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__NOTOC__ | __NOTOC__ | ||
{{Carcinoid syndrome}} | {{Carcinoid syndrome}} | ||
{{CMG}}{{AE}}{{PSD}} | {{CMG}}{{AE}}{{PSD}}{{Anum}} | ||
==Overview== | ==Overview== | ||
The predominant therapy for carcinoid syndrome is surgical resection. Supportive therapy for carcinoid syndrome includes [[somatostatin]] analogs, [[interferons]], and [[radionuclides]]. | The predominant [[therapy]] for [[Carcinoid Syndrome|carcinoid syndrome]] is [[surgical resection]]. [[Supportive therapy]] for [[Carcinoid Syndrome|carcinoid syndrome]] includes [[somatostatin]] [[Analogue|analogs]][[Telotristat ethyl|,Telotristat]],[[interferons]], and [[radionuclides]]. | ||
==Medical Therapy== | ==Medical Therapy== | ||
Standard treatments for patients with gastrointestinal | [[Standard treatment|Standard treatments]] for [[patients]] with [[Gastrointestinal tract|gastrointestinal]] [[carcinoid tumors]] include the following:<ref>Treatment Option Overview for GI Carcinoid Tumors | ||
. NATIONAL CANCER INSTITUTE . http://www.cancer.gov/types/gi-carcinoid-tumors/hp/gi-carcinoid-treatment-pdq#link/_97_toc Accessed on September 22, 2015</ref> | . NATIONAL CANCER INSTITUTE . http://www.cancer.gov/types/gi-carcinoid-tumors/hp/gi-carcinoid-treatment-pdq#link/_97_toc Accessed on September 22, 2015</ref> | ||
*[[Somatostatin]] | *[[Somatostatin]] [[analogue]] | ||
* Telotristat | * [[Telotristat ethyl|Telotristat]] | ||
*[[Interferons]] | *[[Interferons]] | ||
*Treatment of hepatic metastases | *Treatment of [[hepatic]] [[metastases]] | ||
*[[Radionuclides]] | *[[Radionuclides]] | ||
*Management of carcinoid-related fibrosis | *Management of [[Carcinoid Disease|carcinoid]]-related [[fibrosis]] | ||
*[[Surgery]] | *[[Surgery]] | ||
===Somatostatin Analogs=== | ===Somatostatin Analogs=== | ||
* Somatostatin analogs includes octreotide and lanreotide. | * [[Somatostatin|Somatostatin analogs]] includes [[octreotide]] and [[Lanreotide acetate|lanreotide]]. | ||
* Somatostatin acts by binding to somatostatin receptors expressed on the majority of carcinoid tumors | * [[Somatostatin]] acts by binding to [[Somatostatin receptor|somatostatin receptors]] expressed on the majority of [[carcinoid tumors]]. | ||
* Flushing and diarrhea are significantly improved in over 80 percent of patients with the carcinoid syndrome with somatostatin therapy.<ref name="pmid27214300">{{cite journal |vauthors=Vinik AI, Wolin EM, Liyanage N, Gomez-Panzani E, Fisher GA |title=EVALUATION OF LANREOTIDE DEPOT/AUTOGEL EFFICACY AND SAFETY AS A CARCINOID SYNDROME TREATMENT (ELECT): A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL |journal=Endocr Pract |volume=22 |issue=9 |pages=1068–80 |date=September 2016 |pmid=27214300 |doi=10.4158/EP151172.OR |url=}}</ref> | * [[Flushing]] and [[Diarrheal|diarrhea]] are significantly improved in over 80 percent of [[patients]] with the [[Carcinoid Syndrome|carcinoid syndrome]] with [[somatostatin]] [[therapy]].<ref name="pmid27214300">{{cite journal |vauthors=Vinik AI, Wolin EM, Liyanage N, Gomez-Panzani E, Fisher GA |title=EVALUATION OF LANREOTIDE DEPOT/AUTOGEL EFFICACY AND SAFETY AS A CARCINOID SYNDROME TREATMENT (ELECT): A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL |journal=Endocr Pract |volume=22 |issue=9 |pages=1068–80 |date=September 2016 |pmid=27214300 |doi=10.4158/EP151172.OR |url=}}</ref> | ||
