Difference between revisions of "Neuroendocrine tumor"

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'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]].'''
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Is there a regimen missing from this list?  Would you like to share a different dosage/schedule or an additional reference for a regimen?  Have you noticed an error?  Do you have an idea that will help the site grow to better meet your needs and the needs of many others?  You are [[How_to_contribute|invited to contribute to the site]].
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[[#top|Back to Top]]
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{{#lst:Editorial board transclusions|endo}}
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''Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit [[Neuroendocrine tumor - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''<br>
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<big>Note: This page is now exclusively focused on those tumors commonly called carcinoids, which may or may not be associated with the carcinoid syndrome; there are now separate pages for '''[[pancreatic NET]]''' and other endocrine cancers. Neuroendocrine tumors of unknown primary and poorly differentiated (high-grade) neuroendocrine carcinomas are usually treated with a '''[[small cell lung cancer]]''' regimen; see [[Neuroendocrine carcinoma|this page]] for histology-specific options.</big>
 
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|<div style="background-color: #66FF66; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} regimens on this page</b></font></div>
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|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
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<div style="background-color: #66CCFF; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} variants on this page</b></font></div>
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<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 
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=Guidelines=
 +
'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
 +
==CommNETS/NANETS==
 +
*'''2020:''' Singh et al. [https://doi.org/10.1016/j.jtho.2020.06.021 Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society Guidelines for the Diagnosis and Management of Patients With Lung Neuroendocrine Tumors: An International Collaborative Endorsement and Update of the 2015 European Neuroendocrine Tumor Society Expert Consensus Guidelines] [https://www.ncbi.nlm.nih.gov/pubmed/32663527 PubMed]
  
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=Adrenal gland tumors, adrenocortical carcinoma - adjuvant therapy=
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==[https://www.esmo.org/ ESMO]==
 +
*'''2021:''' Baudin et al. [https://doi.org/10.1016/j.annonc.2021.01.003 Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/33482246/ PubMed]
 +
**'''2012:''' Öberg et al. [https://doi.org/10.1093/annonc/mds267 Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/22997444/ PubMed]
 +
**'''2010:''' Oberg et al. [https://doi.org/10.1093/annonc/mdq191 Neuroendocrine bronchial and thymic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/20555085/ PubMed]
 +
**'''2009:''' Oberg & Jelic. [https://doi.org/10.1093/annonc/mdp157 Neuroendocrine bronchial and thymic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454438/ PubMed]
 +
**'''2008:''' Oberg & Jelic. [https://doi.org/10.1093/annonc/mdn116 Neuroendocrine bronchial and thymic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456740/ PubMed]
 +
*'''2012:''' Öberg et al. [https://doi.org/10.1093/annonc/mds295 Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.] [https://pubmed.ncbi.nlm.nih.gov/22997445/ PubMed]
  
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==Mitotane (Lysodren) {{#subobject:ef7e79|Regimen=1}}==
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==French Intergroup==
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{| class="wikitable" style="float:right; margin-left: 5px;"
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*'''2020:''' de Mestier et al. [https://doi.org/10.1016/j.dld.2020.02.011 Digestive Neuroendocrine Neoplasms (NEN): French Intergroup clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, GTE, RENATEN, TENPATH, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR)] [https://pubmed.ncbi.nlm.nih.gov/32234416/ PubMed]
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'''There is limited and controversial clinical trial information about adjuvant mitotane use.  See the references for additional case series and expert recommendation articles.'''
 
  
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===Regimen #1, Wängberg et al. 2010 {{#subobject:45870b|Variant=1}}===
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==NANETS==
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Level of Evidence:
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*'''2017:''' Strosberg et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5642985/ The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Midgut Neuroendocrine Tumors] [https://www.ncbi.nlm.nih.gov/pubmed/28609356 PubMed]
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<span
 
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style="background:#EEEE00;
 
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padding:3px 6px 3px 6px;
 
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border-color:black;
 
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border-width:2px;
 
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border-style:solid;">Phase II</span>
 
  
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''Patients started on adjuvant mitotane within 4 weeks of their surgical resection.''
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*'''2013:''' Kunz et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4304762/ Consensus Guidelines for the Management and Treatment of Neuroendocrine Tumors] [https://www.ncbi.nlm.nih.gov/pubmed/23591432 PubMed]
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*[[Mitotane (Lysodren)]] 2000 mg PO per day (frequency not specified, such as whether the total daily dose was divided into a few doses throughout the day); within the first 2 to 3 months, [[Mitotane (Lysodren)]] dose was adjusted to achieve a target therapeutic drug level of 14 to 20 mg/L
 
  
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'''2 to 3-year course'''
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==NCCN==
 +
*''NCCN does not currently have guidelines at this granular level; please see [https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448 NCCN Guidelines - Neuroendocrine and Adrenal Tumors]''.
 +
**'''2015:''' Kulke et al. [https://doi.org/10.6004/Jnccn.2015.0011 Neuroendocrine tumors, version 1.2015.] [https://pubmed.ncbi.nlm.nih.gov/25583772/ PubMed]
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**'''2012:''' Kulke et al. [https://doi.org/10.6004/Jnccn.2012.0075 Neuroendocrine tumors.] [https://pubmed.ncbi.nlm.nih.gov/22679117/ PubMed]
 +
**'''2009:''' Clark et al. [https://doi.org/10.6004/Jnccn.2009.0050 NCCN Clinical Practice Guidelines in Oncology: neuroendocrine tumors.] [https://pubmed.ncbi.nlm.nih.gov/19635226/ PubMed]
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**'''2006:''' Clark et al. [https://doi.org/10.6004/Jnccn.2006.0013 Neuroendocrine tumors.] [https://pubmed.ncbi.nlm.nih.gov/16451769/ PubMed]
  
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===Regimen #2, Haak et al. 1994 {{#subobject:67a83e|Variant=1}}===
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=All lines of therapy=
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Level of Evidence:
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==Capecitabine & Temozolomide {{#subobject:d67u17|Regimen=1}}==
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<span
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<div class="toccolours" style="background-color:#eeeeee">
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style="background:#EEEE00;
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===Regimen {{#subobject:9a3c15|Variant=1}}===
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padding:3px 6px 3px 6px;
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{| class="wikitable sortable" style="width: 60%; text-align:center;"  
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border-color:black;
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!style="width: 33%"|Study
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border-width:2px;
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!style="width: 33%"|Dates of enrollment
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border-style:solid;">Phase II</span>
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!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
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''Haak et al. 1994 concluded that "mitotane treatment in adrenocortical carcinoma is effective only when high
 
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serum levels [trough of at least 14 mg/L] can be achieved."''
 
