This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yao, J. C. Articles by Ajani, J. A. Search for Related Content PubMed PubMed Citation Articles by Yao, J. C. Articles by Ajani, J. A. Social Bookmarking                            What's this?

Targeting Vascular Endothelial Growth Factor in Advanced Carcinoid Tumor: A Random Assignment Phase II Study of Depot Octreotide With Bevacizumab and Pegylated Interferon Alfa-2b

James C. Yao, Alexandria Phan, Paulo M. Hoff, Helen X. Chen, Chusilp Charnsangavej, Sai-Ching J. Yeung, Kenneth Hess, Chaan Ng, James L. Abbruzzese, Jaffer A. Ajani

From the Departments of Gastrointestinal Medical Oncology, Diagnostic Imaging, General Internal Medicine, Ambulatory Treatment & Emergency Care and Biostatistics and Applied Mathematics, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD

Corresponding author: James C. Yao, MD, Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas M.D. Anderson Cancer, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: jyao{at}mdanderson.org

	ABSTRACT

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

 
Purpose Effective systemic therapy for advanced carcinoid is lacking. The combination of bevacizumab (BEV) and pegylated (PEG) interferon alfa-2b was evaluated among patients with metastatic or unresectable carcinoid tumors.

Patients and Methods Forty-four patients on stable doses of octreotide were randomly assigned to 18 weeks of treatment with bevacizumab or PEG interferon alfa-2b. At disease progression (PD) or at the end of 18 weeks (whichever occurred earlier), patients received bevacizumab plus PEG interferon until progression. Functional computer tomography (CT) scans were performed to measure effect on tumor blood flow.

Results In the bevacizumab arm, four patients (18%) achieved confirmed partial response (PR), 17 patients (77%) had stable disease (SD), and one patient (5%) had PD. In the PEG interferon arm, 15 patients (68%) had SD and six patients (27%) had PD. Progression-free survival (PFS) rates after 18 weeks of monotherapy were 95% in bevacizumab versus 68% on the PEG interferon arm. The overall median PFS for all 44 patients is 63 weeks. Compared with paired baseline measurements on functional CT scans, we observed a 49% (P < .01) and 28% (P < .01) decrease in tumor blood flow at day 2 and week 18 among patients treated with bevacizumab. No significant changes in tumor blood flow were observed following PEG interferon. PEG interferon alfa-2b treatment was associated with decrease in plasma basic fibroblast growth factor (bFGF; P = .04) and increase in plasma interleukin-18 (IL-18; P < .01). No significant changes in bFGF or IL-18 following treatment with bevacizumab were observed.

Conclusion Bevacizumab therapy resulted in objective responses, reduction of tumor blood flow, and longer PFS in patients with carcinoid than PEG interferon treatment.

	INTRODUCTION

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

 
Carcinoid tumors can originate from neuroendocrine cells scattered throughout the body. Their clinical course can often be indolent, but resistant to therapy. While generally thought to be rare, its incidence in the Surveillance, Epidemiology, and End Results registry has been rising over the last three decades.^1,2

Currently, there is no approved agent to treat patients with advanced carcinoid tumor growth in the United States. Interferon alfa was approved by the European Medicines Agency treating of metastatic carcinoid tumors with syndrome. While the ability of interferon to decrease tumor bulk is limited, it may have significant cytostatic activity.^3,4 In one study, patients who had undergone surgical debulking were randomly assigned to octreotide or octreotide plus interferon. An improvement in time-to-progression was observed in the interferon arm (hazard ratio, 0.28; 95% CI, 0.16 to 0.45).⁵

Carcinoid tumors are vascular and are known to express vascular endothelial growth factor (VEGF).^6,7 Recent studies have demonstrated the expression of VEGFR-FLK and VEGFR-FLT1 on carcinoid tumor cells.⁸ VEGF expression in resected human carcinoid tumors has also been found to correlate with metastases and decreased PFS duration.⁹ In a xenograft model of a human carcinoid, treatment with an anti-VEGF monoclonal antibody was found to inhibit tumor growth and metastases.¹⁰

While carcinoids have the reputation of being more indolent, most patients diagnosed with metastatic disease will eventually succumb to the disease. In this randomized phase II study, we examine the activity of bevacizumab, or pegylated (PEG) interferon alfa-2b, as monotherapy followed by a combination of the two agents in patients with advanced carcinoid tumors.