*Experimentally, somatostatin has been shown to have a [[cytostatic]] effect on tumor cells. This effect involves hyperphosphorylation of the [[retinoblastoma]] gene product and G1 | *[[Experimentally|Experimentally,]] [[somatostatin]] has been shown to have a [[cytostatic]] effect on [[Tumor cell|tumor cells]]. This effect involves [[hyperphosphorylation]] of the [[retinoblastoma]] [[gene]] product and [[G1]] [[cell cycle]] arrest.<ref name="pmid11095353">{{cite journal |vauthors=Ducreux M, Ruszniewski P, Chayvialle JA, Blumberg J, Cloarec D, Michel H, Raymond JM, Dupas JL, Gouerou H, Jian R, Genestin E, Hammel P, Rougier P |title=The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors |journal=Am. J. Gastroenterol. |volume=95 |issue=11 |pages=3276–81 |date=November 2000 |pmid=11095353 |doi=10.1111/j.1572-0241.2000.03210.x |url=}}</ref> | ||
*[[Lanreotide]], a long-acting [[somatostatin]] [[Analogue|analog]] administered every 10 to 14 days, has an efficacy similar to that of [[octreotide]] and an agreeable formulation for [[patient]] use. The effects of [[Lanreotide acetate|lanreotide]] on [[Symptoms|symptom]] relief are comparable to those of [[octreotide]], with 75% to 80% of patients reporting decreased [[diarrhea]] and [[flushing]]. However, there appears to be little improvement in [[Tumor cell|tumor]] responses over shorter-acting [[octreotide]]. | |||
*Depot [[formulation]]<nowiki/>s include long-acting repeatable (LAR) [[octreotide]] and a slow-release depot preparation of [[lanreotide]]. | |||
*[[Lanreotide]], a long-acting somatostatin analog administered every 10 to 14 days, has an efficacy similar to that of [[octreotide]] and an agreeable formulation for patient use. The effects of lanreotide on symptom relief are comparable to those of octreotide, with 75% to 80% of patients reporting decreased [[diarrhea]] and [[flushing]]. However, there appears to be little improvement in tumor responses over shorter-acting octreotide. | *The typical [[duration]] of treatment with [[somatostatin]] analogs is approximately 12 months because of the development of [[tachyphylaxis]]. | ||
*Depot | [[Adverse effects]] of [[somatostatin]] analog administration include: | ||
*The typical duration of treatment with somatostatin analogs is approximately 12 months because of the development of [[tachyphylaxis]] | |||
Adverse effects of somatostatin analog administration include: | |||
*[[Nausea]] | *[[Nausea]] | ||
*[[Cramping]] | *[[Cramping]] | ||
*[[Loose stools]] | *[[Loose stools]] | ||
*[[Steatorrhea]] | *[[Steatorrhea]] | ||
*Cardiac conduction abnormalities and [[ | *[[Cardiac]] [[Conduction System|conduction abnormalities]] and [[arrhythmia]]<nowiki/>s | ||
*Endocrine disturbances (e.g., [[hypothyroidism]], [[hypoglycemia]], or [[hyperglycemia]] | *[[Endocrine|Endocrine disturbances]] (e.g., [[hypothyroidism]], [[hypoglycemia]], or [[hyperglycemia]] | ||
*Gastric atony | *[[Gastric]] [[atony]] | ||
===Telotristat=== | ===Telotristat=== | ||
* Telotristat is an oral inhibitor | * [[Telotristat ethyl|Telotristat]] is an [[oral]] [[inhibitor]] o[[Tryptophan hydroxylase|f tryptophan hydroxylase]] which [[catalyzes]] the conversion of l-[[tryptophan]] into [[serotonin]]..<ref name="pmid29503551">{{cite journal |vauthors=Chan DL, Singh S |title=Developments in the treatment of carcinoid syndrome - impact of telotristat |journal=Ther Clin Risk Manag |volume=14 |issue= |pages=323–329 |date=2018 |pmid=29503551 |pmc=5824756 |doi=10.2147/TCRM.S126143 |url=}}</ref> | ||
* Tryptophan hydroxylase is an aromatic amino acid hydroxylase and is the rate-limiting enzyme in serotonin synthesis. | * [[Tryptophan hydroxylase]] is an [[Aromatic amino acids|aromatic amino acid]] [[hydroxylase]] and is the rate-limiting [[enzyme]] in [[serotonin]] [[synthesis]]. | ||
* Somatostatin analogs (SSAs) are the mainstay of treatment, but are unable to ameliorate symptoms in all patients due to dose-limiting side effects and tachyphylaxis. | * [[Somatostatin|Somatostatin analogs]] (SSAs) are the mainstay of treatment, but are unable to ameliorate [[symptoms]] in all [[patients]] due to [[dose]]-limiting [[side effects]] and [[tachyphylaxis]]. | ||