−
*[[Mitotane (Lysodren)]] 1000 to 2000 mg PO QID (total dose per day: 4000 to 8000 mg), with target mitotane trough of above 14 mg/L
 
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−
'''2-year course "if resection was judged to be complete or for 1 year after apparent disappearance of the tumour"'''
 
−
 
 
−
Supportive medications:
 
−
*Hydrocortisone (Cortef) 30 to 120 mg per day or Fludrocortisone (Florinef) 0.1 to 0.4 mg per day
 
−
*Metoclopramide (Reglan) and Loperamide (Imodium) prn "gastrointestinal side-effects"
 
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−
===References===
 
−
# Vassilopoulou-Sellin R, Guinee VF, Klein MJ, Taylor SH, Hess KR, Schultz PN, Samaan NA. Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer. 1993 May 15;71(10):3119-23. [http://onlinelibrary.wiley.com/doi/10.1002/1097-0142%2819930515%2971:10%3C3119::AID-CNCR2820711037%3E3.0.CO;2-8/abstract link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/8490842 PubMed]
 
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# Haak HR, Hermans J, van de Velde CJ, Lentjes EG, Goslings BM, Fleuren GJ, Krans HM. Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer. 1994 May;69(5):947-51. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1968906/ link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/8180029 PubMed] content property of [http://hemonc.org HemOnc.org]
 
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# Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, Rossetto R, Buci L, Sperone P, Grossrubatscher E, Reimondo G, Bollito E, Papotti M, Saeger W, Hahner S, Koschker AC, Arvat E, Ambrosi B, Loli P, Lombardi G, Mannelli M, Bruzzi P, Mantero F, Allolio B, Dogliotti L, Berruti A. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007 Jun 7;356(23):2372-80. [http://www.nejm.org/doi/full/10.1056/NEJMoa063360 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/17554118 PubMed]
 
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# Veytsman I, Nieman L, Fojo T. Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma. J Clin Oncol. 2009 Sep 20;27(27):4619-29. doi: 10.1200/JCO.2008.17.2775. Epub 2009 Aug 10. [http://jco.ascopubs.org/content/27/27/4619.full link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/19667279 PubMed]
 
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# Wängberg B, Khorram-Manesh A, Jansson S, Nilsson B, Nilsson O, Jakobsson CE, Lindstedt S, Odén A, Ahlman H. The long-term survival in adrenocortical carcinoma with active surgical management and use of monitored mitotane. Endocr Relat Cancer. 2010 Feb 18;17(1):265-72. doi: 10.1677/ERC-09-0190. Print 2010 Mar. [http://erc.endocrinology-journals.org/content/17/1/265.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20026647 PubMed]
 
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==Mitotane & Streptozocin {{#subobject:942057|Regimen=1}}==
 
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{| class="wikitable" style="float:right; margin-left: 5px;"
 
 
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|[[#toc|back to top]]
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|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099746/ Jeong et al. 2021 (Asan-ONCHBP-2017-002)]
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|2017-2021
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| style="background-color:#91cf61" |Phase 2
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===Regimen, Khan et al. 2010 {{#subobject:3a7fbd|Variant=1}}===
 
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Level of Evidence:
 
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<span
 
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style="background:#EEEE00;
 
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padding:3px 6px 3px 6px;
 
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border-color:black;
 
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border-width:2px;
 
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border-style:solid;">Phase II</span>
 
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====Induction course====
 
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*[[Streptozocin (Zanosar)]] 1000 mg IV once per day on days 1 to 5
 
−
 
 
−
'''5-day course, followed by main regimen'''
 
−
 
 
−
====Main regimen====
 
−
*[[Mitotane (Lysodren)]] 1000 to 4000 mg/day PO; daily dose is taken in 2 to 3 divided doses per day
 
−
*[[Streptozocin (Zanosar)]] 2000 mg IV once per day on days 1 to 5
 
−
 
 
−
'''21-day cycles; duration of therapy not clearly specified'''
 
−
 
 
−
Supportive medications:
 
−
*[[Antiemesis|5-HT3 antagonists]] prior to streptozocin
 
−
*Hydrocortisone (Cortef) 25 to 100 mg/day
 
−
 
 
−
===References===
 
−
# Khan TS, Imam H, Juhlin C, Skogseid B, Gröndal S, Tibblin S, Wilander E, Oberg K, Eriksson B. Streptozocin and o,p'DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use. Ann Oncol. 2000 Oct;11(10):1281-7. [http://annonc.oxfordjournals.org/content/11/10/1281.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/11106117 PubMed]
 
−
 
 
−
=Adrenal gland tumors, adrenocortical carcinoma - recurrent, locally advanced, or metastatic disease=
 
−
 
 
−
==Mitotane (Lysodren) {{#subobject:e99e96|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
 
|-
 
|-
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|[[#toc|back to top]]
 
 
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<div class="toccolours" style="background-color:#b3e2cd">
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===Regimen, Veytsman et al. 2009 {{#subobject:17527c|Variant=1}}===
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====Chemotherapy====
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*[[Mitotane (Lysodren)]] 1000 to 2000 mg PO per day (frequency not specified, such as whether the total daily dose was divided into a few doses throughout the day); then increase daily dose of [[Mitotane (Lysodren)]] by 1000 to 2000 mg every 1 to 2 weeks to the maximum tolerated dose, not to exceed 6000 mg ("never > 6 to 10 g/d").  Target mitotane drug level is 10 to 14 mg/L.
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*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup> PO twice per day on days 1 to 14
−
 
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*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day on days 10 to 14
 +
'''28-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# '''Review:''' Veytsman I, Nieman L, Fojo T. Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma. J Clin Oncol. 2009 Sep 20;27(27):4619-29. doi: 10.1200/JCO.2008.17.2775. Epub 2009 Aug 10. [http://jco.ascopubs.org/content/27/27/4619.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19667279 PubMed]
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# '''Asan-ONCHBP-2017-002:''' Jeong H, Shin J, Jeong JH, Kim KP, Hong SM, Kim YI, Ryu JS, Ryoo BY, Yoo C. Capecitabine plus temozolomide in patients with grade 3 unresectable or metastatic gastroenteropancreatic neuroendocrine neoplasms with Ki-67 index <55%: single-arm phase II study. ESMO Open. 2021 Jun;6(3):100119. [https://doi.org/10.1016/j.esmoop.2021.100119 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099746/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33901869/ PubMed] [https://clinicaltrials.gov/study/NCT03079440 NCT03079440]
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==Mitotane & EDP {{#subobject:8a7788|Regimen=1}}==
 
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{| class="wikitable" style="float:right; margin-left: 5px;"
 
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|[[#toc|back to top]]
 
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|}
 
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EDP: '''<u>E</u>'''toposide, '''<u>D</u>'''oxorubicin, '''<u>P</u>'''latinol (Cisplatin)
 
  
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===Regimen #1 {{#subobject:ded16a|Variant=1}}===
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==Doxorubicin & Fluorouracil {{#subobject:bd83do|Regimen=1}}==
−
{| border="1" style="text-align:center;" !align="left"  
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<div class="toccolours" style="background-color:#eeeeee">
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|'''Study'''
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===Regimen {{#subobject:d3fu72|Variant=1}}===
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|[[Levels_of_Evidence#Evidence|'''Evidence''']]
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{| class="wikitable sortable" style="width: 100%; text-align:center;"  
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|'''Comparator'''
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!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
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|[http://www.nejm.org/doi/full/10.1056/NEJMoa1200966 Fassnacht et al. 2012 (FIRM-ACT)]
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|[https://doi.org/10.1200/JCO.2005.03.616 Sun et al. 2005]
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|<span
+
|1981-1990
−
style="background:#00CD00;
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|style="background-color:#1a9851"|Phase 2/3 (C)
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padding:3px 6px 3px 6px;
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|[[#Fluorouracil_.26_Streptozocin|Fluorouracil & Streptozocin]]
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border-color:black;
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| style="background-color:#fc8d59" |Seems to have inferior OS
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border-width:2px;
 
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border-style:solid;">Phase III</span>
 
