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Patient-Reported Outcomes and Quality of Life with Sunitinib Versus Placebo for Pancreatic Neuroendocrine Tumors: Results From an International Phase III Trial

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Abstract

Objective

The objective of this analysis was to compare patient-reported outcomes and health-related quality of life (HRQoL) in a pivotal phase III trial of sunitinib versus placebo in patients with progressive, well-differentiated pancreatic neuroendocrine tumors (NCT00428597).

Patients and Methods

Patients received sunitinib 37.5 mg (n = 86) or placebo (n = 85) on a continuous daily-dosing schedule until disease progression, unacceptable adverse events (AEs), or death. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 at baseline, Day 1 of every 4-week cycle, and end of treatment or withdrawal. Changes ≥10 points on each scale or item were deemed clinically meaningful.

Results

Sunitinib had anti-tumor effects and improved progression-free survival (PFS) compared with placebo. The study was terminated early for this reason and because of more serious AEs and deaths with placebo. Baseline HRQoL scores were well balanced between study arms, and were generally maintained over time in both groups. In the first 10 cycles, there were no significant differences between groups in global HRQoL, cognitive, emotional, physical, role, and social functioning domains, or symptom scales, except for worsening diarrhea with sunitinib (p < 0.0001 vs. placebo). Insomnia also worsened with sunitinib (p = 0.0372 vs. placebo), but the difference was not clinically meaningful.

Conclusion

With the exception of diarrhea (a recognized side effect), sunitinib had no impact on global HRQoL, functional domains, or symptom scales during the progression-free period. Hence, in patients with pancreatic neuroendocrine tumors, sunitinib provided a benefit in PFS without adversely affecting HRQoL.

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References

  1. Yao JC, Eisner MP, Leary C, Dagohoy C, Phan A, Rashid A, et al. Population-based study of islet cell carcinoma. Ann Surg Oncol. 2007;14:3492–500. doi:10.1245/s10434-007-9566-6.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063–72. doi:10.1200/JCO.2007.15.4377.

    Article  PubMed  Google Scholar 

  3. Kulke MH, Bendell J, Kvols L, Picus J, Pommier R, Yao J. Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumors. J Hematol Oncol. 2011;4:29. doi:10.1186/1756-8722-4-29.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Vinik E, Carlton CA, Silva MP, Vinik AI. Development of the Norfolk quality of life tool for assessing patients with neuroendocrine tumors. Pancreas. 2009;38:e87–95. doi:10.1097/MPA.0b013e31819b6441.

    Article  PubMed  Google Scholar 

  5. Vinik A, Casellini C, Perry RR, Feliberti E, Vingan H. Diagnosis and management of pancreatic neuroendocrine tumors (PNETS). In: De Groot LJ, Beck-Peccoz P, Chrousos G et al. editors. Endotext. South Dartmouth, Mass: MDText.com Inc. pp endotext.org.

  6. Jimenez-Fonseca P, Carmona-Bayonas A, Martin-Perez E, Crespo G, Serrano R, Llanos M, et al. Health-related quality of life in well-differentiated metastatic gastroenteropancreatic neuroendocrine tumors. Cancer Metastasis Rev. 2015;34:381–400. doi:10.1007/s10555-015-9573-1.

    Article  CAS  PubMed  Google Scholar 

  7. Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003;2:471–8.

    Article  CAS  PubMed  Google Scholar 

  8. Yao VJ, Sennino B, Davis RB, Christensen J, Hu-Lowe D, Roberts G, Et al. (2006) Combined anti-VEGFR and anti-PDGFR actions of sunitinib on blood vessels in preclinical tumor models [abstract]. 18th EORTC NCI-AACR Symposium, Prague, Czech Republic. Eur J Cancer Supplements 27-8.

  9. Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, 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. doi:10.1200/JCO.2005.02.2194.

    Article  CAS  PubMed  Google Scholar 

  10. Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol. 2008;26:3403–10. doi:10.1200/JCO.2007.15.9020.

    Article  CAS  PubMed  Google Scholar 

  11. Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501–13. doi:10.1056/NEJMoa1003825.

    Article  CAS  PubMed  Google Scholar 

  12. Carey MS, Bacon M, Tu D, Butler L, Bezjak A, Stuart GC. The prognostic effects of performance status and quality of life scores on progression-free survival and overall survival in advanced ovarian cancer. Gynecol Oncol. 2008;108:100–5. doi:10.1016/j.ygyno.2007.08.088.