	PATIENTS AND METHODS

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

 
Study Population
The study population consisted of patients with a pathologically confirmed metastastic carcinoid tumor, while poorly differentiated, small-cell, and high-grade neuroendocrine tumors were excluded. Prior liver-directed therapy was allowed, provided measurable disease remained. One prior cytotoxic chemotherapy was allowed, while prior interferon was not allowed. Additional eligibility criteria included Zubrod performance status 2; granulocyte count greater than 1,500/mm³; hemoglobin greater than 8 g/dL; platelet count greater than 100,000/mm³; bilirubin less than 1.5 times the upper limit of normal; creatinine 1.5 mg/dL; AST and ALT 2.5x the upper limit of the normal. All patients were on a stable dose of depot octreotide not exceeding 30 mg every 3 weeks before study entry and continued this same prestudy dose throughout the course of the study. This study was approved by the institutional review board.

Study Objective and Design
After informed consent was obtained, patients were randomly assigned to one of two treatment arms. During the initial 18 weeks, patients received either PEG interferon alfa-2b 0.5 mcg/kg subcutaneously once per week or bevacizumab 15 mg/kg intravenously once every 3 weeks. All patients continued depot octreotide at the prestudy dosage. After the completion of the 18-week therapy, or at first evidence of disease progression (PD), patients were allowed to proceed to stage II. During stage II, patients received both PEG interferon and bevacizumab.

Study Evaluations
Pretreatment and on-study evaluations included history, physical examination, laboratory tests, and tumor markers (chromogranin A and urinary 5-hydroxyindoleacetic acid [5-HIAA]). Tumor measurements were made by computer tomography (CT) scans or magnetic resonance imaging (MRI) at baseline and every 9 weeks.

Response and progression were evaluated in this study using the criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee.¹¹ Progression-free survival (PFS) and overall survival durations were measured from the date of study entry. Biochemical response was evaluated among patients with elevated markers at baseline and defined by either a 50% reduction in tumor markers or normalization of the elevated tumor marker.

Safety was assessed based on Common Toxicity Criteria, version 2. Dose reductions for PEG interferon were required for neutrophil count less than 0.75 x 10⁹/L or platelet count less than 80 x 10⁹/L and for Common Toxicity Criteria grade 3/4 nonhematologic toxicities. Bevacizumab doses were held for proteinuria 2 g per 24 hours, or other grade 3/4 toxicities. Bevacizumab was permanently discontinued for grade 4 hypertension.

Statistical Considerations
A two-stage random assignment phase II design was used for this trial (Fig 1). In this design, 44 patients were to eventually receive the combination regimen. However, in the first six courses (stage I, 18 weeks), half of the patients (n = 22) were to receive bevacizumab and the other half (n = 22) received PEG interferon alone. Such a design provides the following data: (1) if RR in the single agent portion is 0 of 22 patients, we would have 90% confidence to declare that the RR of single agent is less than 10%; (2) all treated patients (a total of 44) would be evaluable for the response rate and PFS data of the combination regimen (stage II).

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Study schema. Patients on a stable dose of depot octreotide for 2 months were enrolled onto one of two arms. Functional computer tomography were obtained at pretreatment baseline, 2 days after first dose of bevacizumab, 9 weeks after the first dose of pegylated (PEG) interferon alfa-2b, and 18 weeks after the start of initial treatment. PD, disease progression.

Functional CT
To assess the effect of treatment on tumor blood flow, functional CT scans were offered as an optional procedure for patients with lesions that were at least 2 cm in craniocaudal extension. Scans were obtained at pretreatment baseline, 2 days after first dose of bevacizumab, 9 weeks after the first dose of PEG interferon, and 18 weeks after the start of initial treatment.