−
|[[Neuroendocrine_tumors#Mitotane_.26_Streptozocin_2|Mitotane & Streptozocin]]
 
 
|-
 
|-
 
|}
 
|}
−
 
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<div class="toccolours" style="background-color:#b3e2cd">
−
''Mitotane is started at least 1 week before the other chemotherapy; the rest of the therapy is as described below.''
+
====Chemotherapy====
−
*[[Mitotane (Lysodren)]] on days 1 to 28, with target mitotane trough of 14 to 20 mg/L (initial dose and frequency not specified)
+
*[[Doxorubicin (Adriamycin)]] by the following symptom-based criteria:
−
*[[Etoposide (Vepesid)]] 100 mg/m2 IV once per day on days 2 to 4
+
**No jaundice: 40 mg/m<sup>2</sup> IV push once on day 1
−
*[[Doxorubicin (Adriamycin)]] 40 mg/m2 IV once on day 1
+
**Jaundiced: 25 mg/m<sup>2</sup> IV push once on day 1
−
*[[Cisplatin (Platinol)]] 40 mg/m2 IV once per day on days 3 & 4
+
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV push once per day on days 1 to 5
−
 
+
'''35-day cycles'''
−
Supportive medications:
+
</div></div>
−
*[[:Category:Steroids|Glucocorticoid]] replacement was recommended in all patients except those with persistent Cushing's syndrome.
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===Regimen #2 {{#subobject:2dd6a8|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|-
 
−
|[http://erc.endocrinology-journals.org/content/12/3/657.long Berruti et al. 2005]
 
−
|<span
 
−
style="background:#EEEE00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
−
|-
 
−
|}
 
−
 
 
−
*[[Mitotane (Lysodren)]] 1000 mg PO per day (frequency not specified, such as whether the total daily dose was divided into a few doses throughout the day) on days 1 to 28; then [[Mitotane (Lysodren)]] dose is increased as tolerated up to 4000 mg/day or maximum tolerated dose
 
−
*[[Etoposide (Vepesid)]] 100 mg/m2 IV once per day on days 5 to 7
 
−
*[[Doxorubicin (Adriamycin)]] 20 mg/m2 IV once per day on days 1 & 8
 
−
*[[Cisplatin (Platinol)]] 40 mg/m2 IV once per day on days 2 & 9
 
−
 
 
−
'''28-day cycle x up to 6 cycles, given until progression of disease, unacceptable toxicity, or patient refusal'''
 
  
 
===References===
 
===References===
−
# Berruti A, Terzolo M, Sperone P, Pia A, Della Casa S, Gross DJ, Carnaghi C, Casali P, Porpiglia F, Mantero F, Reimondo G, Angeli A, Dogliotti L. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer. 2005 Sep;12(3):657-66. [http://erc.endocrinology-journals.org/content/12/3/657.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16172198 PubMed]
+
# '''ECOG E1281:''' Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG; [[Study_Groups#ECOG|ECOG]]. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005 Aug 1;23(22):4897-904. [https://doi.org/10.1200/JCO.2005.03.616 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16051944/ PubMed]
−
# Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, Sorbye H, Torpy DJ, Stepan V, Schteingart DE, Arlt W, Kroiss M, Leboulleux S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabarin A, Quinkler M, de la Fouchardière C, Schlumberger M, Mantero F, Weismann D, Beuschlein F, Gelderblom H, Wilmink H, Sender M, Edgerly M, Kenn W, Fojo T, Müller HH, Skogseid B; FIRM-ACT Study Group. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012 Jun 7;366(23):2189-97. Epub 2012 May 2. [http://www.nejm.org/doi/full/10.1056/NEJMoa1200966 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22551107 PubMed]
 
  
−
==Mitotane & Streptozocin {{#subobject:bd8397|Regimen=1}}==
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==Everolimus monotherapy {{#subobject:99989f|Regimen=1}}==
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{| class="wikitable" style="float:right; margin-left: 5px;"
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<div class="toccolours" style="background-color:#eeeeee">
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===Regimen {{#subobject:4ef82e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
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!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
|-
 
|-
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|[[#toc|back to top]]
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|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063317/ Yao et al. 2015 (RADIANT-4)]
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|}
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−
 
+
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-93-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
−
===Regimen {{#subobject:d34072|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"  
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1200966 Fassnacht et al. 2012 (FIRM-ACT)]
+
|} -->
−
|<span
+
|2012-04 to 2013-08
−
style="background:#00CD00;
+
|style="background-color:#1a9851"|Phase 3 (E-RT-esc)
−
padding:3px 6px 3px 6px;
+
|[[Neuroendocrine_tumor_-_null_regimens#Placebo|Placebo]]
−
border-color:black;
+
| style="background-color:#d9ef8b" |Superior PFS (primary endpoint)<br>Median PFS: 11 vs 3.9 mo<br>(HR 0.48, 95% CI 0.35-0.67)<br><br>Might have superior OS (secondary endpoint)<br>Median OS: NYR vs NYR<br>(HR 0.64, 95% CI 0.40-1.05)
−
border-width:2px;
+
|style="background-color:#eeee01"|Equivalent HRQoL
−
border-style:solid;">Phase III</span>
 
−
|[[Neuroendocrine_tumors#Mitotane_.26_EDP|Mitotane & EDP]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
''Mitotane is started at least 1 week before the other chemotherapy; the rest of the therapy is as described below.''
+
====Targeted therapy====
−
*[[Mitotane (Lysodren)]] on days 1 to 21, with target mitotane trough of 14 to 20 mg/L (initial dose and frequency not specified)
+
*[[Everolimus (Afinitor)]] 10 mg PO once per day
−
*[[Streptozocin (Zanosar)]] 1000 mg IV once per day on days 1 to 5 of cycle 1; then [[Streptozocin (Zanosar)]] 2000 mg IV once on day 1 of cycles 2 and on
+
'''Continued indefinitely'''
−
 
+
</div></div>
−
Supportive medications:
 
−
*[[:Category:Steroids|Glucocorticoid]] replacement was recommended in all patients except those with persistent Cushing's syndrome.
 
−
 
 
−
'''21-day cycles'''
 
  
 
===References===
 
===References===
−
# Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, Sorbye H, Torpy DJ, Stepan V, Schteingart DE, Arlt W, Kroiss M, Leboulleux S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabarin A, Quinkler M, de la Fouchardière C, Schlumberger M, Mantero F, Weismann D, Beuschlein F, Gelderblom H, Wilmink H, Sender M, Edgerly M, Kenn W, Fojo T, Müller HH, Skogseid B; FIRM-ACT Study Group. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012 Jun 7;366(23):2189-97. doi: 10.1056/NEJMoa1200966. Epub 2012 May 2. [http://www.nejm.org/doi/full/10.1056/NEJMoa1200966 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22551107 PubMed]
+
# '''RADIANT-4:''' Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H, Voi M, Pacaud LB, Rouyrre N, Sachs C, Valle JW, Fave GD, Van Cutsem E, Tesselaar M, Shimada Y, Oh DY, Strosberg J, Kulke MH, Pavel ME; RAD001 in Advanced Neuroendocrine Tumours Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016 Mar 5;387(10022):968-977. Epub 2015 Dec 17. [https://doi.org/10.1016/S0140-6736(15)00817-X link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063317/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26703889/ PubMed] [https://clinicaltrials.gov/study/NCT01524783 NCT01524783]
−
 
