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Published in: Annals of Surgical Oncology 5/2016

01-12-2016 | Pancreatic Tumors

Resection of the Primary Tumor Followed by Peptide Receptor Radionuclide Therapy as Upfront Strategy for the Treatment of G1–G2 Pancreatic Neuroendocrine Tumors with Unresectable Liver Metastases

Authors: Emilio Bertani, MD, Nicola Fazio, MD, Davide Radice, MSc, Claudio Zardini, MD, Chiara Grana, MD, Lisa Bodei, MD, Luigi Funicelli, MD, Carlo Ferrari, MD, Francesca Spada, MD, Stefano Partelli, MD, PhD, Massimo Falconi, MD

Published in: Annals of Surgical Oncology | Special Issue 5/2016

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Abstract

Background

A low burden of disease represents an independent favorable prognostic factor of response to peptide receptor radionuclide therapy (PRRT) in patients affected by gastro-entero-pancreatic neuroendocrine tumors. However, it is not clear whether this is due to a lower diffusion of the disease or thanks to debulking surgery.

Methods

From 1996 to 2013 those patients diagnosed with G1–G2 pancreatic neuroendocrine tumor (PNET) and synchronous liver metastases who were not deemed eligible for liver radical surgery but were eligible to receive upfront PRRT were prospectively included in the study. Two groups of comparison were identified: those submitted for primary tumor resection before PRRT and those who were not. The outcome was evaluated as: objective response to PRRT (OR), progression-free survival (PFS), and overall survival (OS).

Results

Of the 94 subjects, 31 were previously submitted for primary tumor resection. After propensity score adjustments, patients who underwent surgery before PRRT showed higher stabilization or objective responses after PRRT (p = .006), and this translated into a better median PFS (70 vs. 30 months; p = .002) and OS (112 vs. 65 months; p = .011), for operated versus nonoperated patients, respectively. At multivariate analysis, operated patients showed a statistically significantly improved PFS: HR, 5.11 (95 % CI 1.43–18.3); p = .012, whereas Ki-67 in continuous fashion was correlated significantly with OS: 1.13 (95 % CI 1–1.27); p = .048.

