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Introduction: Recent Advances in the Genetics, Diagnosis, and Treatment of Neuroendocrine Tumors
THE EVOLVING LANDSCAPE OF NEUROENDOCRINE TUMORS
Introduction: Recent Advances in the Genetics, Diagnosis, and Treatment of Neuroendocrine Tumors
N
euroendocrine tumors (NETs) represent an extremely heterogeneous group of tumors, which share expression of neuroendocrine markers and the ability to secrete bioactive amines/peptides. Historically, the rarity of these cancers, coupled with their variable clinical manifestations and natural history (eg, related to site of origin, hormone production, proliferative index) was perceived as a major barrier to clinical investigation. Progress was slow, with few advances over a 30-year period, except for the development of streptozocin-based chemotherapy for pancreatic neuroendocrine tumors (PanNETs) and somatostatin analogs for symptom control in carcinoid tumors.1,2 In the past decade, the field has evolved dramatically, leading to new treatment options for patients with medullary thyroid carcinoma and PanNETs, innovative clinical development paradigms, and revised tumor classification schemes.3– 6 Perhaps most importantly, the identification of novel therapeutic targets, coupled with the demonstration that accrual to NET trials is feasible, has led to enhanced interest by academic researchers and the pharmaceutical industry in developing novel therapies for these diseases. As a result, we have witnessed a dramatic increase in the number of clinical trials available to patients (including studies focused on genetics, biomarkers, diagnostics, imaging, therapy, natural history, and supportive care).7 In this issue of Seminars in Oncology, recent advances related to understanding and treating NETs will be reviewed, as will areas of unmet need and as yet unanswered scientific questions. Perhaps one of the most significant recent developments in the field is the recognition that carcinoid tumors and PanNETs vary with respect to underlying tumor biology and response to therapy, paving the way for separate paths for clinical investigation for these diseases. Modern classification schemes have emerged (reviewed by Klimstra in this issue), which emphasize the value of the proliferative index as a means of distinguishing between well-differentiated and poorly 0270-9295/ - see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2012.12.001
Seminars in Oncology, Vol 40, No 1, February 2013, pp 1-3
differentiated tumors.8 –10 It is worth noting, however, that the optimal cutpoints for proliferative rate remain the subject of ongoing debate.11 For years NETs were bundled with other tumor types arising in the same organ, as no formal tumor-node-metastasis (TNM)based staging systems existed.12 In response to growing evidence that NETs are characterized by distinct tumor biology and patterns of spread, the American Joint Committee on Cancer (AJCC) recently incorporated staging systems specific for different types of NET.8 As discussed by Öberg in this edition of Seminars, the genetics of most NETs remain a mystery, although recent data suggest that nearly 30% of patients with pheochromocytoma/paraganglioma have underlying germline mutations in succinate dehydrogenase pathway genes (including a sizeable subgroup of patients with apparently sporadic tumors).13 Similarly, RET mutations occur in the majority of medullary thyroid cancers and, as in paraganglioma and pheochromocytoma, the precise mutation dictates the phenotype.14 A familial syndrome of small bowel carcinoid has recently been identified, but the genetic drivers are not consistent across families.15 Furthermore, work by Jiao et al suggests that ⬎80% of sporadic PanNETs have mutations in genes encoding for proteins implicated in chromatin remodeling (eg, MEN1, DAXX, ATRX).16 The clinical significance of these findings remains uncertain but is an area of intense interest, particularly since ⬍15% of PanNETs harbor mutations in components of the mammalian target of rapamycin (mTOR) pathway.16 Despite these advances, many questions remain regarding the precise genetic alterations underlying most sporadic NETs, as well as the optimal surveillance and treatment of patients suffering from inherited cancer syndromes. Several ongoing studies offer hope that these issues will be addressed in the coming years. In terms of therapy, liver-directed strategies continue to play a significant role in the treatment of patients with liver-dominant well-differentiated NETs (reviewed by Wang and colleagues in this issue). However, the relative merits of ablation, resection, embolization, transplant, and liver-directed radiation therapy remain unclear, as randomized trials are lacking.17,18 Without such studies, patient, physician, and institu1
2