+
## '''HRQoL analysis:''' Pavel ME, Singh S, Strosberg JR, Bubuteishvili-Pacaud L, Degtyarev E, Neary MP, Carnaghi C, Tomasek J, Wolin E, Raderer M, Lahner H, Valle JW, Pommier R, Van Cutsem E, Tesselaar MET, Fave GD, Buzzoni R, Hunger M, Eriksson J, Cella D, Ricci JF, Fazio N, Kulke MH, Yao JC. Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1411-1422. Epub 2017 Aug 30. [https://doi.org/10.1016/S1470-2045(17)30471-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28838862/ PubMed]
−
=Carcinoid tumors=
 
−
 
 
−
==Interferon alfa-2b (Intron-A) {{#subobject:557a2f|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#toc|back to top]]
 
−
|}
 
  
−
===Regimen {{#subobject:a0cb2f|Variant=1}}===
+
==Everolimus & Octreotide {{#subobject:d69a17|Regimen=1}}==
−
{| border="1" style="text-align:center;" !align="left"  
+
<div class="toccolours" style="background-color:#eeeeee">
−
|'''Study'''
+
===Regimen variant #1 {{#subobject:9dd15|Variant=1}}===
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
|'''Comparator'''
+
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/21/14/2689.long Faiss et al. 2003]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008]
−
|<span
+
|2005-2006
−
style="background:#00CD00;
+
| style="background-color:#91cf61" |Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[#Lanreotide_.28Somatuline.29|Lanreotide]]<br> [[#Lanreotide_.26_Interferon_alfa-2b|Lanreotide & Interferon alfa-2b]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Interferon alfa-2b (Intron-A)]] 5 million units SC given once per day, 3 times per week
+
====Targeted therapy====
−
 
+
*[[Everolimus (Afinitor)]] 5 mg PO once per day on days 1 to 28
−
'''Given until progression of disease'''
+
====Endocrine therapy====
−
 
+
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1
−
''Patients who progressed on monotherapy then received combination lanreotide & interferon alfa.''
+
'''28-day cycles'''
−
 
+
</div></div><br>
−
===References===
+
<div class="toccolours" style="background-color:#eeeeee">
−
# Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. [http://jco.ascopubs.org/content/21/14/2689.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12860945 PubMed]
+
===Regimen variant #2 {{#subobject:867317|Variant=1}}===
−
 
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
==Lanreotide (Somatuline) {{#subobject:c44a4e|Regimen=1}}==
+
!style="width: 20%"|Study
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[[#toc|back to top]]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ Yao et al. 2008]
−
|}
+
|2005-2006
−
 
+
| style="background-color:#91cf61" |Phase 2
−
===Regimen {{#subobject:171ae2|Variant=1}}===
+
| style="background-color:#d3d3d3" |
−
{| border="1" style="text-align:center;" !align="left"
+
| style="background-color:#d3d3d3" |
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/21/14/2689.long Faiss et al. 2003]
+
|[https://doi.org/10.1016/S0140-6736(11)61742-X Pavel et al. 2011 (RADIANT-2)]
−
|<span
+
|2007-2010
−
style="background:#00CD00;
+
|style="background-color:#1a9851"|Phase 3 (E-esc)
−
padding:3px 6px 3px 6px;
+
|[[#Octreotide_LAR_monotherapy|Octreotide LAR]]
−
border-color:black;
+
|style="background-color:#91cf60"|Seems to have superior PFS (primary endpoint)<br>Median PFS: 16.4 vs 11.3 mo<br>(HR 0.77, 95% CI 0.59-1.00)
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[#Interferon_alfa-2b_.28Intron-A.29|Interferon alfa-2b]]<br> [[#Lanreotide_.26_Interferon_alfa-2b|Lanreotide & Interferon alfa-2b]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''Note: RADIANT-2 did not meet its primary endpoint, based on a pre-specified p-value cutoff of 0.0246.''
−
*[[Lanreotide (Somatuline)]] 1 mg SC TID
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Targeted therapy====
−
'''Given until progression of disease'''
+
*[[Everolimus (Afinitor)]] 10 mg PO once per day on days 1 to 28
−
 
+
====Endocrine therapy====
−
''Patients who progressed on monotherapy then received combination lanreotide & interferon alfa.''
+
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1
−
 
+
'''28-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. [http://jco.ascopubs.org/content/21/14/2689.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12860945 PubMed]
+
# Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008 Sep 10;26(26):4311-8. [https://doi.org/10.1200/jco.2008.16.7858 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653122/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18779618/ PubMed]
−
 
+
# '''RADIANT-2:''' Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. 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 Dec 10;378(9808):2005-12. Epub 2011 Nov 25. [https://doi.org/10.1016/S0140-6736(11)61742-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22119496/ PubMed] [https://clinicaltrials.gov/study/NCT00412061 NCT00412061]
−
==Lanreotide & Interferon alfa-2b {{#subobject:ce8ef2|Regimen=1}}==
+
## '''Update:''' Pavel ME, Baudin E, Öberg KE, Hainsworth JD, Voi M, Rouyrre N, Peeters M, Gross DJ, Yao JC. Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. 2017 Jul 1;28(7):1569-1575. [https://doi.org/10.1093/annonc/mdx193 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7360141/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28444114/ PubMed]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
==Fluorouracil & Streptozocin {{#subobject:bd8397|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:d34072|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[[#toc|back to top]]
+
|[https://doi.org/10.1200/JCO.1984.2.11.1255 Engstrom et al. 1984 (ECOG E5275)]
−
|}
+
|1976-1981
−
 
+
|style="background-color:#1a9851"|Phase 3 (E-esc)
−
===Regimen {{#subobject:87b3d6|Variant=1}}===
+
|[[#Doxorubicin_monotherapy_888|Doxorubicin]]
−
{| border="1" style="text-align:center;" !align="left"
+
| style="background-color:#ffffbf" |Did not meet co-primary endpoints of ORR/OS
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/21/14/2689.long Faiss et al. 2003]
+
|[https://doi.org/10.1200/JCO.2005.03.616 Sun et al. 2005]
−
|<span
+
|1981-1990
−
style="background:#00CD00;
+
|style="background-color:#1a9851"|Phase 2/3 (E-switch-ic)
−
padding:3px 6px 3px 6px;
+
|[[#Doxorubicin_.26_Fluorouracil|Doxorubicin & Fluorouracil]]
−
border-color:black;
+
| style="background-color:#91cf60" |Seems to have superior OS
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[#Interferon_alfa-2b_.28Intron-A.29|Interferon alfa-2b]]<br> [[#Lanreotide_.28Somatuline.29|Lanreotide]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Lanreotide (Somatuline)]] 1 mg SC TID
+
====Chemotherapy====
−
*[[Interferon alfa-2b (Intron-A)]] 5 million units SC given once per day, 3 times per week
+
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV push once per day on days 1 to 5, 36 to 40
 +
*[[Streptozocin (Zanosar)]] 500 mg/m<sup>2</sup> IV push once per day on days 1 to 5
 +
'''10-week cycles'''
 +
</div></div>
  