Conclusions

Primary tumor resection prior to PRRT can be safely proposed in G1–G2 PNETs with diffuse liver metastases because it seems to enhance response to PRRT and to improve significantly PFS.
Literature
1.
go back to reference Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13 715 carcinoid tumors. Cancer. 2003;97:934–59.CrossRefPubMed Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13 715 carcinoid tumors. Cancer. 2003;97:934–59.CrossRefPubMed
2.
go back to reference Yao JC, Hassan M, Phan A, 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.CrossRefPubMed Yao JC, Hassan M, Phan A, 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.CrossRefPubMed
3.
go back to reference Chamberlain RS, Canes D, Brown KT, et al. Hepatic neuroendocrine metastases: does intervention alter outcomes? J Am Coll Surg. 2000;190:432–45.CrossRefPubMed Chamberlain RS, Canes D, Brown KT, et al. Hepatic neuroendocrine metastases: does intervention alter outcomes? J Am Coll Surg. 2000;190:432–45.CrossRefPubMed
4.
go back to reference Hockwald SN, Conlon KC, Brennan MF. Nonfunctional pancreatic islet cell tumors. In: Doherty G, Skogseid B, editors. Surgical endocrinology. 1st ed. Philadelphia: Lippincott Williams & Wilkins; 2001. pp. 361–73. Hockwald SN, Conlon KC, Brennan MF. Nonfunctional pancreatic islet cell tumors. In: Doherty G, Skogseid B, editors. Surgical endocrinology. 1st ed. Philadelphia: Lippincott Williams & Wilkins; 2001. pp. 361–73.
5.
go back to reference Panzuto F, Boninsegna L, Fazio N, et al. Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression. J Clin Oncol. 2011;29:2372–7.CrossRefPubMed Panzuto F, Boninsegna L, Fazio N, et al. Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression. J Clin Oncol. 2011;29:2372–7.CrossRefPubMed
6.
go back to reference Evans DB, Skibber JM, Lee JE, et al. Nonfunctioning islet cell carcinoma of the pancreas. Surgery. 1993;114:1175–81.PubMed Evans DB, Skibber JM, Lee JE, et al. Nonfunctioning islet cell carcinoma of the pancreas. Surgery. 1993;114:1175–81.PubMed
7.
go back to reference Solorzano CC, Lee JE, Pisters PW, et al. Nonfunctioning islet cell carcinoma of the pancreas: survival results in a contemporary series of 163 patients. Surgery. 2001;130:1078–85.CrossRefPubMed Solorzano CC, Lee JE, Pisters PW, et al. Nonfunctioning islet cell carcinoma of the pancreas: survival results in a contemporary series of 163 patients. Surgery. 2001;130:1078–85.CrossRefPubMed
8.
9.
go back to reference Kwekkeboom DJ, Teunissen JJ, Bakker WH, et al. Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3] octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol. 2005;23:2754–62.CrossRefPubMed Kwekkeboom DJ, Teunissen JJ, Bakker WH, et al. Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3] octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol. 2005;23:2754–62.CrossRefPubMed
10.
go back to reference Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26:2124–30.CrossRefPubMed Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26:2124–30.CrossRefPubMed
11.
go back to reference Bertani E, Fazio N, Botteri E, et al. Resection of the primary pancreatic neuroendocrine tumor in patients with unresectable liver metastases: possible indications for a multimodal approach. Surgery. 2014;155:607–14.CrossRefPubMed Bertani E, Fazio N, Botteri E, et al. Resection of the primary pancreatic neuroendocrine tumor in patients with unresectable liver metastases: possible indications for a multimodal approach. Surgery. 2014;155:607–14.CrossRefPubMed
12.
go back to reference Capurso G, Bettini R, Rinzivillo M, Boninsegna L, Delle Fave G, Falconi M. Role of resection of the primary pancreatic neuroendocrine tumour only inpatients with unresectable metastatic liver disease: a systematic review. Neuroendocrinology. 2011;93:223–9.CrossRefPubMed Capurso G, Bettini R, Rinzivillo M, Boninsegna L, Delle Fave G, Falconi M. Role of resection of the primary pancreatic neuroendocrine tumour only inpatients with unresectable metastatic liver disease: a systematic review. Neuroendocrinology. 2011;93:223–9.CrossRefPubMed
13.
go back to reference Bodei L, Cremonesi M, Grana CM, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging. 2011;38:2125–35.CrossRefPubMed Bodei L, Cremonesi M, Grana CM, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging. 2011;38:2125–35.CrossRefPubMed
14.
go back to reference Rindi G, Arnold R, Bosman FT. Nomenclature and classification of neuroendocrine neoplasm of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, et al., editors. WHO classification of tumor of the digestive system. Lyon: International Agency for Research on Cancer (IRAC), 2010. pp. 13–14. Rindi G, Arnold R, Bosman FT. Nomenclature and classification of neuroendocrine neoplasm of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, et al., editors. WHO classification of tumor of the digestive system. Lyon: International Agency for Research on Cancer (IRAC), 2010. pp. 13–14.
15.
go back to reference Falconi M, Eriksson B, Kaltsas G, et al. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016;103:153–71.CrossRefPubMed Falconi M, Eriksson B, Kaltsas G, et al. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016;103:153–71.CrossRefPubMed
16.
go back to reference Kulke MH, Anthony LB, Bushnell DL, et al. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas. 2010;39:735–52.CrossRefPubMedPubMedCentral Kulke MH, Anthony LB, Bushnell DL, et al. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas. 2010;39:735–52.CrossRefPubMedPubMedCentral
17.
go back to reference Kulke MH, Shah MH, Benson AB 3rd, et al. Neuroendocrine tumors, version 1 2015. J Natl Compr Cancer Netw. 2015;13:78–108. Kulke MH, Shah MH, Benson AB 3rd, et al. Neuroendocrine tumors, version 1 2015. J Natl Compr Cancer Netw. 2015;13:78–108.
18.
go back to reference Bettini R, Mantovani W, Boninsegna L, et al. Primary tumour resection in metastatic nonfunctioning pancreatic endocrine carcinomas. Dig Liver Dis. 2009;41:49–55.CrossRefPubMed Bettini R, Mantovani W, Boninsegna L, et al. Primary tumour resection in metastatic nonfunctioning pancreatic endocrine carcinomas. Dig Liver Dis. 2009;41:49–55.CrossRefPubMed
19.
go back to reference Nguyen SQ, Angel LP, Divino CM, Schluender S, Warner RR. Surgery in malignant pancreatic neuroendocrine tumors. J Surg Oncol. 2007;96:397–403.CrossRefPubMed Nguyen SQ, Angel LP, Divino CM, Schluender S, Warner RR. Surgery in malignant pancreatic neuroendocrine tumors. J Surg Oncol. 2007;96:397–403.CrossRefPubMed
20.
go back to reference Frilling A, Modlin IM, Kidd M, et al. Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol. 2014;15:8–21.CrossRef Frilling A, Modlin IM, Kidd M, et al. Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol. 2014;15:8–21.CrossRef
21.
go back to reference Campana D, Capurso G, Partelli S, et al. Radiolabelled somatostatin analogue treatment in gastroenteropancreatic neuroendocrine tumours: factors associated with response and suggestions for therapeutic sequence. Eur J Nucl Med Mol Imaging. 2013;40:1197–205.CrossRefPubMed Campana D, Capurso G, Partelli S, et al. Radiolabelled somatostatin analogue treatment in gastroenteropancreatic neuroendocrine tumours: factors associated with response and suggestions for therapeutic sequence. Eur J Nucl Med Mol Imaging. 2013;40:1197–205.CrossRefPubMed
22.
go back to reference Ezziddin S, Opitz M, Attassi M, et al. Impact of the Ki-67 proliferation index on response to peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging. 2011;38:459–66.CrossRefPubMed Ezziddin S, Opitz M, Attassi M, et al. Impact of the Ki-67 proliferation index on response to peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging. 2011;38:459–66.CrossRefPubMed
23.
go back to reference Metz DC, Choi J, Strosberg J, Heaney AP, Howden CW, Klimstra D, Yao JC. A rationale for multidisciplinary care in treating neuroendocrine tumours. Curr Opin Endocrinol Diabetes Obes. 2012;19:306–13.CrossRefPubMed Metz DC, Choi J, Strosberg J, Heaney AP, Howden CW, Klimstra D, Yao JC. A rationale for multidisciplinary care in treating neuroendocrine tumours. Curr Opin Endocrinol Diabetes Obes. 2012;19:306–13.CrossRefPubMed
Metadata
Title
Resection of the Primary Tumor Followed by Peptide Receptor Radionuclide Therapy as Upfront Strategy for the Treatment of G1–G2 Pancreatic Neuroendocrine Tumors with Unresectable Liver Metastases
Authors
Emilio Bertani, MD
Nicola Fazio, MD
Davide Radice, MSc
Claudio Zardini, MD
Chiara Grana, MD
Lisa Bodei, MD
Luigi Funicelli, MD
Carlo Ferrari, MD
Francesca Spada, MD
Stefano Partelli, MD, PhD
Massimo Falconi, MD
Publication date
01-12-2016
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue Special Issue 5/2016
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-016-5550-3

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