    Article  CAS  PubMed  Google Scholar 

  13. Cella D, Bushmakin AG, Cappelleri JC, Charbonneau C, Michaelson MD, Motzer RJ. Baseline quality of life as a prognostic survival tool in patients receiving sunitinib for metastatic renal cell carcinoma. Br J Cancer. 2012;106:646–50. doi:10.1038/bjc.2011.589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cella D, Cappelleri JC, Bushmakin A, Charbonneau C, Li JZ, Kim ST, et al. Quality of life predicts progression-free survival in patients with metastatic renal cell carcinoma treated with sunitinib versus interferon alfa. J Oncol Pract. 2009;5:66–70. doi:10.1200/JOP.0922004.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, 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. 2000;92:205–16.

    Article  CAS  PubMed  Google Scholar 

  16. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, 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;85:365–76. doi:10.1093/jnci/85.5.365.

    Article  CAS  PubMed  Google Scholar 

  17. Fayers PM, Aaronson NK, Bjordal K, Grønvold M, Curran D, Bottomley A. EORTC QLQ-C30 scoring manual, 3rd edition. 2001 (last update 2001). http://www.eortc.be/qol/files/SCManualQLQ-C30.pdf Accessed 26 May 2016.

  18. Osoba D, Brada M, Yung WK, Prados M. Health-related quality of life in patients treated with temozolomide versus procarbazine for recurrent glioblastoma multiforme. J Clin Oncol. 2000;18:1481–91.

    CAS  PubMed  Google Scholar 

  19. 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;16:139–44.

    CAS  PubMed  Google Scholar 

  20. Hedeker D, Gibbons RD. Application of random-effects pattern-mixture models for missing data in longitudinal studies. Psychol Methods. 1997;2:64–78.

  21. Brunner SM, Weber F, Werner JM, Agha A, Farkas SA, Schlitt HJ, et al. Neuroendocrine tumors of the pancreas: a retrospective single-center analysis using the ENETS TNM-classification and immunohistochemical markers for risk stratification. BMC Surg. 2015;15:49. doi:10.1186/s12893-015-0033-1.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kim SJ, Kim JW, Oh DY, Han SW, Lee SH, Kim DW, et al. Clinical course of neuroendocrine tumors with different origins (the pancreas, gastrointestinal tract, and lung). Am J Clin Oncol. 2012;35:549–56. doi:10.1097/COC.0b013e31821dee0f.

    Article  PubMed  Google Scholar 

  23. Rindi G, Falconi M, Klersy C, Albarello L, Boninsegna L, Buchler MW, et al. TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst. 2012;104:764–77. doi:10.1093/jnci/djs208.

    Article  CAS  PubMed  Google Scholar 

  24. Scott NW, Fayers PM, Aaronson NK, Bottomley A, de Graeff A, Groenvold M, et al. EORTC QLQ-C30 reference values manual. 2008 (last update Jul 2008). http://groups.eortc.be/qol/sites/default/files/img/newsletter/reference_values_manual2008.pdf Accessed 26 May 2016.

  25. Pfizer Inc. SUTENT® (sunitinib malate) prescribing information. 2006 (last update May 2015). http://labeling.pfizer.com/showlabeling.aspx?id=607 Accessed 26 May 2016.

  26. Mühlbacher AC, Juhnke C. Patient preferences versus physicians’ judgement: does it make a difference in healthcare decision making? Appl Health Econ Health Policy. 2013;11:163–80. doi:10.1007/s40258-013-0023-3.

    Article  PubMed  Google Scholar 

  27. Mohamed AF, Hauber AB, Neary MP. Patient benefit-risk preferences for targeted agents in the treatment of renal cell carcinoma. Pharmacoeconomics. 2011;29:977–88. doi:10.2165/11593370-000000000-00000.

    Article  PubMed  Google Scholar 

  28. Raymond E, Faivre S. Learning experiences with sunitinib continuous daily dosing in patients with pancreatic neuroendocrine tumours. Curr Oncol. 2014;21:309–17. doi:10.3747/co.21.1647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Valle JW, Faivre S, Hubner RA, Grande E, Raymond E. Practical management of sunitinib toxicities in the treatment of pancreatic neuroendocrine tumors. Cancer Treat Rev. 2014;40:1230–8. doi:10.1016/j.ctrv.2014.09.001.

    Article  CAS  PubMed  Google Scholar 

  30. Khan S, Krenning EP, van Essen M, Kam BL, Teunissen JJ, Kwekkeboom DJ. Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumors treated with [177Lu-DOTA0, Tyr3]octreotate. J Nucl Med. 2011;52:1361–8. doi:10.2967/jnumed.111.087932.