* Telotristat represents a significant advance in the treatment of carcinoid syndrome diarrhea in patients who have inadequate control on long-acting | * [[Telotristat ethyl|Telotristat]] represents a significant advance in the treatment of [[Carcinoid Syndrome|carcinoid syndrome]] [[Diarrheal|diarrhea]] in [[patients]] who have inadequate control on long-acting [[somatostatin]] [[Analogue|analogues]] and should be considered for [[patients]] with >4 [[bowel]] motions per day on [[somatostatin]] [[Analogue|analogues.]] | ||
===Interferons=== | ===Interferons=== | ||
*The most researched [[interferon]] in the treatment of carcinoid disease is interferon-alpha | *The most [[Research|researched]] [[interferon]] in the treatment of [[carcinoid disease]] is [[interferon-alpha]]. | ||
*[[Interferon-alpha]] (IFNα) is a [[cytokine]] that mediates [[Anti-viral drug|anti-viral,]] anti-proliferative and anti-[[tumour]] activities. | |||
* | *Side-effects includes | ||
#[[Flu]]-like [[symptoms]] | |||
#[[Chronic (medical)|Chronic]] [[fatigue]] | |||
#[[Depression (clinical)|Depression]] | |||
#[[Anemia]] | |||
#[[Neutropenia]]. | |||
===Treatment of Hepatic Metastases=== | ===Treatment of Hepatic Metastases=== | ||
The management of hepatic metastases may include: | The management of [[hepatic]] [[metastases]] may include: | ||
*[[Surgical resection]] | *[[Surgical resection]] | ||
*[[Hepatic artery]] embolization | *[[Hepatic artery]] [[embolization]] especially when complemented by the addition of regional [[chemotherapy]] (trans-[[arterial]] [[chemoembolization]] or [[TACE]])<ref name="pmid16508629">{{cite journal |vauthors=Strosberg JR, Choi J, Cantor AB, Kvols LK |title=Selective hepatic artery embolization for treatment of patients with metastatic carcinoid and pancreatic endocrine tumors |journal=Cancer Control |volume=13 |issue=1 |pages=72–8 |date=January 2006 |pmid=16508629 |doi=10.1177/107327480601300110 |url=}}</ref> | ||
*[[Cryoablation]] and [[Radiofrequency ablation]] (RFA) | *[[Cryoablation]] and [[Radiofrequency ablation]] ([[RFA]]) | ||
* | *[[liver transplantation]]<ref name="Blonski2005">{{cite journal|last1=Blonski|first1=Wojciech C|title=Liver transplantation for metastatic neuroendocrine tumor: A case report and review of the literature|journal=World Journal of Gastroenterology|volume=11|issue=48|year=2005|pages=7676|issn=1007-9327|doi=10.3748/wjg.v11.i48.7676}}</ref> | ||
===Radionuclides=== | ===Radionuclides=== | ||
* The use of somatostatin analogue radiolabeled peptide therapy (PRRT) provides radiation directed to the cells that express somatostatin receptors.<ref name="pmid26943056">{{cite journal |vauthors=Hörsch D, Ezziddin S, Haug A, Gratz KF, Dunkelmann S, Miederer M, Schreckenberger M, Krause BJ, Bengel FM, Bartenstein P, Biersack HJ, Pöpperl G, Baum RP |title=Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: A multi-institutional registry study with prospective follow-up |journal=Eur. J. Cancer |volume=58 |issue= |pages=41–51 |date=May 2016 |pmid=26943056 |doi=10.1016/j.ejca.2016.01.009 |url=}}</ref> | * The use of [[somatostatin]] [[analogue]] radiolabeled [[peptide]] therapy (PRRT) provides [[radiation]] directed to the [[cells]] that express [[somatostatin receptors]].<ref name="pmid26943056">{{cite journal |vauthors=Hörsch D, Ezziddin S, Haug A, Gratz KF, Dunkelmann S, Miederer M, Schreckenberger M, Krause BJ, Bengel FM, Bartenstein P, Biersack HJ, Pöpperl G, Baum RP |title=Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: A multi-institutional registry study with prospective follow-up |journal=Eur. J. Cancer |volume=58 |issue= |pages=41–51 |date=May 2016 |pmid=26943056 |doi=10.1016/j.ejca.2016.01.009 |url=}}</ref> | ||