Functional maps of whole tumor blood flow (BF), blood volume (BV), mean transit time, and permeability surface (PS) maps were generated using CT perfusion II software.¹²

Analysis of Plasma Concentrations of Basic Fibroblast Growth Factor and Interleukin-18
Plasma samples were obtained from patients who consented to have optional blood drawn for analyses of bFGF (basic fibroblast growth factor) and IL-18 (interleukin-18) before and after treatment. ELISA-Kine Plus kits for bFGF and IL-18 were purchased from MP Biomedicals (Irvine, CA) and Medical & Biologic Laboratories Co (Nagoya, Japan), respectively.

	RESULTS

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

 
Patient Population
Between May 2002 and May 2003, 44 patients were enrolled in the study. All patients completed treatment under stage I and were evaluated for response. Two patients on the PEG interferon arm did not return to M.D. Anderson after receiving a combined therapy on stage II. No statistically significant differences in patient characteristics were observed. Details of patient characteristics are provided in Table 1.

A total of eight patients had PD during the initial phase of monotherapy (stage I). In the phase of combination therapy (stage II), the single patient who progressed on bevacizumab continued to progress following 9 weeks of treatment with both drugs. Of the seven patients who had PD during stage I therapy with PEG interferon, one patient achieved PR following the addition of bevacizumab. Five patients achieved SD, while one patient did not return for response evaluation due to physical deterioration. One patient, who had SD with minor tumor growth during the initial 18 weeks on the PEG interferon, also achieved confirmed PR after the addition of bevacizumab. In addition to RECIST response, a substantial number of patients receiving bevacizumab achieved tumor shrinkage of varying amounts below the 30% threshold. Serial tumor measurements are depicted in Figure 2.

View larger version (34K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Percent change in sum of target lesion diameters over time. Lines declining below 100% represents tumor shrinkage. Lines rising above 100% represents tumor growth. (A) and (B) Percent change during stage I where patients received either bevacizumab or PEG interferon. (C) and (D) Percent change over the duration of the study.

Progression-Free Survival and Overall Survival Analyses
Stage I of this random assignment phase II study was designed to explore differences in clinical outcomes between patients treated with bevacizumab or PEG interferon. We observed longer PFS in patients treated with bevacizumab. The PFS rate at week 18 was 95% among patients assigned to the bevacizumab arm and 68% among patients treated with PEG interferon (P = .02; Fig 3).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Progression-free survival (PFS) estimates using the Kaplan-Meier method. (A) Stage I, PFS rate at week 18 was 95% among patients assigned to the bevacizumab (BEV) arm and 68% among patients treated with pegylated (PEG) interferon (P = .02). (B) The overall median PFS duration calculated from date of study entry for all 44 patients is 63 weeks (95% CI, 51 to 75 weeks). The median PFS duration by initial treatment assignment were 66 weeks (95% CI, 54 to 77 weeks) for BEV and 56 weeks (95% CI, 34 to 78) for PEG interferon (P = .34).

At the time of the last follow-up, 27 patients remained alive with disease. The median PFS has not been reached. The 1-year, 2-year, and 3-year survival rates are 93%, 67%, and 56% respectively. As all patients were allowed to cross-over to receive the same treatment at week 18, no difference in survival was expected or observed between initial treatment arms (P = .71).

Safety
Safety was monitored by patient diaries and scheduled laboratory measurements. The details of all adverse events are summarized in Table 2and 3. For patients who experiences grades 3 and 4 adverse events (5%), the rates of occurrence during the first 18 weeks were compared between the patients on the treatment assignment of octreotide plus bevacizumab versus octreotide plus PEG interferon. There were no significant differences in the rates of fatigue, nausea, vomiting, headache, and myalgia. However, granulocytopenia was more common in the PEG interferon arm (14% v 0%; P = .02), and hypertension was more common among patients who received bevacizumab (18% v 0%; P = .01).

For the entire trial, grade 3 or 4 hypertension occurred in 48% of the patients. Seventeen (39%) patients had a history of baseline hypertension before study entry. Of these, 76% required either dose escalation of their existing antihypertensive medications or addition of a new drug. The use of three antihypertensives was required by some patients. Hypertension was generally manageable with medical therapy. Two patients developed grade 4 hypertension requiring admission to intensive care units for blood pressure control, and bevacizumab was discontinued. In both cases, hypertension resolved without organ damage. Four patients developed proteinuria more than 2 gm per 24 hours (reversible with dose delay). All four patients developed grade 3 or 4 hypertension.