 
===References===
 
===References===
−
# Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. [http://jco.ascopubs.org/content/21/14/2689.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12860945 PubMed]
+
# '''ECOG E5275:''' Engstrom PF, Lavin PT, Moertel CG, Folsch E, Douglass HO Jr. Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol. 1984 Nov;2(11):1255-9. [https://doi.org/10.1200/JCO.1984.2.11.1255 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/6238136/ PubMed]
 +
# '''ECOG E1281:''' Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG; [[Study_Groups#ECOG|ECOG]]. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005 Aug 1;23(22):4897-904. [https://doi.org/10.1200/JCO.2005.03.616 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16051944/ PubMed]
  
−
==Octreotide (Sandostatin) {{#subobject:1b6b74|Regimen=1}}==
+
==Interferon alfa-2b monotherapy {{#subobject:557a2f|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:a0cb2f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[[#toc|back to top]]
+
|[https://doi.org/10.1056/NEJM198307213090301 Oberg et al. 1983]
−
|}
+
|NR
−
 
+
| style="background-color:#ffffbe" |Non-randomized, fewer than 20 pts
−
===Regimen #1, Oberg et al. 2004 {{#subobject:eb529b|Variant=1}}===
+
| style="background-color:#d3d3d3" |
−
====Octreotide immediate release (IR)====
+
| style="background-color:#d3d3d3" |
−
*[[Octreotide (Sandostatin)]] 0.1 to 0.5 mg SC given 2 to 4 times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms
 
−
**"A reasonable starting dose is" [[Octreotide (Sandostatin)]] 0.15 mg SC TID
 
−
 
 
−
'''patients may transition to octreotide long-acting release (LAR) treatment as described below; treatment continued indefinitely unless patients have unmanageable side-effects or insufficient control of symptoms'''
 
−
 
 
−
====Octreotide long-acting release (LAR)====
 
−
*[[Octreotide LAR (Sandostatin LAR)]] 20 to 30 mg IM once on day 1, with potentially higher doses if needed for symptom control
 
−
**"As a general rule, if the total [octreotide] IR dose is 200–600 µg/day [0.2 to 0.6 mg/day], LAR 20 mg should be tried, and if total IR dose is 750–1500 µg/day [0.75 to 1.5 mg/day], LAR 30 mg should be tried."
 
−
*[[Octreotide (Sandostatin)]] (dose not specified) SC as needed for additional symptom control
 
−
 
 
−
'''28-day cycles; treatment continued indefinitely unless patients have unmanageable side-effects or insufficient control of symptoms'''
 
−
 
 
−
===Regimen #2 {{#subobject:38d708|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"  
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/27/28/4656.long RInke et al. 2009 (PROMID)]
+
|rowspan=2|[https://doi.org/10.1200/jco.2003.12.142 Faiss et al. 2003]
−
|<span
+
|rowspan=2|1995-1998
−
style="background:#00CD00;
+
|rowspan=2 style="background-color:#1a9851"|Phase 3 (E-de-esc)
−
padding:3px 6px 3px 6px;
+
|1. [[#Lanreotide_monotherapy|Lanreotide]]
−
border-color:black;
+
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[#Placebo|Placebo]]
 
 
|-
 
|-
−
|}
+
|2. [[#Lanreotide_.26_Interferon_alfa-2b|Lanreotide & Interferon alfa-2b]]
−
 
+
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo
−
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1, with potentially higher doses if needed for symptom control
 
−
 
 
−
'''28-day cycles, given until progression of disease'''
 
−
 
 
−
===Regimen #3, Kvols et al. 1986 {{#subobject:29f57|Variant=1}}===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#EEEE00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
−
 
 
−
*[[Octreotide (Sandostatin)]] 0.15 mg SC BID on days 1 & 2, then [[Octreotide (Sandostatin)]] 0.15 mg TID on days 3 and on
 
−
 
 
−
'''"treatment was continued for as long as a clinical improvement was maintained"'''
 
−
 
 
−
===Regimen #4 {{#subobject:a531c2|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
−
|-
 
−
|[http://onlinelibrary.wiley.com/doi/10.1002/bjs.4149/abstract Kölby et al. 2003]
 
−
|<span
 
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Randomized Phase II</span>
 
−
|[[#Octreotide_.26_Interferon_alfa|Octreotide & Interferon alfa]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''Note: Treatment details are from Faiss et al. 2003.''
−
*[[Octreotide (Sandostatin)]] 0.1 mg SC BID; patients with persistent carcinoid symptoms could receive increased doses up to 0.2 mg SC TID
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Immunotherapy====
 +
*[[Interferon alfa-2b (Intron-A)]] 5,000,000 units SC once per day on days 1, 3, 5 (3 times per week)
 +
'''7-day cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Patients who progressed on monotherapy: Second-line [[#Lanreotide_.26_Interferon_alfa-2b|lanreotide & interferon alfa]]
 +
</div></div>
 
===References===
 
===References===
−
# Kvols LK, Moertel CG, O'Connell MJ, Schutt AJ, Rubin J, Hahn RG. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med. 1986 Sep 11;315(11):663-6. [http://www.nejm.org/doi/full/10.1056/NEJM198609113151102 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/2427948 PubMed]
+
# Oberg K, Funa K, Alm G. Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med. 1983 Jul 21;309(3):129-33. [https://doi.org/10.1056/NEJM198307213090301 linkt to original article] [https://pubmed.ncbi.nlm.nih.gov/6191217/ PubMed]
−
# Janson ET, Oberg K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. [http://informahealthcare.com/doi/abs/10.3109/02841869309083916 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/7686765 PubMed]
+
# Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. [https://doi.org/10.1200/jco.2003.12.142 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12860945/ PubMed]
−
# Brentjens R, Saltz L. Islet cell tumors of the pancreas: the medical oncologist's perspective. Surg Clin North Am. 2001 Jun;81(3):527-42. [http://www.sciencedirect.com/science/article/pii/S0039610905701419 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11459269 PubMed]
 
−
# Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003 Jun;90(6):687-93. [http://onlinelibrary.wiley.com/doi/10.1002/bjs.4149/abstract;jsessionid=2B5B8E734C543C53D25392C4527D82D0.d04t02 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12808615 PubMed]
 
−
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [http://annonc.oxfordjournals.org/content/15/6/966.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15151956 PubMed]
 
−
# Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. doi: 10.1200/JCO.2009.22.8510. Epub 2009 Aug 24. [http://jco.ascopubs.org/content/27/28/4656.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19704057 PubMed]
 
−
# Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. 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 Dec 10;378(9808):2005-12. doi: 10.1016/S0140-6736(11)61742-X. Epub 2011 Nov 25. [http://www.sciencedirect.com/science/article/pii/S014067361161742X link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22119496 PubMed]
 
  
−
==Octreotide & Everolimus {{#subobject:d69a17|Regimen=1}}==
+
==Lanreotide monotherapy {{#subobject:c44a4e|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:171ae2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[[#toc|back to top]]
+
|rowspan=2|[https://doi.org/10.1200/jco.2003.12.142 Faiss et al. 2003]
−
|}
+
|rowspan=2|1995-1998
−
===Regimen #1 {{#subobject:867317|Variant=1}}===
+
|rowspan=2 style="background-color:#1a9851"|Phase 3 (E-de-esc)
−
{| border="1" style="text-align:center;" !align="left"  
+
|1. [[#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]]
−
|'''Study'''
+
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
 
|-
 
|-
−
|[http://www.sciencedirect.com/science/article/pii/S014067361161742X Pavel et al. 2011 (RADIANT-2)]
+
|2. [[#Lanreotide_.26_Interferon_alfa-2b|Lanreotide & Interferon alfa-2b]]
−
|<span
+
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[#Octreotide_.28Sandostatin.29|Octreotide LAR]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once every 28 days
+
====Endocrine therapy====
−
*[[Everolimus (Afinitor)]] 10 mg PO once per day
+
*[[Lanreotide (Somatuline)]] 1 mg SC three times per day
−
 
