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Advances in the Management of Unresectable or Metastatic Pancreatic Neuroendocrine Tumors: Chemotherapy, Targeted Therapy, Hormonal Treatment, and Future Directions

  • Bilici, Ahmet (Department of Medical Oncology, Istanbul Medipol University, Medical Faculty)
  • 발행 : 2015.04.03

초록

Pancreatic neuroendocrine tumors (pNETs) are rare and heterogenous tumors and surgery to remove the primary tumor is the mainstay of treatment for resectable disease. However, curative surgery is often not feasible, because half of patients with pNET have metastases at the time of diagnosis. Palliative dubulking surgery and liver-directed therapies are appropriate options for these patients. Streptozocin-based regimens are standard, although temozolamide-based treatments are rapidly gaining wide clinical application. Somatostatin analogs are mainly indicated in hormonally active tumors to ameliorate symptoms. In addition, anti-tumoral activity has been proven in well-differentiated NETs. Recently, there has been tremendous progress in the molecular biology of pNETs; thereby, the efficacy of sunitinib and everolimus in the treatment of patients with metastatic pNETs has been proven by large placebo-controlled phase III trials. Currently, there are no definitively proven predictive biomarkers to evaluate response to medical therapies in patients with pNET. Therefore, further studies are needed to individualize and optimize their management. This article reviews systemic chemotherapy, targeted therapies, and anti-secretory treatments for the management of patients with unresectable or metastatic pNETs, summarized in the light of recent advances.

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참고문헌

  1. Aparicio T, Ducreux M, Baudin E, et al (2001). Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours. Eur J Cancer, 37, 1014-9. https://doi.org/10.1016/S0959-8049(01)00073-9
  2. Arnold R, Rinke A, Klose KJ, et al (2005). Octreotide versus octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: a randomized trial. Clin Gastroenterol Hepatol, 3, 761-71. https://doi.org/10.1016/S1542-3565(05)00481-7
  3. Arnold R, Wittenberg M, Rinke A, et al (2013). 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 (PROMID): Results on long-term survival. J Clin Oncol, 31, abstract 4030.
  4. Bajetta E, Catena L, Procopio G, et al (2007). Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumours? Cancer Chemother Pharmacol, 59, 637-42. https://doi.org/10.1007/s00280-006-0306-6
  5. Baldelli R, Barnabei A, Rizza L, et al (2014). Somatostatin analogs therapy in gastroenteropancreatic neuroendocrine tumors: current aspects and new perspectives. Front Endocrinol (Lausanne), 5, 7.
  6. Ballian N, Loeffler AG, Rajamanickam V, et al (2009). A simplified prognostic system for resected pancreatic neuroendocrine neoplasms. HPB (Oxford), 11, 422-8. https://doi.org/10.1111/j.1477-2574.2009.00082.x
  7. Chan JA, Stuart K, Earle CC, et al (2012). Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol, 30, 2963-8. https://doi.org/10.1200/JCO.2011.40.3147
  8. Chan JA, Blaszkowsky L, Stuart K, et al (2013). A prospective, phase 1/2 study of everolimus and temozolomide in patients with advanced pancreatic neuroendocrine tumor. Cancer, 119, 3212-8 https://doi.org/10.1002/cncr.28142
  9. Caplin ME, Pavel M, Cwikla JB, et al (2014). Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med, 371, 224-33. https://doi.org/10.1056/NEJMoa1316158
  10. Castellano D, Capdevila J, Sastre J, et al (2013). Sorafenib and bevacizumab combination targeted therapy in advanced neuroendocrine tumour: a phase II study of Spanish neuroendocrine tumour group (GETNE0801). Eur J Cancer, 49, 3780-7 https://doi.org/10.1016/j.ejca.2013.06.042
  11. Delaunoit T, Ducreux M, Boige V, et al (2004). The doxorubicin-streptozotocin combination for the treatment of advanced well-differentiated pancreatic endocrine carcinoma; a judicious option? Eur J Cancer, 40, 515-20. https://doi.org/10.1016/j.ejca.2003.09.035
  12. Desai DC, O'Dorisio TM, Schirmer WJ, et al (2001). Serum pancreastatin levels predict response to hepatic artery chemoembolization and somatostatin analogue therapy in metastatic neuroendocrine tumors. Regul Pept, 96, 113-7. https://doi.org/10.1016/S0167-0115(00)00167-1
  13. Duran I, Kortmansky J, Singh D, et al (2006). A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer, 95, 1148-54. https://doi.org/10.1038/sj.bjc.6603419
  14. Eriksson B, Skogseid B, Lundqvist G, et al (1990). Medical treatment and long-term survival in a prospective study of 84 patients with endocrine pancreatic tumors. Cancer, 65, 1883-90. https://doi.org/10.1002/1097-0142(19900501)65:9<1883::AID-CNCR2820650902>3.0.CO;2-3
  15. Fjallskog ML, Lejonklou MH, Oberg KE, Eriksson BK, Janson ET (2003). Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumors. Clin Cancer Res, 9, 1469-73.