The four radionuclide conjugates most commonly used in the treatment of carcinoid disease are: | * The four [[Radionuclides|radionuclide]] [[conjugates]] most commonly used in the treatment of [[carcinoid disease]] are: | ||
*131I-MIBG (iodine-131-meta-iodobenzylguanidine) | **[[Metaiodobenzylguanidine|131I-MIBG (iodine-131-meta-iodobenzylguanidine)]] | ||
*Indium-111 | **[[Indium|Indium-111]] | ||
*Yttrium-90 | **[[Yttrium Y 90-DOTA-tyr3-octreotide|Yttrium-90]] | ||
*Lutetium-177 | **[[Lutetium Lu 177 dotatate|Lutetium-177]] | ||
* | * It is mandatory to quantify [[cells]] with [[somatostatin receptors]] using imaging prior to PRRT therapy. | ||
===Management of Carcinoid-Related Fibrosis=== | ===Management of Carcinoid-Related Fibrosis=== | ||
Currently, there is no effective pharmacologic therapy for [[bowel obstruction]] and [[heart failure]] secondary to [[peritoneal]] | *Currently, there is no effective [[Pharmacological|pharmacologic]] [[therapy]] for [[bowel obstruction]] and [[heart failure]] secondary to [[peritoneal]] [[Fibrosis|fibrosi]]<nowiki/>s and right-sided [[valvular]] [[fibrosis]] respectively. | ||
*In the instance of [[bowel obstruction]], [[Surgery|surgical]] lysis of the [[adhesions]] often is technically demanding because of the cocoon-like effects of extensive [[fibrosis]] stimulated by the various [[Tumour|tumor]]-derived [[growth factors]]. | |||
*[[Valve replacement surgery|Valvular replacement]] usually is required to manage [[Carcinoid Disease|carcinoid heart diseas]]<nowiki/>e.<ref name="pmid15571597">{{cite journal |vauthors=Modlin IM, Shapiro MD, Kidd M |title=Carcinoid tumors and fibrosis: an association with no explanation |journal=Am. J. Gastroenterol. |volume=99 |issue=12 |pages=2466–78 |date=December 2004 |pmid=15571597 |doi=10.1111/j.1572-0241.2004.40507.x |url=}}</ref> | |||
===Symptomatic Therapy=== | ===Symptomatic Therapy=== | ||
* | *Nonspecific supportive care of [[patients]] is to avoid factors that induce [[flushing]] or [[Bronchospasm|bronchospastic]] episodes includes the following: | ||
:*Ingestion of [[alcohol]], certain cheeses, capsaicin-containing foods | :*Ingestion of [[alcohol]], certain [[Cheese|cheeses]], [[capsaicin]]-containing foods and [[Nut (fruit)|nuts]] | ||
:*Stressful situations | :*[[Stress|Stressful]] situations | ||
:*[[Physical activity]] | :*[[Physical activity]] | ||
*[[Diarrhea]] may be treated with conventional anti-diarrheal agents such as [[loperamide]] or [[diphenoxylate]] | *[[Diarrhea]] may be treated with conventional [[anti-diarrheal]] agents such as [[loperamide]] or [[diphenoxylate]] | ||
*Severe [[diarrhea]] may be treated with the [[5-HT receptor 2C|5-HT receptor subtype 2 antagonist]] [[cyproheptadine]], which is effective in as many as 50% of [[patients]] and may also help alleviate [[anorexia]] or [[cachexia]] in [[patients]] with a [[malignant carcinoid syndrome]]. | |||
* | *Treatment of s[[Skin rashes|kin rashes]], particularly in [[histamine]]-secreting [[Carcinoid tumors|gastric carcinoid tumors]] can be done with [[Histamine receptors|histamine 1 receptor]] blockade with [[fexofenadine]] and [[loratadine]] | ||
*[[Bronchospasm]] can be managed with [[theophylline]] or beta-2 adrenergic receptor agonists such as [[albuterol]]. | *[[Bronchospasm]] can be managed with [[theophylline]] or [[beta-2 adrenergic receptor]] [[agonists]] such as [[albuterol]]. | ||
==References== | ==References== | ||
Latest revision as of 22:22, 6 May 2019
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2] Anum Gull M.B.B.S.[3]
Overview
The predominant therapy for carcinoid syndrome is surgical resection. Supportive therapy for carcinoid syndrome includes somatostatin analogs,Telotristat,interferons, and radionuclides.