Correlative Studies
As an optional procedure, 24 patients (12 patients per arm) consented to have functional CT scans performed to monitor changes blood flow associated with therapy. We compared the changes in tumor blood flow parameters by the Wilcoxon signed ranks test. Among the patients assigned to the bevacizumab arm, we observed significant decreases in mean tumor BF, BV, and PS (Fig 4). Compared with paired baseline measurements, tumor BF decreased by 49% (P < .01) and 28% (P < .01) at day 2 and week 18. Similarly, BV decreased by 34% (P = .01) and 24% (P = .01) at day 2 and week 18, respectively, and PS decreased by 33% (P = .09) at day 2 and 40% (P = .04) at week 18. No significant changes in mean transit time were observed. It should be noted that day 2 fCT measurements were made near the peak level of bevacizumab after the first dose, while the week 18 measurements were made near trough level after repeated doses (approximately 3 weeks after the last dose of bevacizumab). No significant changes in tumor blood flow parameters were associated with therapy with PEG interferon (Fig 4).

View larger version (69K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. (A) Representative blood flow parametric map showing decrease in tumor blood flow following treatment. (B) Changes in anatomic computed tomography in the same patient. (C) Changes in functional computed tomography parameters among 24 patients (12 per arm). BEV, bevacizumab; PEG, pegylated interferon.

Plasma FGF and IL-18
Measurements of plasma bFGF and IL-18 were performed among 36 patients who consented to have blood drawn. Treatment with PEG interferon was associated with a significant reduction in plasma bFGF (Wilcoxon signed ranks test). Compared with baseline measurements, the relative reductions at weeks –9 and –18 were 57% (P = .04) and 52% (P = .01), respectively. Treatment with PEG interferon was also associated with significant increases in plasma IL-18. Compared with baseline measurements, the relative increase in IL-18 at weeks –9 and –18 were 58% (P < .01) and 57% (P < .01), respectively.

No significant changes in plasma bFGF or IL-18 were associated with bevacizumab therapy. Changes in bFGF and IL-18 were not correlated with outcome due to limitation of our sample size.

	DISCUSSION

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

 
Our prior study showed that among low-grade neuroendocrine tumors, VEGF expression is associated with metastasis and shortened PFS. Our goal in this study is to combine bevacizumab with other agents with potential antiangiogenic activity for therapy in advanced carcinoid tumors. Octreotide is commonly used for the control of carcinoid syndrome and has also been reported to have antiangiogenic properties.^13-23 In a xenograft model of a neuroendocrine tumor, treatment with octreotide resulted in decreased plasma VEGF, bFGF, and microvessel density.²⁰ Decrease in plasma VEGF and insulinlike growth factor 1 have been observed in human studies.^13,16 In addition, octreotide has also been described to inhibit endothelial proliferation through somatostatin receptors present on endothelial cells.²⁴

Interferon alfa has also been widely studied in carcinoids and has been described to have antiangiogenic properties. A recent in vitro study showed that interferon decreased transcription of VEGF gene expression through a Sp1 and/or Sp3 dependent inhibition of VEGF promoter activity.²⁵ Further, it has been suggested that the antiangiogenic property of interferon is best explored by continuous low-dose exposure. We used a pegylated formulation of interferon at one third of the recommended dose for hepatitis C to explore its antiangiogenic properties.

Bevacizumab in our study had antitumor activity against a wide variety of carcinoid tumors including those from foregut, midgut, and hindgut. This is supported by observation of PRs as well as minor responses to bevacizumab. Although the trial was not powered or designed to compare the two treatment assignments, the observation of a more favorable PFS rate during the 18 weeks of monotherapy with bevacizumab versus PEG interferon is promising. In fact, the PFS of the octreotide plus PEG interferon group is similar to those previously reported in a phase II study of octreotide plus short-acting interferon alfa (67% at 3 months).²⁶ The overall median PFS of 63 weeks also compares favorably to results with chemotherapy. For example, in the recently reported phase III study^26a of fluorouracil plus doxorubicin or streptozocin (E1281), the median PFS was shorter at 4.5 and 5.3 months respectively. The observed decrease in tumor blood flow suggests that the activity of bevacizumab is mediated at least in part through its effect on the vasculature.

