r
SYMPOSIUM PAPER For reprint orders, please contact: [email protected]
Liver metastases from neuroendocrine tumors
Andrew Kennedy*
Neuroendocrine tumors (NETs) are a heterogeneous group of rare neoplasms that arise from the hormone-producing cells of the body’s nervous and endocrine systems. They are most frequently found in the small intestine and lung/bronchus, reflecting the density of neuroendocrine cells in these tissues [1] . Each type of tumor has distinctive clinical, histochemical and secretory features depending upon the cell type from which the tumor is derived and its location. Overall, the incidence of NETs is rising [2] . The annual incidence of gastrointestinal and lung NETs are estimated to be between 2.55 and 3.5 per 100,000 of the population (5.96 per 100,000 of the African–American population), while pancreatic islet cell NETs occur in approximately 0.13–0.3 per 100,000 [1] . Although many clinicians consider NETs to be mostly benign, these neoplasms can exhibit a malignant clinical course with the development of metastatic disease, which is a predictor of poor survival (Table 1) [3] . Without obvious signs or symptoms, the diagnosis of NETs is often delayed, with 20–30% of patients presenting with advanced disease [3] , including many (particularly with gastroenteropancreatic NETs) which metastasize in the liver [4] . Surgery should be offered when NETs are resectable and there is curative intent (or when debulking offers palliation) to patients who are fit and have disease that is limited to the primary/regional lymph nodes and/or potentially resectable metastases in the liver. For patients who are not fit for surgery, the aim of treatment is to improve symptom control (i.e., paraneoplastic endocrine or carcinoid syndrome) in order to maintain optimal quality of life and, where possible, improve survival. Treatment choices for the palliation of nonresectable disease include somatostatin analogs, biotherapy, targeted radionuclide therapy and locoregional treatments for predominantly localized liver disease (e.g., ablation [radiofrequency or microwave ablation], selective internal radiation therapy [SIRT] or transarterial embolization [TAE]/transarterial chemoembolization [TACE]; Figure 1) [5,6,7] .
KEYWORDS
• advanced neuroendocrine tumors • ENETS consensus • liver • metastases • selective internal radiation therapy • transarterial
chemoembolization
Selective internal radiation therapy The hallmark of metastatic NETs (mNETs) is the hypervascular arterialization of the liver metastases [8] , which makes these tumors a particularly attractive target for intra-arterial therapies. However, SIRT utilizing much smaller microspheres (25–35 μm) than those required for TACE (100–700 μm) differs significantly in its mechanism of action. Whereas the primary mechanism of SIRT is radiation cell killing [9] at the neovascular rim of the growing tumor, the mechanism of action for TACE is almost exclusively via hypoxia-induced cell death. ●●Advantages & disadvantages of SIRT in mNETs
When considering the appropriateness of SIRT for the management of mNETs, it is important to remember that the extent of hepatic disease tends to be prognostic for survival. Moreover, *Radiation Oncology Research, Sarah Cannon Research Institute, 3322 West End Avenue, Suite 800 Nashville, TN 37203, USA; Tel.: +1 615 524 4200; Fax: +1 615 524 4700; [email protected]
10.2217/FON.14.231 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(15s), 83–87
part of
ISSN 1479-6694
83
Symposium Paper Kennedy Table 1. Survival analysis of patients with well-differentiated to moderately differentiated neuroendocrine tumors: actuarial survival by disease site in patients with G1/G2 neuroendocrine tumors diagnosed from 1988 to 2004. Primary tumor site Median survival (months)
Distant metastases survival rate (%)
3-year
5-year
10-year
Jejunum/ileum Duodenum Caecum Appendix† Pancreas Rectum† Lung Colon
65 57 55 31 27 26 17 7
70 60 61 42 42 37 34 20
54 46 48 25 27 24 27 14
30 27 23 11 11 3 15 6
Metastases of these tumors are rare [5]. Based on data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program from the USA, adapted from [3]. †
mNETs often present in young, otherwise healthy patients with noncirrhotic livers who have had minimal chemotherapy and often no prior surgery. However, the tumors in the liver may be diffuse and/or numerous. One of the key challenges in the management of mNETs in the liver is often the multifocal nature of the disease in the liver (Figure 2) , which requires careful consideration of the functional liver reserve for the safe delivery of SIRT.