    Article  CAS  PubMed  Google Scholar 

  31. Davies AH, Larsson G, Ardill J, Friend E, Jones L, Falconi M, et al. Development of a disease-specific Quality of Life questionnaire module for patients with gastrointestinal neuroendocrine tumours. Eur J Cancer. 2006;42:477–84. doi:10.1016/j.ejca.2005.10.025.

    Article  CAS  PubMed  Google Scholar 

  32. Vinik AI, Raymond E. Pancreatic neuroendocrine tumors: approach to treatment with focus on sunitinib. Therap Adv Gastroenterol. 2013;6:396–411. doi:10.1177/1756283X13493878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors wish to thank all of the participating patients and their families, as well as the global network of investigators, research nurses, study coordinators, and operations staff. The views expressed in this manuscript reflect those of the authors and do not necessarily reflect the official views of the authors’ institutions. Medical writing assistance was provided by Nicola Crofts and Susanne Gilbert at ACUMED® (New York, NY, USA), an Ashfield company, part of UDG Healthcare plc, and by Vardit Dror, PhD, of Engage Scientific Solutions, with funding from Pfizer Inc.

Author information

Authors and Affiliations

  1. Strelitz Diabetes Research Center and Neuroendocrine Unit, Eastern Virginia Medical School, Strelitz Diabetes Center, Norfolk, VA, USA

    Aaron Vinik

  2. Quality of Life Department, European Organization for Research and Treatment of Cancer, Brussels, Belgium

    Andrew Bottomley

  3. Pfizer Inc, New York, NY, USA

    Beata Korytowsky, Rajiv Mundayat, Arlene Reisman & Zhixiao Wang

  4. Seoul National University College of Medicine, Seoul, Korea

    Yung-Jue Bang

  5. Paoli-Calmettes Institute, Marseille, France

    Jean-Luc Raoul

  6. The University of Manchester/The Christie NHS Foundation Trust, Manchester, UK

    Juan W. Valle

  7. McGill University Hospital Center, Montreal, Canada

    Peter Metrakos

  8. Bad Berka Central Clinic, Bad Berka, Germany

    Dieter Hörsch

  9. Pfizer Oncology, La Jolla, CA, USA

    Richard C. Chao

  10. Hôpital Beaujon, Clichy, France

    Eric Raymond

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Corresponding author

Correspondence to Aaron Vinik.

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Funding Statement

This study was funded by Pfizer Inc.

Conflicts of Interest

Dr Vinik is a board member at Medscape and has received consultancy fees from Pfizer, Merck, Pamlab, NeuroMetrix and ISIS Pharmaceuticals; research funding from Pfizer, the American Diabetes Association, the National Institutes of Health, Impeto Medical, Daiichi Sankyo, Tercica, ViroMed, Intarcia Therapeutics and Novo Nordisk; and honoraria from Merck and Pamlab. Dr Bottomley has reported no potential conflicts of interest. Ms Korytowsky was an employee of Pfizer at the time the study was conducted. Dr Bang has received consultancy fees and research funding from Pfizer. Dr Raoul has reported no potential conflicts of interest. Dr Valle has received honoraria from Pfizer, Novartis and Ipsen and research funding from Novartis. Dr Metrakos has received consulting fees from Novartis, Ipsen and Pfizer, and research funding from Novartis and Pfizer. Dr Hörsch has received honoraria and travel support from Pfizer, Novartis, Ipsen and Lexicon and research funding from Novartis, ITG, Eckart and Ziegler, Covidien and MSD. Mr Mundayat is an employee of Pfizer. Ms Reisman is an employee of Pfizer. Dr Wang was an employee of Pfizer at the time the study was conducted. Dr Chao was an employee of Pfizer at the time the study was conducted and owns Pfizer stock. Dr Raymond has received consulting fees and research funding from Pfizer, Novartis and Ipsen.

Presented in part at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, USA, June 4–8, 2010, and the North American Neuroendocrine Tumor Society (NANETS) Neuroendocrine Tumor Symposium, Santa Fe, New Mexico, USA, October 29–30, 2010.

Additional information

Beata Korytowsky, Zhixiao Wang and Richard C. Chao are former Pfizer employees.

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Vinik, A., Bottomley, A., Korytowsky, B. et al. Patient-Reported Outcomes and Quality of Life with Sunitinib Versus Placebo for Pancreatic Neuroendocrine Tumors: Results From an International Phase III Trial. Targ Oncol 11, 815–824 (2016). https://doi.org/10.1007/s11523-016-0462-5

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