While we did not observe any substantial tumor shrinkage following PEG interferon, we did observe a higher percentage of patients achieving 5-HIAA response. As these patients were on a stable dose of octreotide at study entry, our data suggests that low-dose PEG interferon may be useful as an adjunct in combination with octreotide for control of refractory carcinoid syndrome. This is supported by prior studies suggesting synergism between somatostatin analogs and immediate release interferon in controlling carcinoid syndrome.^26-28 Treatment with interferon was also associated reduction in the growth stimulatory cytokine bFGF and increase in antitumor cytokine IL-18. However, we did not observe a significant change in tumor blood flow parameters. In our prior study with imatinib, increase of bFGF was associated with tumor growth.²⁹ Thus, the effect of interferon may be mediated through FGF receptors that may be present on carcinoid cells.³⁰

We further acknowledge that this study was not designed to compare the efficacy of bevacizumab with a standard dose of interferon, which has been described to prolong PFS⁵ and has an objective response rate of approximate 12%.⁴ Indeed, PEG interferon may well have contributed to the favorable median overall PFS observed in this study. For example, the median PFS survival of 63 weeks (14.4 months) is longer than the median PFS reported in studies using single agent sunitinib (42 weeks)³¹ or sorafinib (7.8 months)³² in advanced carcinoid tumors.

In this random assignment run-in study, treatment with VEGF monoclonal antibody bevacizumab led to rapid and sustained decrease in tumor blood flow, favorable PFS, and tumor regression. However, the number of patients included in our study is limited, and the study was not designed to compare the efficacy of standard dose interferon and bevacizumab. A larger confirmatory study (S0518) sponsored by the Southwest Oncology Group and the National Cancer Institute and supported by Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, and North Central Cancer Treatment Group through Cancer Trials Support Unit is underway. The primary objective of the trial will be to compare the progression-free survival of depot octreotide plus either bevacizumab 15 mg/kg every 3 weeks or conventional dosing of interferon at 5 million units three times per week.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

 
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: None Consultant or Advisory Role: James C. Yao, Genentech (C); Paulo M. Hoff, Genentech (U) Stock Ownership: None Honoraria: Paulo M. Hoff, Genentech Research Funding: Chusilp Charnsangavej, GE Medical Systems Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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

 
Conception and design: James C. Yao, Helen X. Chen, Chusilp Charnsangavej, Sai-Ching J. Yeung, Kenneth Hess, James L. Abbruzzese, Jaffer A. Ajani

Financial support: Helen X. Chen

Provision of study materials or patients: James C. Yao, Alexandria Phan, Paulo M. Hoff, Sai-Ching J. Yeung, Jaffer A. Ajani

Collection and assembly of data: James C. Yao, Alexandria Phan, Paulo M. Hoff, Chusilp Charnsangavej, Chaan Ng

Data analysis and interpretation: James C. Yao, Helen X. Chen, Chusilp Charnsangavej, Sai-Ching J. Yeung, Kenneth Hess, Chaan Ng

Manuscript writing: James C. Yao, Helen X. Chen, Jaffer A. Ajani

Final approval of manuscript: James C. Yao, Alexandria Phan, Paulo M. Hoff, Helen X. Chen, Chusilp Charnsangavej, Sai-Ching J. Yeung, Kenneth Hess, Chaan Ng, James L. Abbruzzese, Jaffer A. Ajani

	NOTES

 
Supported in part by grants from National Cancer Institute (N01-CM-17003 and 22XSO94A), Schering Plough, and the American Society of Clinical Oncology. This trial was sponsored by Cancer Therapy Evaluation Program of NCI under the Clinical Research and Development Agreement (CRADA) with Genentech Inc.