tional preferences will continue to influence choice of intervention in patients with unresectable disease. With regard to resectable primary or metastatic tumors, there continues to be no randomized data to support the use of adjuvant therapy, despite the emerging evidence for active agents in the setting of advanced disease. The systemic therapy for carcinoid continues to be a major challenge (summarized in the article by Pavel, Kidd, and Modlin). Beyond somatostatin analogs, no standard therapy exists and additional treatment strategies are desperately needed.19 Furthermore, the results of the RADIANT-2 trial underscore the limitations related to imaging in NETs (reviewed by Leung and Schwartz in this issue), given the loss of power and informative censoring that occurred due to discordant assessments between local and central reviewers.20 However, progress is likely in the near future, as evidenced by the numerous ongoing and recent trials exploring new imaging modalities, novel somatostatin analogs (SSTa), peptide receptor radiotherapy (PRRT), vascular endothelial growth factor (VEGF) inhibitors, mTOR inhibitors, and other therapeutic strategies. To this end, the randomized phase III trial of bevacizumab versus interferon in patients with high-risk carcinoid tumors (Southwest Oncology Group [SWOG]-0518) recently closed, and the results are eagerly anticipated. The article by Toumpanakis and Caplin provides a detailed discussion of next generation of SSTa, for use alone (for symptom control or tumor treatment) or in the context of PRRT. Unlike carcinoid, significant advances have been made in PanNETs over the last few years, culminating in the US Food and Drug Administration approval of both everolimus and sunitinib for progressive disease (reviewed by Kulke in this issue). Unfortunately, the role of chemotherapy continues to be controversial, as traditional streptozocin-based regimens have been plagued by an unfavorable risk to benefit ratio.21,22 Temozolomide-based chemotherapy regimens are of great interest, but definitive studies have not yet been performed.23 Targeted agents appear to hold great promise for treatment of medullary thyroid cancer (MTC), as indicated by the recent FDA approvals of vandetanib and cabozantanib in this disease. In contrast, progress in the treatment of paraganglioma and pheochromocytoma has been limited. Strosberg discusses the treatment of rare NETs in his article entitled, “Update on the Management of Unusual Neuroendocrine Tumors: Pheochromocytoma and Paraganglioma, Medullary Thyroid Cancer, and Adrenal Cortical Carcinoma.” Advances in the treatment of high-grade NETs also have been slow, thus the disease continues to be treated according to small cell lung cancer guidelines, despite predictably poor outcomes (as outlined by Smith and Reidy-Lagunes in this issue).24
E.K. Bergsland
Given the chronic nature of most NETs, along with their predilection to secrete hormones and bioactive amines, the ability to prevent and/or palliate symptoms is of paramount importance. As reviewed by Anthony in his “Practical Guide to the Supportive Care of Patients with Functional Neuroendocrine Tumors,” physicians must be aware of the various symptom complexes associated with functional tumors and anticipate the triggers (eg, surgery in a carcinoid patient) and treatments specific to individual hormones and/or bioactive amines. SSTa play a pivotal role in the control of hormone-mediated symptoms.25 Novel SSTa are under study, as are other innovative strategies such as the use of a tryptophan hydroxlase inhibitor to block serotonin excess.26,27 In short, many patients enjoy a good quality of life with maneuvers to decrease symptoms. Recognizing that radiographic progression can be extremely indolent (measured over many years in some cases), defining the optimal timing for initiation of anti-tumor therapy in well-differentiated tumors continues to be a key concern, and is at the root of ongoing efforts to identify predictive and prognostic biomarkers.
Emily K. Bergsland, MD UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA Guest Editor REFERENCES 1. Kvols LK, Moertel CG, O’Connell MJ, et al. Treatment of the malignant carcinoid syndrome. Evaluation of a longacting somatostatin analogue. N Engl J Med. 1986;315: 663– 6. 2. Moertel C, Lefkopoulo M, Lipsitz S, et al. Streptozocindoxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Eng J Med. 1992;326:519 –23. 3. Wells S, Robinson B, Gagel R, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134 – 41. 4. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501–13. 5. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011; 364:514 –23. 6. Schoffski P, Elisei R, Muller S, et al. An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantanib (XL184) in medullary thyroid carcinoma (MTC) patients with documented RECIST progression at baseline. J Clin Oncol. 2012;30: abstract 5508. 7. National Cancer Institute, Search for Clinical trials. 2012. http://www.cancer.gov/clinicaltrials/search. 8. Edge S, Byrd D, Carducci M, et al. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.