Resection/ treatment Patients with NELM
High risk: neoadjuvant/ adjuvant
Currently, TACE/TAE is the established and recommended therapy, although the clear superiority of one transarterial technique over others has not been demonstrated through a randomized controlled trial [10] . Chemotherapy options have increased over the last few years, including newer treatments that remain to be evaluated in carefully controlled safety studies with SIRT. There is currently a lack of evidence on the impact of SIRT on overall survival [5] .
Detection of early recurrence
Low risk: A resection/TX
Treatment
B Observation
RFA
Palliative treatment
RFA TAE/ TACE SIRT PRRT Medical
A
TAE/ TACE
B
Continue
SIRT PRRT
Monitoring treatment effect
Switch to alternative
Medical
Figure 1. Potential strategies for metastatic neuroendocrine tumors in the liver in the era of personalized medicine. A: Genetic/metabolic signatures; B: Circulating tumor cells/mRNA; NELM: Neuroendocrineliver metastases; PRRT: Peptide receptorradionuclide therapy; RFA: Radiofrequency ablation; SIRT: Selective internal radiotherapy; TACE: Transarterialchemoembolization; TAE: Transarterial embolisation; TACE: Transarterialchemoembolisation; Tx: Treatment. Reproduced with permission from [5].
84
Future Oncol. (2014) 10(15s)
future science group
Liver metastases from neuroendocrine tumors Patient selection for SIRT still needs to be refined in patients with mNETs. In my opinion, SIRT is indicated for mNETs in the liver when: there is liver-dominant tumor burden; liver tumor growth exceeds the growth of extrahepatic metastases; and SIRT may reduce the burden of tumor in the liver and thereby alleviate the symptoms associated with paraneoplastic syndrome, hepatic capsule stretching (pain) or biliary obstruction/portal vein compression. ●●Toxicities with SIRT
In the USA, more than 99% of cases are discharged the same day after SIRT. Potentially serious events include: radiation/radioembolization-induced liver disease: incidence 1% (range: 0–4%); gastrointestinal ulcer: incidence
SYMPOSIUM PAPER For reprint orders, please contact: [email protected]
Liver metastases from neuroendocrine tumors
Andrew Kennedy*
Neuroendocrine tumors (NETs) are a heterogeneous group of rare neoplasms that arise from the hormone-producing cells of the body’s nervous and endocrine systems. They are most frequently found in the small intestine and lung/bronchus, reflecting the density of neuroendocrine cells in these tissues [1] . Each type of tumor has distinctive clinical, histochemical and secretory features depending upon the cell type from which the tumor is derived and its location. Overall, the incidence of NETs is rising [2] . The annual incidence of gastrointestinal and lung NETs are estimated to be between 2.55 and 3.5 per 100,000 of the population (5.96 per 100,000 of the African–American population), while pancreatic islet cell NETs occur in approximately 0.13–0.3 per 100,000 [1] . Although many clinicians consider NETs to be mostly benign, these neoplasms can exhibit a malignant clinical course with the development of metastatic disease, which is a predictor of poor survival (Table 1) [3] . Without obvious signs or symptoms, the diagnosis of NETs is often delayed, with 20–30% of patients presenting with advanced disease [3] , including many (particularly with gastroenteropancreatic NETs) which metastasize in the liver [4] . Surgery should be offered when NETs are resectable and there is curative intent (or when debulking offers palliation) to patients who are fit and have disease that is limited to the primary/regional lymph nodes and/or potentially resectable metastases in the liver. For patients who are not fit for surgery, the aim of treatment is to improve symptom control (i.e., paraneoplastic endocrine or carcinoid syndrome) in order to maintain optimal quality of life and, where possible, improve survival. Treatment choices for the palliation of nonresectable disease include somatostatin analogs, biotherapy, targeted radionuclide therapy and locoregional treatments for predominantly localized liver disease (e.g., ablation [radiofrequency or microwave ablation], selective internal radiation therapy [SIRT] or transarterial embolization [TAE]/transarterial chemoembolization [TACE]; Figure 1) [5,6,7] .