Presented in part at the American Society of Clinical Oncology Annual Meeting, Orlando, FL, May 13-17, 2005, and the 9th International Symposium on Anti-angiogenic Agents, February 1 to 3, 2007, San Diego, CA.

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

	REFERENCES

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

 
1. Modlin IM, Lye KD, Kidd M: A 5-decade analysis of 13,715 carcinoid tumors. Cancer 97:934-959, 2003[CrossRef][Medline]

2. Yao JC, Vauthey JN: Primary and metastatic hepatic carcinoid: Is there an algorithm? Ann Surg Oncol 10:1133-1135, 2003[CrossRef][Medline]

3. Faiss S, Pape UF, Bohmig M, et al: Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors: The International Lanreotide and Interferon Alfa Study Group. J Clin Oncol 21:2689-2696, 2003[Abstract/Free Full Text]

4. Schnirer II, Yao JC, Ajani JA: Carcinoid: A comprehensive review. Acta Oncol 42:672-692, 2003[CrossRef][Medline]

5. Klby L, Persson G, Franzen S, et al: Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg 90:687-693, 2003[CrossRef][Medline]

6. Terris B, Scoazec JY, Rubbia L, et al: Expression of vascular endothelial growth factor in digestive neuroendocrine tumours. Histopathology 32:133-138, 1998[CrossRef][Medline]

7. Ambs S, Bennett WP, Merriam WG, et al: Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer and the relation to p53. Br J Cancer 78:233-239, 1998[Medline]

8. Hobday TJ, Rubin J, Goldberg R, et al: Molecular markers in metastatic gastrointestinal neuroendocrine tumors. Proc Am Soc Clin Oncol 22:269a, 2003 (abstr 1078)

9. Phan AT, Wang L, Xie K, et al: Association of VEGF expression with poor prognosis among patients with low-grade neuroendocrine carcinoma. J Clin Oncol 24:18s, 2006 (suppl; abstr 4091)[CrossRef]

10. Konno H, Arai T, Tanaka T, et al: Antitumor effect of a neutralizing antibody to vascular endothelial growth factor on liver metastasis of endocrine neoplasm. Japanese Journal of Cancer Res 89:933-939, 1998

11. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

12. Lee TY: Functional CT: Physiological models. Trends Biotechnol 20:S3-7, 2002[Medline]

13. Cascinu S: Drug therapy in diarrheal diseases in oncology/hematology patients. Crit Rev Oncol Hematol 18:37-50, 1995[CrossRef][Medline]

14. Danesi R, Benelli U, Del Bianchi S, et al: Octreotide inhibits endothelial cell proliferation and angiogenesis in the chick chorioallantoic membrane and in the rat cornea. Proc Annu Meet Am Assoc Cancer Res, Orlando, FL, 1993 (abstr A2109)

15. Danesi R, Agen C, Benelli U, et al: Inhibition of experimental angiogenesis by the somatostatin analogue octreotide acetate (SMS 201-995). Clin Cancer Res 3:265-272, 1997[Abstract]

16. Fazekas T, Pavics L, Pollak R, et al: [Gastric carcinoid (apudoma) associated with pernicious anemia]. Orv Hetil 129:1269-1271, 1988[Medline]

17. Reubi JC, Horisberger U, Laissue J: High density of somatostatin receptors in veins surrounding human cancer tissue: Role in tumor-host interaction? Int J Cancer 56:681-688, 1994[Medline]

18. Wang C, Tang C: Inhibition of human gastric cancer metastasis by ocreotide in vitro and in vivo [Chinese]. Zhonghua Yi Xue Za Zhi 82:19-22, 2002[Medline]

19. Jia WD, Xu GL, Xu RN, et al: Octreotide acts as an antitumor angiogenesis compound and suppresses tumor growth in nude mice bearing human hepatocellular carcinoma xenografts. J Cancer Res Clin Oncol 129:327-334, 2003[CrossRef][Medline]

20. Koizumi M, Onda M, Tanaka N, et al: Antiangiogenic effect of octreotide inhibits the growth of human rectal neuroendocrine carcinoma. Digestion 65:200-206, 2002[CrossRef][Medline]