Introduction
9. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010;39:707–12. 10. Rindi G, Arnold R, Bosman F, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. Lyon: IARC Press; 2010. 11. Sorbye H, Welin S, Langer SW, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol. 2013.24:152– 60. 12. Klimstra D, Modlin I, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010; 39:707–12. 13. Gill AJ, Benn DE, Chou A, et al. Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. Hum Pathol. 2010;41:805–14. 14. Raue F, Frank-Raue K. Update multiple endocrine neoplasia type 2. Fam Cancer. 2010;9:449 –57. 15. Cunningham JL, Diaz de Stahl T, Sjoblom T, et al. Common pathogenetic mechanism involving human chromosome 18 in familial and sporadic ileal carcinoid tumors. Genes Chromosomes Cancer. 2011;50:82–94. 16. Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199 – 203. 17. Mayo SC, de Jong MC, Pulitano C, et al. Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis. Ann Surg Oncol. 2010;17:3129 –36. 18. Pitt SC, Knuth J, Keily JM, et al. Hepatic neuroendocrine metastases: chemo- or bland embolization? J Gastrointest Surg. 2008;12:1951– 60. 19. Rinke A, Muller HH, Schade-Brittinger C, et al. Placebocontrolled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor
3
20.
21.
22.
23.
24.
25.
26.
27.
growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27:4656 – 63. Pavel ME, Hainsworth JD, Baudin E, et al. 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. 2011;378:2005–12. Cheng PN, Saltz LB. Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma. Cancer. 1999;86:944 – 8. McCollum AD, Kulke MH, Ryan DP, et al. Lack of efficacy of streptozocin and doxorubicin in patients with advanced pancreatic endocrine tumors. Am J Clin Oncol. 2004;27:485– 8. Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011;117:268 –75. Strosberg JR, Coppola D, Klimstra DS, et al. The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas. Pancreas. 2010;39:799 – 800. Modlin IM, Pavel M, Kidd M, et al. Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther. 2010;31:169 – 88. Wiedenmann B, Pavel M, Seufferlein T, et al. The effect of telotristat etiprate on clinical and biochemical responses in patients with symptomatic carcinoid syndrome: preliminary results of an ongoing phase II, multicenter, open-label, serial-ascending dose study. J Clin Oncol. 2012;30:abstract e14564. Kvols L, Wiedenmann B, Oberg K, et al. Safety and efficacy of pasireotide (SOM230) in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR: results of a phase II study, Pro Am Soc Clin Oncol. 2006; abstract 171.
Introduction: Recent Advances in the Genetics, Diagnosis, and Treatment of Neuroendocrine Tumors
N
euroendocrine tumors (NETs) represent an extremely heterogeneous group of tumors, which share expression of neuroendocrine markers and the ability to secrete bioactive amines/peptides. Historically, the rarity of these cancers, coupled with their variable clinical manifestations and natural history (eg, related to site of origin, hormone production, proliferative index) was perceived as a major barrier to clinical investigation. Progress was slow, with few advances over a 30-year period, except for the development of streptozocin-based chemotherapy for pancreatic neuroendocrine tumors (PanNETs) and somatostatin analogs for symptom control in carcinoid tumors.1,2 In the past decade, the field has evolved dramatically, leading to new treatment options for patients with medullary thyroid carcinoma and PanNETs, innovative clinical development paradigms, and revised tumor classification schemes.3– 6 Perhaps most importantly, the identification of novel therapeutic targets, coupled with the demonstration that accrual to NET trials is feasible, has led to enhanced interest by academic researchers and the pharmaceutical industry in developing novel therapies for these diseases. As a result, we have witnessed a dramatic increase in the number of clinical trials available to patients (including studies focused on genetics, biomarkers, diagnostics, imaging, therapy, natural history, and supportive care).7 In this issue of Seminars in Oncology, recent advances related to understanding and treating NETs will be reviewed, as will areas of unmet need and as yet unanswered scientific questions. Perhaps one of the most significant recent developments in the field is the recognition that carcinoid tumors and PanNETs vary with respect to underlying tumor biology and response to therapy, paving the way for separate paths for clinical investigation for these diseases. Modern classification schemes have emerged (reviewed by Klimstra in this issue), which emphasize the value of the proliferative index as a means of distinguishing between well-differentiated and poorly 0270-9295/ - see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2012.12.001
Seminars in Oncology, Vol 40, No 1, February 2013, pp 1-3
