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

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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.

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References

  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

    Article  PubMed  Google Scholar 

  2. Metz DC, Jensen RT (2008) Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology 135:1469–1492. doi:10.1053/j.gastro.2008.05.047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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, Lyon

    Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 92:205–216

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 68:227–232

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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. 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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

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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).

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Author notes

  1. Kyong Joo Lee and Jae Hee Cho contributed equally to this study as co-authors.

  2. Yong Tae Kim and Woo Jin Lee contributed equally to this study as co-respondents.

Authors and Affiliations

  1. Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, South Korea

    Kyong Joo Lee

  2. Department of Internal Medicine, Gachon University, Gil Medical Center, Incheon, South Korea

    Jae Hee Cho

  3. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea

    Sang Hyub Lee, Ji Kon Ryu, Woo Hyun Paik & Yong Tae Kim

  4. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea

    Si Young Song & Seungmin Bang

  5. Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Kwang Hyuk Lee & Jong Kyun Lee

  6. Department of Internal Medicine, Inha University College of Medicine, Incheon, South Korea

    Seok Jeong

  7. Center for Liver Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, 10408, South Korea

    Sang Myung Woo & Woo Jin Lee

  8. Department of Internal Medicine, Soon Chun Hyang University Cheonan Hospital, Soon Chun Hyang University College of Medicine, Cheonan, South Korea

    Tae Hoon Lee

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  1. Kyong Joo Lee
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Correspondence to Yong Tae Kim or Woo Jin Lee.

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Lee, K.J., Cho, J.H., Lee, S.H. et al. Clinical outcomes of everolimus in patients with advanced, nonfunctioning pancreatic neuroendocrine tumors: a multicenter study in Korea. Cancer Chemother Pharmacol 80, 799–805 (2017). https://doi.org/10.1007/s00280-017-3421-7

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  • DOI: https://doi.org/10.1007/s00280-017-3421-7

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