  16. Fjallskog ML, Sundin A, Westlin JE, et al (2002). Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol, 19, 35-42. https://doi.org/10.1385/MO:19:1:35
  17. Fine RL, Gulati AP, Tsushima D, et al (2014). Prospective phase II study of capecitabine and temozolomide (CAPTEM) for progressive, moderately, and well-differentiated metastatic neuroendocrine tumors. J Clin Oncol, 32, abstract 179.
  18. Forrer F, Valkema R, Kwekkeboom DJ, de Jong M, Krenning EP (2007). Neuroendocrine tumors. peptide receptor radionuclide therapy. Best Pract Res Clin Endocrinol Metab, 21, 111-29. https://doi.org/10.1016/j.beem.2007.01.007
  19. Gulenchyn KY, Yao X, Asa SL, Singh S, Law C (2012). Radionuclide therapy in neuroendocrine tumours: a systematic review. Clin Oncol (R Coll Radiol), 24, 294-308. https://doi.org/10.1016/j.clon.2011.12.003
  20. Hainsworth JD, Spigel DR, Litchy S, Greco FA (2006). Phase II trial of paclitaxel, carboplatin, and etoposide in advanced poorly differentiated neuroendocrine carcinoma: a minnie pearl cancer research network Study. J Clin Oncol, 24, 3548-54. https://doi.org/10.1200/JCO.2005.05.0575
  21. Halfdanarson TR, Rubin J, Farnell MB, Grant CS, Petersen GM (2008). Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors. Endocr Relat Cancer, 15, 409-27. https://doi.org/10.1677/ERC-07-0221
  22. Hirshberg B, Cochran C, Skarulis MC, et al (2005). Malignant insulinoma: spectrum of unusual clinical features. Cancer, 104, 264-72. https://doi.org/10.1002/cncr.21179
  23. Hobday TJ, Qin R, Moore MJ, et al (2013). Multicenter phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in pancreatic neuroendocrine tumor (PNET). J Clin Oncol, 31, abstract 4032.
  24. Jensen RT, Berna MJ, Bingham DB, Norton JA (2008). Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer, 113, 1807-43. https://doi.org/10.1002/cncr.23648
  25. Khagi S, Saif MW (2015). Pancreatic neuroendocrine tumors: targeting the molecular basis of disease. Curr Opin Oncol, 27, 38-43. https://doi.org/10.1097/CCO.0000000000000146
  26. Kennedy AS, Dezarn WA, McNeillie P, et al (2008). Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in 148 patients. Am J Clin Oncol, 31, 271-9. https://doi.org/10.1097/COC.0b013e31815e4557
  27. Knigge U, Hansen CP, Stadil F (2008). Interventional treatment of neuroendocrine liver metastases. Surgeon, 6, 232-9. https://doi.org/10.1016/S1479-666X(08)80033-9
  28. Kouvaraki MA, Ajani JA, Hoff P, et al (2004). Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol, 22, 4762-71. https://doi.org/10.1200/JCO.2004.04.024
  29. Kulke MH, Hornick JL, Frauenhoffer C, et al (2009). O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res, 15, 338-45. https://doi.org/10.1158/1078-0432.CCR-08-1476
  30. Kunz PL, Kuo T, Zahn JM, et al (2010). A phase II study of capecitabine, oxaliplatin, and bevacizumab for metastatic or unresectable neuroendocrine tumors. J Clin Oncol, 28, abstract 4104.
  31. Kulke MH, Lenz HJ, Meropol NJ, et al (2008). Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol, 26, 3403-10. https://doi.org/10.1200/JCO.2007.15.9020
  32. Kulke MH, Stuart K, Enzinger PC, et al (2006). Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol, 24, 401-6. https://doi.org/10.1200/JCO.2005.03.6046
  33. Kwekkeboom DJ, de Herder WW, Kam BL, et al (2008). Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol, 26, 2124-30. https://doi.org/10.1200/JCO.2007.15.2553
  34. Kvols L, Wiedenmann B, Oberg K, et al (2006). The SOM230 carcinoid study group. safety and efficacy of pasireotide (SOM230) in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR: results of a phase II study. J Clin Oncol, 24, abstract 4082.