differentiated tumors.8 –10 It is worth noting, however, that the optimal cutpoints for proliferative rate remain the subject of ongoing debate.11 For years NETs were bundled with other tumor types arising in the same organ, as no formal tumor-node-metastasis (TNM)based staging systems existed.12 In response to growing evidence that NETs are characterized by distinct tumor biology and patterns of spread, the American Joint Committee on Cancer (AJCC) recently incorporated staging systems specific for different types of NET.8 As discussed by Öberg in this edition of Seminars, the genetics of most NETs remain a mystery, although recent data suggest that nearly 30% of patients with pheochromocytoma/paraganglioma have underlying germline mutations in succinate dehydrogenase pathway genes (including a sizeable subgroup of patients with apparently sporadic tumors).13 Similarly, RET mutations occur in the majority of medullary thyroid cancers and, as in paraganglioma and pheochromocytoma, the precise mutation dictates the phenotype.14 A familial syndrome of small bowel carcinoid has recently been identified, but the genetic drivers are not consistent across families.15 Furthermore, work by Jiao et al suggests that ⬎80% of sporadic PanNETs have mutations in genes encoding for proteins implicated in chromatin remodeling (eg, MEN1, DAXX, ATRX).16 The clinical significance of these findings remains uncertain but is an area of intense interest, particularly since ⬍15% of PanNETs harbor mutations in components of the mammalian target of rapamycin (mTOR) pathway.16 Despite these advances, many questions remain regarding the precise genetic alterations underlying most sporadic NETs, as well as the optimal surveillance and treatment of patients suffering from inherited cancer syndromes. Several ongoing studies offer hope that these issues will be addressed in the coming years. In terms of therapy, liver-directed strategies continue to play a significant role in the treatment of patients with liver-dominant well-differentiated NETs (reviewed by Wang and colleagues in this issue). However, the relative merits of ablation, resection, embolization, transplant, and liver-directed radiation therapy remain unclear, as randomized trials are lacking.17,18 Without such studies, patient, physician, and institu1
2
tional preferences will continue to influence choice of intervention in patients with unresectable disease. With regard to resectable primary or metastatic tumors, there continues to be no randomized data to support the use of adjuvant therapy, despite the emerging evidence for active agents in the setting of advanced disease. The systemic therapy for carcinoid continues to be a major challenge (summarized in the article by Pavel, Kidd, and Modlin). Beyond somatostatin analogs, no standard therapy exists and additional treatment strategies are desperately needed.19 Furthermore, the results of the RADIANT-2 trial underscore the limitations related to imaging in NETs (reviewed by Leung and Schwartz in this issue), given the loss of power and informative censoring that occurred due to discordant assessments between local and central reviewers.20 However, progress is likely in the near future, as evidenced by the numerous ongoing and recent trials exploring new imaging modalities, novel somatostatin analogs (SSTa), peptide receptor radiotherapy (PRRT), vascular endothelial growth factor (VEGF) inhibitors, mTOR inhibitors, and other therapeutic strategies. To this end, the randomized phase III trial of bevacizumab versus interferon in patients with high-risk carcinoid tumors (Southwest Oncology Group [SWOG]-0518) recently closed, and the results are eagerly anticipated. The article by Toumpanakis and Caplin provides a detailed discussion of next generation of SSTa, for use alone (for symptom control or tumor treatment) or in the context of PRRT. Unlike carcinoid, significant advances have been made in PanNETs over the last few years, culminating in the US Food and Drug Administration approval of both everolimus and sunitinib for progressive disease (reviewed by Kulke in this issue). Unfortunately, the role of chemotherapy continues to be controversial, as traditional streptozocin-based regimens have been plagued by an unfavorable risk to benefit ratio.21,22 Temozolomide-based chemotherapy regimens are of great interest, but definitive studies have not yet been performed.23 Targeted agents appear to hold great promise for treatment of medullary thyroid cancer (MTC), as indicated by the recent FDA approvals of vandetanib and cabozantanib in this disease. In contrast, progress in the treatment of paraganglioma and pheochromocytoma has been limited. Strosberg discusses the treatment of rare NETs in his article entitled, “Update on the Management of Unusual Neuroendocrine Tumors: Pheochromocytoma and Paraganglioma, Medullary Thyroid Cancer, and Adrenal Cortical Carcinoma.” Advances in the treatment of high-grade NETs also have been slow, thus the disease continues to be treated according to small cell lung cancer guidelines, despite predictably poor outcomes (as outlined by Smith and Reidy-Lagunes in this issue).24
E.K. Bergsland
Given the chronic nature of most NETs, along with their predilection to secrete hormones and bioactive amines, the ability to prevent and/or palliate symptoms is of paramount importance. As reviewed by Anthony in his “Practical Guide to the Supportive Care of Patients with Functional Neuroendocrine Tumors,” physicians must be aware of the various symptom complexes associated with functional tumors and anticipate the triggers (eg, surgery in a carcinoid patient) and treatments specific to individual hormones and/or bioactive amines. SSTa play a pivotal role in the control of hormone-mediated symptoms.25 Novel SSTa are under study, as are other innovative strategies such as the use of a tryptophan hydroxlase inhibitor to block serotonin excess.26,27 In short, many patients enjoy a good quality of life with maneuvers to decrease symptoms. Recognizing that radiographic progression can be extremely indolent (measured over many years in some cases), defining the optimal timing for initiation of anti-tumor therapy in well-differentiated tumors continues to be a key concern, and is at the root of ongoing efforts to identify predictive and prognostic biomarkers.
