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Cancer Chemotherapy and Pharmacology

, Volume 80, Issue 4, pp 799–805 | Cite as

Clinical outcomes of everolimus in patients with advanced, nonfunctioning pancreatic neuroendocrine tumors: a multicenter study in Korea

  • Kyong Joo Lee
  • Jae Hee Cho
  • Sang Hyub Lee
  • Si Young Song
  • Kwang Hyuk Lee
  • Seok Jeong
  • Ji Kon Ryu
  • Sang Myung Woo
  • Seungmin Bang
  • Jong Kyun Lee
  • Tae Hoon Lee
  • Woo Hyun Paik
  • Yong Tae KimEmail author
  • Woo Jin LeeEmail author
Original Article

Abstract

Purpose

Everolimus is a standard treatment option for advanced pancreatic neuroendocrine tumors (pNETs). This multicenter study evaluated the efficacy and safety of everolimus in low and intermediate grade advanced pNETs.

Methods

Tumors were graded according to the World Health Organization 2010 classification system. Patients with low or intermediate grade pNETs who received everolimus as first- or second-line chemotherapy between 2002 and 2014 were included.

Results

A total of 40 patients with metastatic or recurrent pNETs were included in this study. The median age was 54.5 years (range 19–83 years). Twelve patients (30%) experienced recurrence. There were 11 patients (27.5%) with low grade pNETs and 29 (72.5%) with intermediate. Everolimus was administered as first-line therapy in 30 patients (75%) and as second-line therapy in 10 patients (25%). The median progression-free survival (PFS) of patients with low and intermediate grade pNETs was significantly different (median not reached vs. 11 months, P = 0.015). On multivariate analysis, tumor grade (intermediate grade; HR 6.52, 95% CI 1.31–32.27, P = 0.022) was the only independent prognostic factor for PFS in pNETs. The most common adverse events were stomatitis, skin rash, and anemia.

Conclusions

World Health Organization 2010 grade is the most important determinant for PFS in patients undergoing everolimus treatment for pNETs with an acceptable incidence of adverse events.

Keywords

Everolimus Pancreatic neuroendocrine tumor World Health Organization classification Tumor grade Prognosis 

Notes

Acknowledgements

This study was conducted as a part of the Korean Gastroenteropancreatic Neuroendocrine Tumor Registry research project of the Korean Society of Gastrointestinal Cancer (KSGC).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