  35. Missiaglia E, Dalai I, Barbi S, et al (2010). Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol, 28, 245-55. https://doi.org/10.1200/JCO.2008.21.5988
  36. Mitry E, Baudin E, Ducreux M, et al (1999). Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin. Br J Cancer, 81, 1351-5. https://doi.org/10.1038/sj.bjc.6690325
  37. Modlin IM, Pavel M, Kidd M, Gustafsson BI (2010). Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther, 31, 169-88.
  38. Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D (1992). Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med, 326, 519-23. https://doi.org/10.1056/NEJM199202203260804
  39. Niederle MB, Hackl M, Kaserer K, Niederle B (2010). Gastroenteropancreatic neuroendocrine tumours: the current incidence and staging based on the WHO and European Neuroendocrine Tumour Society classification: an analysis based on prospectively collected parameters. Endocr Relat Cancer, 17, 909-18. https://doi.org/10.1677/ERC-10-0152
  40. Norton JA, Alexander HR, Fraker DL, et al (2003). Possible primary lymph node gastrinoma: occurrence, natural history, and predictive factors: a prospective study. Ann Surg, 237, 650-7.
  41. Oberg K (1992). Interferons in the management of neuroendocrine tumors and their possible mechanism of action. Yale J Biol Med, 65, 519-29.
  42. Oberg K (2000). Interferon in the management of neuroendocrine GEP-tumors: a review. Digestion, 62, 92-7. https://doi.org/10.1159/000051862
  43. Oberg K, Casanovas O, Castano JP, et al (2013). Molecular pathogenesis of neuroendocrine tumors: implications for current and future therapeutic approaches. Clin Cancer Res, 19, 2842-9. https://doi.org/10.1158/1078-0432.CCR-12-3458
  44. Olsen IH, Langer SW, Jepsen I, et al (2012). First-line treatment of patients with disseminated poorly differentiated neuroendocrine carcinomas with carboplatin, etoposide, and vincristine: a single institution experience. Acta Oncol, 51, 97-100. https://doi.org/10.3109/0284186X.2011.582881
  45. O'Toole D, Ducreux M, Bommelaer G, et al (2000). Treatment of carcinoid syndrome: a prospective crossover evaluation of lanreotide versus octreotide in terms of efficacy, patient acceptability, and tolerance. Cancer, 88, 770-6. https://doi.org/10.1002/(SICI)1097-0142(20000215)88:4<770::AID-CNCR6>3.0.CO;2-0
  46. Pavel M, Baudin E, Couvelard A, et al (2012); Barcelona Consensus Conference participants. ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology, 95, 157-76. https://doi.org/10.1159/000335597
  47. Phan, AT, Yao, JC, Fogelman, DR, et al (2010). A prospective, multi-institutional phase II study of GW786034 (pazopanib) and depot octreotide (sandostatin LAR) in advanced low-grade neuroendocrine carcinoma (LGNEC). J Clin Oncol, 28, abstract 4001.
  48. Panzuto F, Di Fonzo M, Iannicelli E, et al (2006). Long-term clinical outcome of somatostatin analogues for treatment of progressive, metastatic, well-differentiated entero-pancreatic endocrine carcinoma. Ann Oncol, 17, 461-6. https://doi.org/10.1093/annonc/mdj113
  49. Ramage JK, Ahmed A, Ardill J, et al (2012). UK and Ireland neuroendocrine tumour society. guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut, 61, 6-32. https://doi.org/10.1136/gutjnl-2011-300831
  50. Ramanathan RK, Cnaan A, Hahn RG, Carbone PP, Haller DG (2001). Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern cooperative oncology group-E6282. Ann Oncol, 12, 1139-43. https://doi.org/10.1023/A:1011632713360
  51. Raymond E, Dahan L, Raoul JL, et al (2011). Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med, 364, 501-13. https://doi.org/10.1056/NEJMoa1003825
  52. Raymond E, Hobday T, Castellano D, et al (2011). Therapy innovations: tyrosine kinase inhibitors for the treatment of pancreatic neuroendocrine tumors. Cancer Metastasis Rev, 30, 19-26. https://doi.org/10.1007/s10555-011-9291-2
  53. Rinke A, Muller HH, Schade-Brittinger C, et al (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, 4656-63. https://doi.org/10.1200/JCO.2009.22.8510
  54. Schmid HA (2008). Pasireotide (SOM230): development, mechanism of action and potential applications. Mol Cell Endocrinol, 286, 69-74. https://doi.org/10.1016/j.mce.2007.09.006
  55. Strosberg JR, Nasir A, Hodul P, Kvols L (2008). Biology and treatment of metastatic gastrointestinal neuroendocrine tumors. Gastrointest Cancer Res, 2, 113-25.
