-based combinations remain the first line standard, but major objective responses are less common than had been previously thought. Because of the overall modest success of current chemotherapeutic regimens, patients with advanced disease in need of treatment should be encouraged to enroll in clinical trials testing newer antineoplastic agents or newer treatment strategies.

A Phase II study of high-dose paclitaxel in patients with advanced neuroendocrine tumors.

BACKGROUND: New agents with antitumor activity in patients with neuroendocrine tumors are sorely needed. A Phase II study of high-dose paclitaxel in patients with metastatic carcinoid and islet cell tumors was performed at the Mayo Clinic. Granulocyte-colony-stimulating factor (GCSF) also was administered to ameliorate neutropenia. METHODS: Twenty-four patients (14 with carcinoid tumors, 9 with islet cell tumors, and 1 with an anaplastic tumor) were enrolled on this Phase II study of paclitaxel given as a 24-hour continuous infusion at a dose of 250 mg/m(2) every 3 weeks plus GCSF at a dose of 5 microg/kg/day subcutaneously, beginning 24 hours after the completion of the paclitaxel dose and continuing until the absolute neutrophil count was > 10,000/microL. RESULTS: All 24 patients were evaluable for analysis. The overall response rate was 8% (95% confidence interval [95% CI], 0-0.11). At last follow-up all patients except 1 had developed disease progression, with an estimated median time to disease progression of 3.2 months (95% CI, 1.6-6.0 months). The estimated median survival was 1.5 years (95% CI, 1.0-1.8 years). Hematologic toxicity was significant with 12 of 24 patients developing Grade 4 (according to the National Cancer Institute Common Toxicity Criteria scale) neutropenia; however, there were no septic deaths reported. There were 17 episodes of Grade 4 neutropenia in these 12 patients and the duration of these events ranged from 2-5 days. More common nonhematologic toxicities included arthralgia (21 patients), anorexia (15 patients), nausea (15 patients), diarrhea (12 patients), and allergic reactions (2 patients). CONCLUSIONS: Given the lack of antitumor activity of paclitaxel and the significant hematologic toxicity observed despite the use of GCSF support in the current study cohort of patients with neuroendocrine tumors, further studies of this combination in this particular patient population are not recommended.