Medical Therapy
Standard treatments for patients with gastrointestinal carcinoid tumors include the following:[1]
- Somatostatin analogue
- Telotristat
- Interferons
- Treatment of hepatic metastases
- Radionuclides
- Management of carcinoid-related fibrosis
- Surgery
Somatostatin Analogs
- Somatostatin analogs includes octreotide and lanreotide.
- Somatostatin acts by binding to somatostatin receptors expressed on the majority of carcinoid tumors.
- Flushing and diarrhea are significantly improved in over 80 percent of patients with the carcinoid syndrome with somatostatin therapy.[2]
- Experimentally, somatostatin has been shown to have a cytostatic effect on tumor cells. This effect involves hyperphosphorylation of the retinoblastoma gene product and G1 cell cycle arrest.[3]
- Lanreotide, a long-acting somatostatin analog administered every 10 to 14 days, has an efficacy similar to that of octreotide and an agreeable formulation for patient use. The effects of lanreotide on symptom relief are comparable to those of octreotide, with 75% to 80% of patients reporting decreased diarrhea and flushing. However, there appears to be little improvement in tumor responses over shorter-acting octreotide.
- Depot formulations include long-acting repeatable (LAR) octreotide and a slow-release depot preparation of lanreotide.
- The typical duration of treatment with somatostatin analogs is approximately 12 months because of the development of tachyphylaxis.
Adverse effects of somatostatin analog administration include:
- Nausea
- Cramping
- Loose stools
- Steatorrhea
- Cardiac conduction abnormalities and arrhythmias
- Endocrine disturbances (e.g., hypothyroidism, hypoglycemia, or hyperglycemia
- Gastric atony
Telotristat
- Telotristat is an oral inhibitor of tryptophan hydroxylase which catalyzes the conversion of l-tryptophan into serotonin..[4]
- Tryptophan hydroxylase is an aromatic amino acid hydroxylase and is the rate-limiting enzyme in serotonin synthesis.
- Somatostatin analogs (SSAs) are the mainstay of treatment, but are unable to ameliorate symptoms in all patients due to dose-limiting side effects and tachyphylaxis.
- Telotristat represents a significant advance in the treatment of carcinoid syndrome diarrhea in patients who have inadequate control on long-acting somatostatin analogues and should be considered for patients with >4 bowel motions per day on somatostatin analogues.
Interferons
- The most researched interferon in the treatment of carcinoid disease is interferon-alpha.
- Interferon-alpha (IFNα) is a cytokine that mediates anti-viral, anti-proliferative and anti-tumour activities.
- Side-effects includes
Treatment of Hepatic Metastases
The management of hepatic metastases may include:
- Surgical resection
- Hepatic artery embolization especially when complemented by the addition of regional chemotherapy (trans-arterial chemoembolization or TACE)[5]
- Cryoablation and Radiofrequency ablation (RFA)
- liver transplantation[6]
Radionuclides
- The use of somatostatin analogue radiolabeled peptide therapy (PRRT) provides radiation directed to the cells that express somatostatin receptors.[7]
- The four radionuclide conjugates most commonly used in the treatment of carcinoid disease are:
- It is mandatory to quantify cells with somatostatin receptors using imaging prior to PRRT therapy.