  56. Singh S, Dey C, Kennecke H, et al (2014) Consensus recommendations for the diagnosis and management of pancreatic neuroendocrine tumors: Guidelines from a Canadian national expert group. Ann Surg Oncol, [Epub ahead of print].
  57. Shojamanesh H, Gibril F, Louie A, et al (2002). Prospective study of the antitumor efficacy of long-term octreotide treatment in patients with progressive metastatic gastrinoma. Cancer, 94, 331-43. https://doi.org/10.1002/cncr.10195
  58. Sowa-Staszczak A, Pach D, Stefanska A, et al (2011). Can treatment using radiolabelled somatostatin analogue increase the survival rate in patients with non-functioning neuroendocrine pancreatic tumours? Nucl Med Rev Cent East Eur, 14, 73-8. https://doi.org/10.5603/NMR.2011.00019
  59. Strosberg JR, Fine RL, Choi J, et al (2011). First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer, 117, 268-75. https://doi.org/10.1002/cncr.25425
  60. Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG (2005). 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, 4897-904. https://doi.org/10.1200/JCO.2005.03.616
  61. Tokunaga C, Yoshino K, Yonezawa K (2004). mTOR integrates amino acid- and energy-sensing pathways. Biochem Biophys Res Commun, 313, 443-6. https://doi.org/10.1016/j.bbrc.2003.07.019
  62. Venook AP, Ko AH, Ko AH, et al (2008). Phase II trial of FOLFOX plus bevacizumab in advanced, progressive neuroendocrine tumors. J Clin Oncol, 26, abstract 216.
  63. Villard L, Romer A, Marincek N, et al (2012). Cohort study of somatostatin-based radiopeptide therapy with [(90)Y-DOTA]-TOC versus [(90)Y-DOTA]-TOC plus [(177)Lu-DOTA]-TOC in neuroendocrine cancers. J Clin Oncol, 30, 1100-6. https://doi.org/10.1200/JCO.2011.37.2151
  64. Yao JC, Phan A, Hoff PM, et al (2008). Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol, 26, 1316-23. https://doi.org/10.1200/JCO.2007.13.6374
  65. Yao JC, Lombard-Bohas C, Baudin E, et al (2010). Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol, 28, 69-76. https://doi.org/10.1200/JCO.2009.24.2669
  66. Yao JC, Hassan M, Phan A, et al (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, 3063-72. https://doi.org/10.1200/JCO.2007.15.4377
  67. Yao JC, Shah MH, Ito T, et al (2011). RAD001 in advanced neuroendocrine tumors, third trial (RADIANT-3) study group. everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med, 364, 514-23. https://doi.org/10.1056/NEJMoa1009290
  68. Yao KA, Talamonti MS, Nemcek A, et al (2001). Indications and results of liver resection and hepatic chemoembolization for metastatic gastrointestinal neuroendocrine tumors. Surgery, 130, 677-82. https://doi.org/10.1067/msy.2001.117377
  69. Yucel B, Babacan NA, Kacan T, et al (2014). Survival analysis and prognostic factors for neuroendocrine tumors in Turkey. Asian Pac J Cancer Prev, 14, 6687-92.
  70. Zeng YJ, Liu L, Wu H, et al (2013). Clinicopathological features and prognosis of gastroenteropancreatic neuroendocrine tumors: analysis from a single-institution. Asian Pac J Cancer Prev, 14, 5775-81. https://doi.org/10.7314/APJCP.2013.14.10.5775
  71. Zhang J, Francois R, Iyer R, et al (2013). Current understanding of the molecular biology of pancreatic neuroendocrine tumors. J Natl Cancer Inst, 105, 1005-17. https://doi.org/10.1093/jnci/djt135
  72. Zitzmann K, De Toni EN, Brand S, et al (2007). The novel mTOR inhibitor RAD001 (everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells. Neuroendocrinology, 85, 54-60. https://doi.org/10.1159/000100057