Emily K. Bergsland, MD UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA Guest Editor REFERENCES 1. Kvols LK, Moertel CG, O’Connell MJ, et al. Treatment of the malignant carcinoid syndrome. Evaluation of a longacting somatostatin analogue. N Engl J Med. 1986;315: 663– 6. 2. Moertel C, Lefkopoulo M, Lipsitz S, et al. Streptozocindoxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Eng J Med. 1992;326:519 –23. 3. Wells S, Robinson B, Gagel R, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134 – 41. 4. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501–13. 5. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011; 364:514 –23. 6. Schoffski P, Elisei R, Muller S, et al. An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantanib (XL184) in medullary thyroid carcinoma (MTC) patients with documented RECIST progression at baseline. J Clin Oncol. 2012;30: abstract 5508. 7. National Cancer Institute, Search for Clinical trials. 2012. http://www.cancer.gov/clinicaltrials/search. 8. Edge S, Byrd D, Carducci M, et al. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.
Introduction
9. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010;39:707–12. 10. Rindi G, Arnold R, Bosman F, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. Lyon: IARC Press; 2010. 11. Sorbye H, Welin S, Langer SW, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol. 2013.24:152– 60. 12. Klimstra D, Modlin I, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010; 39:707–12. 13. Gill AJ, Benn DE, Chou A, et al. Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. Hum Pathol. 2010;41:805–14. 14. Raue F, Frank-Raue K. Update multiple endocrine neoplasia type 2. Fam Cancer. 2010;9:449 –57. 15. Cunningham JL, Diaz de Stahl T, Sjoblom T, et al. Common pathogenetic mechanism involving human chromosome 18 in familial and sporadic ileal carcinoid tumors. Genes Chromosomes Cancer. 2011;50:82–94. 16. Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199 – 203. 17. Mayo SC, de Jong MC, Pulitano C, et al. Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis. Ann Surg Oncol. 2010;17:3129 –36. 18. Pitt SC, Knuth J, Keily JM, et al. Hepatic neuroendocrine metastases: chemo- or bland embolization? J Gastrointest Surg. 2008;12:1951– 60. 19. Rinke A, Muller HH, Schade-Brittinger C, et al. Placebocontrolled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor
3
20.
21.
22.
23.
24.
25.
26.
27.
growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27:4656 – 63. Pavel ME, Hainsworth JD, Baudin E, et al. 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. 2011;378:2005–12. Cheng PN, Saltz LB. Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma. Cancer. 1999;86:944 – 8. McCollum AD, Kulke MH, Ryan DP, et al. Lack of efficacy of streptozocin and doxorubicin in patients with advanced pancreatic endocrine tumors. Am J Clin Oncol. 2004;27:485– 8. Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011;117:268 –75. Strosberg JR, Coppola D, Klimstra DS, et al. The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas. Pancreas. 2010;39:799 – 800. Modlin IM, Pavel M, Kidd M, et al. Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther. 2010;31:169 – 88. Wiedenmann B, Pavel M, Seufferlein T, et al. The effect of telotristat etiprate on clinical and biochemical responses in patients with symptomatic carcinoid syndrome: preliminary results of an ongoing phase II, multicenter, open-label, serial-ascending dose study. J Clin Oncol. 2012;30:abstract e14564. Kvols L, Wiedenmann B, Oberg K, et al. Safety and efficacy of pasireotide (SOM230) in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR: results of a phase II study, Pro Am Soc Clin Oncol. 2006; abstract 171.