Management of Carcinoid-Related Fibrosis
- Currently, there is no effective pharmacologic therapy for bowel obstruction and heart failure secondary to peritoneal fibrosis and right-sided valvular fibrosis respectively.
- In the instance of bowel obstruction, surgical lysis of the adhesions often is technically demanding because of the cocoon-like effects of extensive fibrosis stimulated by the various tumor-derived growth factors.
- Valvular replacement usually is required to manage carcinoid heart disease.[8]
Symptomatic Therapy
- Nonspecific supportive care of patients is to avoid factors that induce flushing or bronchospastic episodes includes the following:
- Diarrhea may be treated with conventional anti-diarrheal agents such as loperamide or diphenoxylate
- Severe diarrhea may be treated with the 5-HT receptor subtype 2 antagonist cyproheptadine, which is effective in as many as 50% of patients and may also help alleviate anorexia or cachexia in patients with a malignant carcinoid syndrome.
- Treatment of skin rashes, particularly in histamine-secreting gastric carcinoid tumors can be done with histamine 1 receptor blockade with fexofenadine and loratadine
- Bronchospasm can be managed with theophylline or beta-2 adrenergic receptor agonists such as albuterol.
References
- ↑ Treatment Option Overview for GI Carcinoid Tumors . NATIONAL CANCER INSTITUTE . http://www.cancer.gov/types/gi-carcinoid-tumors/hp/gi-carcinoid-treatment-pdq#link/_97_toc Accessed on September 22, 2015
- ↑ Vinik AI, Wolin EM, Liyanage N, Gomez-Panzani E, Fisher GA (September 2016). "EVALUATION OF LANREOTIDE DEPOT/AUTOGEL EFFICACY AND SAFETY AS A CARCINOID SYNDROME TREATMENT (ELECT): A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL". Endocr Pract. 22 (9): 1068–80. doi:10.4158/EP151172.OR. PMID 27214300.
- ↑ Ducreux M, Ruszniewski P, Chayvialle JA, Blumberg J, Cloarec D, Michel H, Raymond JM, Dupas JL, Gouerou H, Jian R, Genestin E, Hammel P, Rougier P (November 2000). "The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors". Am. J. Gastroenterol. 95 (11): 3276–81. doi:10.1111/j.1572-0241.2000.03210.x. PMID 11095353.
- ↑ Chan DL, Singh S (2018). "Developments in the treatment of carcinoid syndrome - impact of telotristat". Ther Clin Risk Manag. 14: 323–329. doi:10.2147/TCRM.S126143. PMC 5824756. PMID 29503551.
- ↑ Strosberg JR, Choi J, Cantor AB, Kvols LK (January 2006). "Selective hepatic artery embolization for treatment of patients with metastatic carcinoid and pancreatic endocrine tumors". Cancer Control. 13 (1): 72–8. doi:10.1177/107327480601300110. PMID 16508629.
- ↑ Blonski, Wojciech C (2005). "Liver transplantation for metastatic neuroendocrine tumor: A case report and review of the literature". World Journal of Gastroenterology. 11 (48): 7676. doi:10.3748/wjg.v11.i48.7676. ISSN 1007-9327.
- ↑ Hörsch D, Ezziddin S, Haug A, Gratz KF, Dunkelmann S, Miederer M, Schreckenberger M, Krause BJ, Bengel FM, Bartenstein P, Biersack HJ, Pöpperl G, Baum RP (May 2016). "Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: A multi-institutional registry study with prospective follow-up". Eur. J. Cancer. 58: 41–51. doi:10.1016/j.ejca.2016.01.009. PMID 26943056.
- ↑ Modlin IM, Shapiro MD, Kidd M (December 2004). "Carcinoid tumors and fibrosis: an association with no explanation". Am. J. Gastroenterol. 99 (12): 2466–78. doi:10.1111/j.1572-0241.2004.40507.x. PMID 15571597.