References

  1. 1.
    Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB (2008) One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26:3063–3072. doi: 10.1200/JCO.2007.15.4377 CrossRefPubMedGoogle Scholar
  2. 2.
    Metz DC, Jensen RT (2008) Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology 135:1469–1492. doi: 10.1053/j.gastro.2008.05.047 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Gastrointestinal Pathology Study Group of Korean Society of Pathologists, Cho MY, Kim JM, Sohn JH, Kim MJ, Kim KM, Kim WH, Kim H, Kook MC, Park DY, Lee JH, Chang H, Jung ES, Kim HK, Jin SY, Choi JH, Gu MJ, Kim S, Kang MS, Cho CH, Park MI, Kang YK, Kim YW, Yoon SO, Bae HI, Joo M, Moon WS, Kang DY, Chang SJ (2012) Current trends of the incidence and pathological diagnosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in Korea 2000–2009: multicenter Study. Cancer Res Treat 44:157–165. doi: 10.4143/crt.2012.44.3.157 CrossRefGoogle Scholar
  4. 4.
    Cho JH, Ryu JK, Song SY, Hwang JH, Lee DK, Woo SM, Joo YE, Jeong S, Lee SO, Park BK, Cheon YK, Han J, Kim TN, Lee JK, Moon SH, Kim H, Park ET, Hwang JC, Kim TH, Jeon TJ, Cho CM, Choi HS, Lee WJ (2016) Prognostic validity of the American Joint Committee on cancer and the european neuroendocrine tumors staging classifications for pancreatic neuroendocrine tumors: a retrospective nationwide multicenter study in South Korea. Pancreas 45:941–946. doi: 10.1097/MPA.0000000000000586 CrossRefPubMedGoogle Scholar
  5. 5.
    Ito T, Igarashi H, Nakamura K, Sasano H, Okusaka T, Takano K, Komoto I, Tanaka M, Imamura M, Jensen RT, Takayanagi R, Shimatsu A (2015) Epidemiological trends of pancreatic and gastrointestinal neuroendocrine tumors in Japan: a nationwide survey analysis. J Gastroenterol 50:58–64. doi: 10.1007/s00535-014-0934-2 CrossRefPubMedGoogle Scholar
  6. 6.
    Liu CT, Chen MH, Chen JS, Chen LT, Shan YS, Lu CH, Su YL, Ku FC, Chou WC, Chen YY (2016) The efficacy and safety of everolimus for the treatment of progressive gastroenteropancreatic neuroendocrine tumors: a multi-institution observational study in Taiwan. Asia Pac J Clin Oncol 12:396–402. doi: 10.1111/ajco.12571 CrossRefPubMedGoogle Scholar
  7. 7.
    Luo G, Javed A, Strosberg JR, Jin K, Zhang Y, Liu C, Xu J, Soares K, Weiss MJ, Zheng L, Wolfgang CL, Cives M, Wong J, Wang W, Sun J, Shao C, Wang W, Tan H, Li J, Ni Q, Shen L, Chen M, He J, Chen J, Yu X (2017) Modified staging classification for pancreatic neuroendocrine tumors on the basis of the American Joint Committee on Cancer and European Neuroendocrine Tumor Society Systems. J Clin Oncol 35:274–280. doi: 10.1200/JCO.2016.67.8193 CrossRefPubMedGoogle Scholar
  8. 8.
    Kim M, Lee S, Lee J, Park SH, Park JO, Park YS, Kang WK, Kim ST (2016) The role of plasma chromogranin A as assessment of treatment response in non-functioning gastroenteropancreatic neuroendocrine tumors. Cancer Res Treat 48:153–161. doi: 10.4143/crt.2014.183 CrossRefPubMedGoogle Scholar
  9. 9.
    International Agency for Research on Cancer, Bosman FT, Carneiro F, Hruban RH, Theise ND (2010) WHO classification of tumours of the digestive system (IARC WHO Classification of Tumours), 4th edn. International Agency for Research on Cancer, LyonGoogle Scholar
  10. 10.
    Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, Helm J, Kvols L (2011) First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 117:268–275. doi: 10.1002/cncr.25425 CrossRefPubMedGoogle Scholar
  11. 11.
    Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Horsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364:501–513. doi: 10.1056/NEJMoa1003825 CrossRefPubMedGoogle Scholar
  12. 12.
    Yao JC, Pavel M, Lombard-Bohas C, Van Cutsem E, Voi M, Brandt U, He W, Chen D, Capdevila J, de Vries EG, Tomassetti P, Hobday T, Pommier R, Oberg K (2016) Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: overall survival and circulating biomarkers from the randomized, phase III RADIANT-3 study. J Clin Oncol 34:3906–3913. doi: 10.1200/JCO.2016.68.0702 CrossRefGoogle Scholar
  13. 13.
    Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlackova E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P, Investigators C (2014) Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371:224–233. doi: 10.1056/NEJMoa1316158 CrossRefPubMedGoogle Scholar
  14. 14.
    Yoo C, Cho H, Song MJ, Hong SM, Kim KP, Chang HM, Chae H, Kim TW, Hong YS, Ryu MH, Kang YK, Kim SC, Ryoo BY (2017) Efficacy and safety of everolimus and sunitinib in patients with gastroenteropancreatic neuroendocrine tumor. Cancer Chemother Pharmacol 79:139–146. doi: 10.1007/s00280-016-3215-3 CrossRefPubMedGoogle Scholar
  15. 15.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) 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 92:205–216CrossRefPubMedGoogle Scholar
  16. 16.
    Oh DY, Kim TW, Park YS, Shin SJ, Shin SH, Song EK, Lee HJ, Lee KW, Bang YJ (2012) Phase 2 study of everolimus monotherapy in patients with nonfunctioning neuroendocrine tumors or pheochromocytomas/paragangliomas. Cancer 118:6162–6170. doi: 10.1002/cncr.27675 CrossRefPubMedGoogle Scholar
  17. 17.
    Lee L, Ito T, Igarashi H, Ueda K, Fujiyama T, Kawabe K, Ogawa Y (2017) Impact of everolimus on Japanese patients with advanced pancreatic neuroendocrine neoplasms. J Hepatobiliary Pancreat Sci 24:95–102. doi: 10.1002/jhbp.418 CrossRefPubMedGoogle Scholar