+
'''Continued indefinitely'''  
−
'''Given until progression of disease or unacceptable toxicity'''
+
</div>
−
 
+
<div class="toccolours" style="background-color:#cbd5e7">
−
===Regimen #2, Yao et al. 2008 {{#subobject:9dd15|Variant=1}}===
+
====Subsequent treatment====
−
Level of Evidence:
+
*Faiss et al. 2003, patients who progressed on monotherapy: Second-line [[#Lanreotide_.26_Interferon_alfa-2b|Lanreotide & interferon alfa]]
−
<span
+
</div></div>
−
style="background:#EEEE00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
−
 
 
−
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1
 
−
*[[Everolimus (Afinitor)]] 5 or 10 mg PO once per day on days 1 to 28
 
−
**Everolimus "dose of 10 mg was associated with superior PFS...however, the study was not prospectively powered for these comparisons. These analyses should be considered exploratory."
 
−
 
 
−
'''28-day cycles x up to 12 cycles or until progression of disease, though treatment could be continued beyond this period if thought by the treating physician to be beneficial'''
 
−
 
 
 
===References===
 
===References===
−
# Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008 Sep 10;26(26):4311-8. [http://jco.ascopubs.org/content/26/26/4311.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18779618 PubMed]
+
# Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. [https://doi.org/10.1200/jco.2003.12.142 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12860945/ PubMed]
−
# Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. 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 Dec 10;378(9808):2005-12. Epub 2011 Nov 25. [http://www.sciencedirect.com/science/article/pii/S014067361161742X link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22119496 PubMed]
+
==Lanreotide LAR monotherapy {{#subobject:c4ugjc|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
==Octreotide & Interferon alfa {{#subobject:dea906|Regimen=1}}==
+
===Regimen {{#subobject:741ae2|Variant=1}}===
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
|-
+
!style="width: 20%"|Study
−
|[[#toc|back to top]]
+
!style="width: 20%"|Dates of enrollment
−
|}
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
 
+
!style="width: 20%"|Comparator
−
===Regimen {{#subobject:b5051e|Variant=1}}===
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
{| border="1" style="text-align:center;" !align="left"  
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
 
|-
 
|-
−
|[http://onlinelibrary.wiley.com/doi/10.1002/bjs.4149/abstract Kölby et al. 2003]
+
|[https://doi.org/10.4158/ep151172.or Vinik et al. 2016 (ELECT)]
−
|<span
+
|2009-05 to 2013-05
−
style="background:#00CD00;
+
| style="background-color:#1a9851"|Phase 3 (E-esc)
−
padding:3px 6px 3px 6px;
+
|[[#Placebo_888|Placebo]]
−
border-color:black;
+
| style="background-color:#1a9850" |Decreased need for short-acting octreotide rescue (primary endpoint)
−
border-width:2px;
 
−
border-style:solid;">Randomized Phase II</span>
 
−
|[[#Octreotide_.28Sandostatin.29|Octreotide LAR]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
''Kölby et al. 2003 did not specifically say whether [[Interferon alfa-2b (Intron-A)]] or [[Interferon alfa-2a (Roferon-A)]] was used.''
+
====Endocrine therapy====
−
*[[Octreotide (Sandostatin)]] 0.1 mg SC BID; patients with persistent carcinoid symptoms could receive increased doses up to [[Octreotide (Sandostatin)]] 0.2 mg SC TID
+
*[[Lanreotide LAR (Somatuline Depot)]] 120 mg IM once on day 1
−
*[[Interferon alfa-2b (Intron-A)]] 3 million units (route not specified) given once per day, 3 days per week; increased as needed based on symptoms up to [[Interferon alfa-2b (Intron-A)]] 5 million units (route not specified) given once per day, 5 days per week
+
'''28-day cycle for 4 cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
−
# Janson ET, Oberg K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. [http://informahealthcare.com/doi/abs/10.3109/02841869309083916 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/7686765 PubMed]
+
# '''ELECT:''' Vinik AI, Wolin EM, Liyanage N, Gomez-Panzani E, Fisher GA; ELECT Study Group. Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment (ELECT): A Randomized, Double-Blind, Placebo-Controlled Trial. Endocr Pract. 2016 Sep;22(9):1068-80. Epub 2016 May 23. [https://doi.org/10.4158/ep151172.or link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27214300/ PubMed] [https://clinicaltrials.gov/study/NCT00774930 NCT00774930]
−
# Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003 Jun;90(6):687-93. [http://onlinelibrary.wiley.com/doi/10.1002/bjs.4149/abstract link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12808615 PubMed]
 
  
−
==Placebo {{#subobject:91a160|Regimen=1}}==
+
==Lanreotide & Interferon alfa-2b {{#subobject:ce8ef2|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:87b3d6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[[#toc|back to top]]
+
|rowspan=2|[https://doi.org/10.1200/jco.2003.12.142 Faiss et al. 2003]
−
|}
+
|rowspan=2|1995-1998
−
 
+
|rowspan=2 style="background-color:#1a9851"|Phase 3 (E-esc)
−
===Regimen {{#subobject:645f1c|Variant=1}}===
+
|1. [[#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]]
−
{| border="1" style="text-align:center;" !align="left"  
+
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/27/28/4656.long RInke et al. 2009 (PROMID)]
+
|2. [[#Lanreotide_monotherapy|Lanreotide]]
−
|<span
+
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR at 12 mo
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[#Octreotide_.28Sandostatin.29|Octreotide LAR]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
''No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.''
+
====Endocrine therapy====
−
 
+
*[[Lanreotide (Somatuline)]] 1 mg SC three times per day
 +
====Immunotherapy====
 +
*[[Interferon alfa-2b (Intron-A)]] 5,000,000 units SC once per day, 3 times per week
 +
</div></div>
 
===References===
 
===References===
−
# Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. [http://jco.ascopubs.org/content/27/28/4656.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19704057 PubMed]
+
# Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. [https://doi.org/10.1200/jco.2003.12.142 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12860945/ PubMed]
−
 
+
==Lutetium Lu 177 dotatate & Octreotide LAR {{#subobject:eca71b|Regimen=1}}==
−
==Temozolomide (Temodar) {{#subobject:5db4de|Regimen=1}}==
+
{| class="wikitable" style="color:white; background-color:#404040"
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
|<small>'''FDA-recommended dose'''</small>
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:7e3904|Variant=1}}===
+
===Regimen {{#subobject:9df044|Variant=1}}===
−
Level of Evidence:
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
<span
+
!style="width: 20%"|Study
−
style="background:#EEEE00;
+
!style="width: 20%"|Dates of enrollment
−
padding:3px 6px 3px 6px;
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
border-color:black;
+
!style="width: 20%"|Comparator
−
border-width:2px;
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
border-style:solid;">Phase II</span>
 
−
 
 
−
*[[Temozolomide (Temodar)]] 100 or 150 mg/m2 PO once per day on days 1 to 5; then [[Temozolomide (Temodar)]] dose may be increased in the following cycle(s) as tolerated up to 200 mg/m2 PO once per day on days 1 to 5
 
−
 
 
−
'''28-day cycles, given until progression of disease or unacceptable toxicity'''
 
−
 
 
−
Supportive medications:
 
−
*Tropisetron (Navoban) (dose/route/schedule not specified) routinely used as an antiemetic
 
−
 
 
−
===References===
 
−
# Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007 May 15;13(10):2986-91. [http://clincancerres.aacrjournals.org/content/13/10/2986.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17505000 PubMed]
 
−
 
 
−
=Neuroendocrine tumors of unknown primary, poorly differentiated (high-grade) neuroendocrine tumors=
 
−
The NCCN Guidelines, Neuroendocrine tumors version 1.2013, suggests that these are treated with a [[small cell lung cancer]] regimen.
 