KEYWORDS
• advanced neuroendocrine tumors • ENETS consensus • liver • metastases • selective internal radiation therapy • transarterial
chemoembolization
Selective internal radiation therapy The hallmark of metastatic NETs (mNETs) is the hypervascular arterialization of the liver metastases [8] , which makes these tumors a particularly attractive target for intra-arterial therapies. However, SIRT utilizing much smaller microspheres (25–35 μm) than those required for TACE (100–700 μm) differs significantly in its mechanism of action. Whereas the primary mechanism of SIRT is radiation cell killing [9] at the neovascular rim of the growing tumor, the mechanism of action for TACE is almost exclusively via hypoxia-induced cell death. ●●Advantages & disadvantages of SIRT in mNETs
When considering the appropriateness of SIRT for the management of mNETs, it is important to remember that the extent of hepatic disease tends to be prognostic for survival. Moreover, *Radiation Oncology Research, Sarah Cannon Research Institute, 3322 West End Avenue, Suite 800 Nashville, TN 37203, USA; Tel.: +1 615 524 4200; Fax: +1 615 524 4700; [email protected]
10.2217/FON.14.231 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(15s), 83–87
part of
ISSN 1479-6694
83
Symposium Paper Kennedy Table 1. Survival analysis of patients with well-differentiated to moderately differentiated neuroendocrine tumors: actuarial survival by disease site in patients with G1/G2 neuroendocrine tumors diagnosed from 1988 to 2004. Primary tumor site Median survival (months)
Distant metastases survival rate (%)
3-year
5-year
10-year
Jejunum/ileum Duodenum Caecum Appendix† Pancreas Rectum† Lung Colon
65 57 55 31 27 26 17 7
70 60 61 42 42 37 34 20
54 46 48 25 27 24 27 14
30 27 23 11 11 3 15 6
Metastases of these tumors are rare [5]. Based on data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program from the USA, adapted from [3]. †
mNETs often present in young, otherwise healthy patients with noncirrhotic livers who have had minimal chemotherapy and often no prior surgery. However, the tumors in the liver may be diffuse and/or numerous. One of the key challenges in the management of mNETs in the liver is often the multifocal nature of the disease in the liver (Figure 2) , which requires careful consideration of the functional liver reserve for the safe delivery of SIRT.
Resection/ treatment Patients with NELM
High risk: neoadjuvant/ adjuvant
Currently, TACE/TAE is the established and recommended therapy, although the clear superiority of one transarterial technique over others has not been demonstrated through a randomized controlled trial [10] . Chemotherapy options have increased over the last few years, including newer treatments that remain to be evaluated in carefully controlled safety studies with SIRT. There is currently a lack of evidence on the impact of SIRT on overall survival [5] .
Detection of early recurrence
Low risk: A resection/TX
Treatment
B Observation
RFA
Palliative treatment
RFA TAE/ TACE SIRT PRRT Medical
A
TAE/ TACE
B
Continue
SIRT PRRT
Monitoring treatment effect
Switch to alternative
Medical
Figure 1. Potential strategies for metastatic neuroendocrine tumors in the liver in the era of personalized medicine. A: Genetic/metabolic signatures; B: Circulating tumor cells/mRNA; NELM: Neuroendocrineliver metastases; PRRT: Peptide receptorradionuclide therapy; RFA: Radiofrequency ablation; SIRT: Selective internal radiotherapy; TACE: Transarterialchemoembolization; TAE: Transarterial embolisation; TACE: Transarterialchemoembolisation; Tx: Treatment. Reproduced with permission from [5].
84
Future Oncol. (2014) 10(15s)
future science group
Liver metastases from neuroendocrine tumors Patient selection for SIRT still needs to be refined in patients with mNETs. In my opinion, SIRT is indicated for mNETs in the liver when: there is liver-dominant tumor burden; liver tumor growth exceeds the growth of extrahepatic metastases; and SIRT may reduce the burden of tumor in the liver and thereby alleviate the symptoms associated with paraneoplastic syndrome, hepatic capsule stretching (pain) or biliary obstruction/portal vein compression. ●●Toxicities with SIRT
In the USA, more than 99% of cases are discharged the same day after SIRT. Potentially serious events include: radiation/radioembolization-induced liver disease: incidence 1% (range: 0–4%); gastrointestinal ulcer: incidence
![[Primary tumor resection of neuroendocrine pancreatic tumors with liver metastases].](/assets/img/hold.png)
