Carcinoid syndrome medical therapy: Difference between revisions

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==Overview==
==Overview==
The predominant therapy for carcinoid syndrome is surgical resection. Supportive therapy for carcinoid syndrome includes [[somatostatin]] analogs,Telotristat,[[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 (GI) carcinoid tumors include the following:<ref>Treatment Option Overview for GI Carcinoid Tumors
[[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]] analogs
*[[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 cell cycle arrest.
*[[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 formulations include long-acting repeatable (LAR) [[octreotide]] and a slow-release depot preparation of [[lanreotide]].
[[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 [[arrhythmias]]
*[[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 of 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>
* [[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 SSAs and should be considered for patients with >4 bowel motions per day on SSAs
* [[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 (IFN-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, anti-proliferative and anti-tumour activities.
*[[Interferon-alpha]] (IFNα) is a [[cytokine]] that mediates [[Anti-viral drug|anti-viral,]] anti-proliferative and anti-[[tumour]] activities.


*Side-effects include initial flu-like symptoms, chronic fatigue, depression, anaemia and neutropenia.
*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]])
*Orthotopic [[liver transplantation]]
*[[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.
* 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]] 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.
*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===
*In addition to the use of long-acting depot formulations of somatostatin analogs as the principal agents in the amelioration of carcinoid symptoms, the nonspecific supportive care of patients includes, advising them to avoid factors that induce [[flushing]] or bronchospastic episodes including the following:
*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, and nuts
:*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]], more pronounced 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.
*[[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]].


*Histamine 1 receptor blockade with [[fexofenadine]], [[loratadine]], [[terfenadine]], or [[diphenhydramine]] may be of benefit in treating skin rashes, particularly in histamine-secreting gastric carcinoid tumors.
*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 Analogs

Adverse effects of somatostatin analog administration include:

Telotristat

Interferons

  • Side-effects includes
  1. Flu-like symptoms
  2. Chronic fatigue
  3. Depression
  4. Anemia
  5. Neutropenia.

Treatment of Hepatic Metastases

The management of hepatic metastases may include:

Radionuclides

Management of Carcinoid-Related Fibrosis

Symptomatic Therapy

References

  1. 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
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.


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