−
 
 
−
=Pancreatic neuroendocrine islet cell tumors=
 
−
 
 
−
==Everolimus (Afinitor) {{#subobject:78dff1|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
 
|-
 
|-
−
|[[#toc|back to top]]
+
|[https://doi.org/10.1158/1078-0432.ccr-16-2743 Brabander et al. 2017 (ERASMUS)]
−
|}
+
|2000-2015
−
 
+
| style="background-color:#ffffbe" |Case series (RT)
−
===Regimen, Yao et al. 2010 & Yao et al. 2011 (RADIANT-3) {{#subobject:5ea369|Variant=1}}===
+
| style="background-color:#d3d3d3" |
−
Level of Evidence:
+
| style="background-color:#d3d3d3" |
−
<span
 
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Everolimus (Afinitor)]] 10 mg PO once per day
 
−
 
 
−
'''given until progression of disease, unacceptable toxicity, drug interruption of 3 weeks or longer, or withdrawal of consent'''
 
−
 
 
−
===References===
 
−
# Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. doi: 10.1200/JCO.2009.24.2669. Epub 2009 Nov 23. [http://jco.ascopubs.org/content/28/1/69.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19933912 PubMed]
 
−
# Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Öberg K; RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. doi: 10.1056/NEJMoa1009290. [http://www.nejm.org/doi/full/10.1056/NEJMoa1009290 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21306238 PubMed]
 
−
# Yao JC, Phan AT, Jehl V, Shah G, Meric-Bernstam F. Everolimus in advanced pancreatic neuroendocrine tumors: the clinical experience. Cancer Res. 2013 Mar 1;73(5):1449-53. doi: 10.1158/0008-5472.CAN-12-3923. Epub 2013 Feb 22. [http://cancerres.aacrjournals.org/content/73/5/1449.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/23436795 PubMed]
 
−
 
 
−
==Lanreotide (Somatuline) Depot/Autogel {{#subobject:8bca3a|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
 
|-
 
|-
−
|[[#toc|back to top]]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ Strosberg et al. 2017 (NETTER-1)]
−
|}
+
|2012-2016
−
 
+
|style="background-color:#1a9851"|Phase 3 (E-RT-esc)
−
===Regimen, Caplin et al. 2014 (CLARINET) & NET729 {{#subobject:a9ee08|Variant=1}}===
+
|[[#Octreotide_LAR_monotherapy|Octreotide LAR]]; high-dose
−
Level of Evidence:
+
|style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: NYR vs 8.4 mo<br>(HR 0.21, 95% CI 0.13-0.33)
−
<span style="background:#00CD00; padding:3px 6px 3px 6px; border-color:black; border-width:2px; border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Lanreotide (Somatuline) | Lanreotide (Somatuline) Depot/Autogel]] 120 mg deep subcutaneous injection once on day 1
 
−
 
 
−
'''4-week cycles x 96 weeks (CLARINET), until progression of disease, or unacceptable toxicity'''; patients in NET729 could be treated for up to 8 years
 
−
 
 
−
===References===
 
−
# Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlácková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33. [http://www.nejm.org/doi/full/10.1056/NEJMoa1316158 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/25014687 PubMed]
 
−
# [http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022074s011lbl.pdf Lanreotide (Somatuline) package insert]
 
−
# NIHR (National Institute for Health Research) Horizon Scanning Centre, School of Health & Population Sciences, University of Birmingham. [http://www.hsc.nihr.ac.uk/files/.../2695.647d3d17.Lanreotide_Nov14.pdf Lanreotide for unresectable, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumours – first line]
 
−
# ClinicalTrials.gov: [https://clinicaltrials.gov/ct2/show/NCT00842348 Study of Lanreotide Autogel 120mg in Patients With Non-functioning Entero- Pancreatic Endocrine Tumour (NET729)]
 
−
 
 
−
==Lanreotide & Interferon alfa {{#subobject:9c5a59|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen, Fjällskog et al. 2002 {{#subobject:652f4d|Variant=1}}===
+
====Radioconjugate therapy====
−
Level of Evidence:
+
*[[Lutetium Lu 177 dotatate (Lutathera)]] 7.4 GBq (200 mCi) IV over 30 minutes once on day 1
−
<span
+
'''8-week cycle for 4 cycles'''
−
style="background:#ff0000;
+
====Endocrine therapy====
−
padding:3px 6px 3px 6px;
+
*[[Octreotide LAR (Sandostatin LAR)]] as follows:
−
border-color:black;
+
**Cycles 1 to 4: 30 mg IM once on day 2, '''given approximately 24 hours after lutetium Lu 177 dotatate'''
−
border-width:2px;
+
**Cycle 5 onwards: 30 mg IM once on day 1
−
border-style:solid;">Pilot, <20 patients reported</span>
+
'''8-week cycle for 4 cycles, then monthly cycles'''
−
 
+
</div></div>
−
''Fjällskog et al. 2002 contained case reports of several patients treated with lanreotide & interferon alfa.  Each patient received individualized therapy rather than a standard regimen.''
 
−
*[[Lanreotide (Somatuline)]] 3 mg SC BID
 
−
*[[Interferon alfa-2b (Intron-A)]] 3 to 5 million units SC given once per day, 3 to 7 days per week (total of 9 to 25 million units per week)
 
  
 
===References===
 
===References===
−
# Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. [http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/12025889 PubMed]
+
# '''NETTER-1:''' Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. [https://doi.org/10.1056/NEJMoa1607427 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28076709/ PubMed] [https://clinicaltrials.gov/study/NCT01578239 NCT01578239]
 +
## '''Update:''' Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. [https://doi.org/10.1016/s1470-2045(21)00572-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34793718/ PubMed]
 +
# '''ERASMUS:''' Brabander T, van der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA, de Herder WW, van Eijck CHJ, Franssen GJH, Krenning EP, Kwekkeboom DJ. Long-Term Efficacy, Survival, and Safety of [177Lu-DOTA0,Tyr3]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors. Clin Cancer Res. 2017 Aug 15;23(16):4617-4624. Epub 2017 Apr 20. [https://doi.org/10.1158/1078-0432.ccr-16-2743 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28428192/ PubMed]
  
−
==Octreotide (Sandostatin) {{#subobject:665a8b|Regimen=1}}==
+
==Octreotide monotherapy {{#subobject:1b6b74|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:eb529b|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"  
 +
!style="width: 25%"|Study
 +
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[[#toc|back to top]]
+
|[http://annonc.oxfordjournals.org/content/15/6/966.long Oberg et al. 2004]
−
|}
+
|style="background-color:#ffffbe"|Consensus guideline
−
 