21. Mentlein R, Eichler O, Forstreuter F, et al: Somatostatin inhibits the production of vascular endothelial growth factor in human glioma cells. Int J Cancer 92:545-550, 2001[CrossRef][Medline]

22. Lawnicka H, Stepien H, Wyczolkowska J, et al: Effect of somatostatin and octreotide on proliferation and vascular endothelial growth factor secretion from murine endothelial cell line (HECa10) culture. Biochem Biophys Res Commun 268:567-571, 2000[CrossRef][Medline]

23. Buscail L, Vernejoul F, Faure P, et al: Controle de la proliferation cellulaire par la somatostatine. Ann Endocrinol 63:2S13-18, 2002[Medline]

24. Adams RL, Adams IP, Lindow SW, et al: Somatostatin receptors 2 and 5 are preferentially expressed in proliferating endothelium. Br J Cancer 92:1493-1498, 2005[CrossRef][Medline]

25. von Marschall Z, Scholz A, Cramer T, et al: Effects of interferon alpha on vascular endothelial growth factor gene transcription and tumor angiogenesis.[comment]. J Natl Cancer Inst 95:437-448, 2003[Abstract/Free Full Text]

26. Frank M, Klose KJ, Wied M, et al: Combination therapy with octreotide and alpha-interferon: Effect on tumor growth in metastatic endocrine gastroenteropancreatic tumors. Am J Gastroenterol 94:1381-1387, 1999[Medline]

26. Sun W, Lipsitz S, Catalano P, et al: Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol 23:4897-4904, 2005[Abstract/Free Full Text]

27. Tiensuu Janson EM, Ahlstrom H, Andersson T, et al: Octreotide and interferon alfa: A new combination for the treatment of malignant carcinoid tumours. Eur J Cancer 28a:1647-1650, 1992[CrossRef]

28. Janson ET, Oberg K: Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol 32:225-229, 1993[Medline]

29. Yao JC, Zhang JX, Rashid A, et al: Clinical and in vitro studies of imatinib in advanced carcinoid tumors. Clin Cancer Res 13:234-240, 2007[Abstract/Free Full Text]

30. Facco C, La Rosa S, Dionigi A, et al: High expression of growth factors and growth factor receptors in ovarian metastases from ileal carcinoids: An immunohistochemical study of 2 cases. Arch Pathol Lab Med 122:828-832, 1998[Medline]

31. Kulke MH, 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 23:310s, 2005 (suppl; abstr 4008)

32. Hobday TJ, Rubin J, Holen K, et al: MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study. J Clin Oncol 25:4504-4505, 2007[Free Full Text]

Submitted August 14, 2007; accepted November 20, 2007.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				L. N. Jackson, L. A. Chen, S. D. Larson, S. R. Silva, P. G. Rychahou, P. J. Boor, J. Li, G. DeFreitas, W. L. Stafford, C. M. Townsend Jr., et al. Development and Characterization of a Novel In vivo Model of Carcinoid Syndrome Clin. Cancer Res., April 15, 2009; 15(8): 2747 - 2755. [Abstract] [Full Text] [PDF]

				J. C. Yao In Reply: J. Clin. Oncol., December 20, 2008; 26(36): 6013 - 6015. [Full Text] [PDF]

				L. K. Kvols Revisiting C.G. Moertel's Land of Small Tumors J. Clin. Oncol., November 1, 2008; 26(31): 5005 - 5007. [Full Text] [PDF]

				J. C. Yao, A. T. Phan, D. Z. Chang, R. A. Wolff, K. Hess, S. Gupta, C. Jacobs, J. E. Mares, A. N. Landgraf, A. Rashid, et al. Efficacy of RAD001 (Everolimus) and Octreotide LAR in Advanced Low- to Intermediate-Grade Neuroendocrine Tumors: Results of a Phase II Study J. Clin. Oncol., September 10, 2008; 26(26): 4311 - 4318. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yao, J. C. Articles by Ajani, J. A. Search for Related Content PubMed PubMed Citation Articles by Yao, J. C. Articles by Ajani, J. A. Social Bookmarking                            What's this?