  18. 18.
    Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Oberg K, Rad001 in Advanced Neuroendocrine Tumors TTSG (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514–523. doi: 10.1056/NEJMoa1009290 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Moertel CG, Kvols LK, O’Connell MJ, Rubin J (1991) Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 68:227–232CrossRefPubMedGoogle Scholar
  20. 20.
    Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Blaker M, Harder J, Arnold C, Gress T, Arnold R, Group PS (2009) 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 27:4656–4663. doi: 10.1200/JCO.2009.22.8510 CrossRefPubMedGoogle Scholar
  21. 21.
    Pavel ME, Hainsworth JD, Baudin E, Peeters M, Horsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC, Group R-S (2011) Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 378:2005–2012. doi: 10.1016/S0140-6736(11)61742-X CrossRefPubMedGoogle Scholar
  22. 22.
    Bajetta E, Catena L, Fazio N, Pusceddu S, Biondani P, Blanco G, Ricci S, Aieta M, Pucci F, Valente M, Bianco N, Mauri CM, Spada F (2014) Everolimus in combination with octreotide long-acting repeatable in a first-line setting for patients with neuroendocrine tumors: an ITMO group study. Cancer 120:2457–2463. doi: 10.1002/cncr.28726 CrossRefPubMedGoogle Scholar
  23. 23.
    Pavel ME, Baudin E, Oberg KE, Hainsworth JD, Voi M, Rouyrre N, Peeters M, Gross DJ, Yao JC (2017) Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. doi: 10.1093/annonc/mdx19310.1093/annonc/mdx193 Google Scholar
  24. 24.
    Panzuto F, Rinzivillo M, Spada F, Antonuzzo L, Ibrahim T, Campana D, Fazio N, Delle Fave G (2017) Everolimus in pancreatic neuroendocrine carcinomas G3. Pancreas 46:302–305. doi: 10.1097/MPA.0000000000000762 CrossRefPubMedGoogle Scholar
  25. 25.
    Fonseca PJ, Uriol E, Galvan JA, Alvarez C, Perez Q, Villanueva N, Berros JP, Izquierdo M, Vieitez JM (2013) Prolonged clinical benefit of everolimus therapy in the management of high-grade pancreatic neuroendocrine carcinoma. Case Rep Oncol 6:441–449. doi: 10.1159/000354754 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Tanaka H, Matsusaki S, Baba Y, Isono Y, Kumazawa H, Sase T, Okano H, Saito T, Mukai K, Kaneko H (2015) Neuroendocrine tumor G3: a pancreatic well-differentiated neuroendocrine tumor with a high proliferative rate. Clin J Gastroenterol 8:414–420. doi: 10.1007/s12328-015-0609-4 CrossRefPubMedGoogle Scholar
  27. 27.
    Martin-Perez E, Capdevila J, Castellano D, Jimenez-Fonseca P, Salazar R, Beguiristain-Gomez A, Alonso-Orduna V, Martinez Del Prado P, Villabona-Artero C, Diaz-Perez JA, Monleon A, Marazuela M, Pachon V, Sastre-Valera J, Sevilla I, Castano A, Garcia-Carbonero R (2013) Prognostic factors and long-term outcome of pancreatic neuroendocrine neoplasms: Ki-67 index shows a greater impact on survival than disease stage. The large experience of the Spanish National Tumor Registry (RGETNE). Neuroendocrinology 98:156–168. doi: 10.1159/000355152 CrossRefPubMedGoogle Scholar
  28. 28.
    Panzuto F, Rinzivillo M, Fazio N, de Braud F, Luppi G, Zatelli MC, Lugli F, Tomassetti P, Riccardi F, Nuzzo C, Brizzi MP, Faggiano A, Zaniboni A, Nobili E, Pastorelli D, Cascinu S, Merlano M, Chiara S, Antonuzzo L, Funaioli C, Spada F, Pusceddu S, Fontana A, Ambrosio MR, Cassano A, Campana D, Carteni G, Appetecchia M, Berruti A, Colao A, Falconi M, Delle Fave G (2014) Real-world study of everolimus in advanced progressive neuroendocrine tumors. Oncologist 19:966–974. doi: 10.1634/theoncologist.2014-0037 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ito T, Okusaka T, Ikeda M, Igarashi H, Morizane C, Nakachi K, Tajima T, Kasuga A, Fujita Y, Furuse J (2012) Everolimus for advanced pancreatic neuroendocrine tumours: a subgroup analysis evaluating Japanese patients in the RADIANT-3 trial. Jpn J Clin Oncol 42:903–911. doi: 10.1093/jjco/hys123 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Kyong Joo Lee
    • 1
  • Jae Hee Cho
    • 2
  • Sang Hyub Lee
    • 3
  • Si Young Song
    • 4
  • Kwang Hyuk Lee
    • 5
  • Seok Jeong
    • 6
  • Ji Kon Ryu
    • 3
  • Sang Myung Woo
    • 7
  • Seungmin Bang
    • 4
  • Jong Kyun Lee
    • 5
  • Tae Hoon Lee
    • 8
  • Woo Hyun Paik
    • 3
  • Yong Tae Kim
    • 3
    Email author
  • Woo Jin Lee
    • 7
    Email author
  1. 1.Department of Internal MedicineYonsei University Wonju College of MedicineWonjuSouth Korea
  2. 2.Department of Internal MedicineGachon University, Gil Medical CenterIncheonSouth Korea
  3. 3.Department of Internal Medicine and Liver Research InstituteSeoul National University College of MedicineSeoulSouth Korea
  4. 4.Department of Internal MedicineYonsei University College of MedicineSeoulSouth Korea
  5. 5.Department of Internal MedicineSamsung Medical Center, Sungkyunkwan University School of MedicineSeoulSouth Korea
  6. 6.Department of Internal MedicineInha University College of MedicineIncheonSouth Korea
  7. 7.Center for Liver CancerNational Cancer CenterGoyangSouth Korea
  8. 8.Department of Internal MedicineSoon Chun Hyang University Cheonan Hospital, Soon Chun Hyang University College of MedicineCheonanSouth Korea

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