 
−
===Regimen #1, Oberg et al. 2004 {{#subobject:cd8cf6|Variant=1}}===
 
−
====Octreotide immediate release (IR)====
 
−
*[[Octreotide (Sandostatin)]] 0.1 to 0.5 mg SC given 2 to 4 times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms
 
−
**"A reasonable starting dose is" [[Octreotide (Sandostatin)]] 0.15 mg SC TID
 
−
 
 
−
'''patients may transition to octreotide long-acting release (LAR) treatment as described below; treatment continued indefinitely unless patients have unmanageable side-effects or insufficient control of symptoms'''
 
−
 
 
−
====Octreotide long-acting release (LAR)====
 
−
*[[Octreotide LAR (Sandostatin LAR)]] 20 to 30 mg IM once on day 1, with potentially higher doses if needed for symptom control
 
−
**"As a general rule, if the total [octreotide] IR dose is 200–600 µg/day, LAR 20 mg should be tried, and if total IR dose is 750–1500 µg/day, LAR 30 mg should be tried."
 
−
*[[Octreotide (Sandostatin)]] (dose not specified) SC as needed for additional symptom control
 
−
 
 
−
'''28-day cycles; treatment continued indefinitely unless patients have unmanageable side-effects or insufficient control of symptoms'''
 
−
 
 
−
===Regimen #2, Rinke et al. 2009 (PROMID) {{#subobject:f0bc1b|Variant=1}}===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1, with potentially higher doses if needed for symptom control
 
−
 
 
−
'''28-day cycles, given until progression of disease'''
 
−
 
 
−
===References===
 
−
# Brentjens R, Saltz L. Islet cell tumors of the pancreas: the medical oncologist's perspective. Surg Clin North Am. 2001 Jun;81(3):527-42. [http://www.sciencedirect.com/science/article/pii/S0039610905701419 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11459269 PubMed]
 
−
# Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [http://annonc.oxfordjournals.org/content/15/6/966.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15151956 PubMed]
 
−
# Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. doi: 10.1200/JCO.2009.22.8510. Epub 2009 Aug 24. [http://jco.ascopubs.org/content/27/28/4656.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19704057 PubMed]
 
−
 
 
−
==Octreotide & Everolimus {{#subobject:d6b3eb|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen #1, Yao et al. 2010 {{#subobject:b0f62f|Variant=1}}===
+
''Note: per the consensus guideline, a "reasonable starting dose" was 0.15 mg SC three times per day.''
−
Level of Evidence:
+
<div class="toccolours" style="background-color:#b3e2cd">
−
<span
+
====Endocrine therapy====
−
style="background:#EEEE00;
+
*[[Octreotide (Sandostatin)]] 0.1 to 0.5 mg SC given 2 to four times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms
−
padding:3px 6px 3px 6px;
+
'''Continued indefinitely'''
−
border-color:black;
+
</div></div><br>
−
border-width:2px;
+
<div class="toccolours" style="background-color:#eeeeee">
−
border-style:solid;">Phase II</span>
+
===Regimen variant #2 {{#subobject:29f57|Variant=1}}===
−
 
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
''Patients in Yao et al. 2010 who received this regimen had already been receiving octreotide LAR for at least 3 months before participating in the study.''
+
!style="width: 25%"|Study
−
*[[Octreotide LAR (Sandostatin LAR)]] =30 mg (whatever their prestudy dose was) IM once every 28 days
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
 
 
−
*[[Everolimus (Afinitor)]] 10 mg PO once per day
 
−
 
 
−
'''given until progression of disease, unacceptable toxicity, drug interruption of 3 weeks or longer, or withdrawal of consent'''
 
−
 
 
−
===Regimen #2, Yao et al. 2008 {{#subobject:f82bb5|Variant=1}}===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#EEEE00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
−
 
 
−
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1
 
−
 
 
−
*[[Everolimus (Afinitor)]] 5 or 10 mg PO once per day on days 1 to 28
 
−
**Everolimus "dose of 10 mg was associated with superior PFS...however, the study was not prospectively powered for these comparisons. These analyses should be considered exploratory."
 
−
 
 
−
'''28-day cycles x up to 12 cycles or until progression of disease, though treatment could be continued beyond this period if thought by the treating physician to be beneficial'''
 
−
 
 
−
===References===
 
−
# Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008 Sep 10;26(26):4311-8. doi: 10.1200/JCO.2008.16.7858. [http://jco.ascopubs.org/content/26/26/4311.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18779618 PubMed]
 
−
# Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. doi: 10.1200/JCO.2009.24.2669. Epub 2009 Nov 23. [http://jco.ascopubs.org/content/28/1/69.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19933912 PubMed]
 
−
 
 
−
==Octreotide & Interferon alfa {{#subobject:1cf4c5|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
 
|-
 
|-
−
|[[#toc|back to top]]
+
|[https://doi.org/10.1056/NEJM198609113151102 Kvols et al. 1986]
−
|}
+
|style="background-color:#91cf61"|Phase 2
−
 
 
−
===Regimen, Fjällskog et al. 2002 {{#subobject:cbf5c4|Variant=1}}===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#ff0000;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Pilot, <20 patients reported</span>
 
−
 
 
−
''Fjällskog et al. 2002 contained case reports of several patients treated with octreotide & interferon alfa.  Each patient received individualized therapy rather than a standard regimen.''
 
−
*[[Octreotide (Sandostatin)]] 0.05 to 0.5 mg SC given 2 to 3 times per day
 
−
*[[Interferon alfa-2b (Intron-A)]] 3 to 5 million units SC given once per day, 3 to 7 days per week (total of 9 to 25 million units per week)
 
−
 
 
−
===References===
 
−
# Janson ET, Oberg K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. [http://informahealthcare.com/doi/abs/10.3109/02841869309083916 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/7686765 PubMed]
 
−
# Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. [http://link.springer.com/article/10.1385%2FMO%3A19%3A1%3A35 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/12025889 PubMed]
 
−
# Fazio N, de Braud F, Delle Fave G, Oberg K. Interferon-alpha and somatostatin analog in patients with gastroenteropancreatic neuroendocrine carcinoma: single agent or combination? Ann Oncol. 2007 Jan;18(1):13-9. Epub 2006 Jun 23. [http://annonc.oxfordjournals.org/content/18/1/13.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16798833 PubMed]
 
−
 
 
−
==Placebo {{#subobject:40b3f6|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen {{#subobject:dd04d4|Variant=1}}===
+
====Endocrine therapy====
−
{| border="1" style="text-align:center;" !align="left"  
+
*[[Octreotide (Sandostatin)]] 0.15 mg SC twice per day on days 1 & 2, then 0.15 mg SC three times per day from day 3 onward
−
|'''Study'''
+
'''Continued indefinitely'''
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
</div></div><br>
−
|'''Comparator'''
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3 {{#subobject:a531c2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/27/28/4656.long RInke et al. 2009 (PROMID)]
+
|[https://doi.org/10.1002/bjs.4149 Kölby et al. 2003]
−
|<span
+
|1991-1998
−
style="background:#00CD00;
+
|style="background-color:#1a9851"|Randomized Phase 2 (C)
−
padding:3px 6px 3px 6px;
+
|[[#Octreotide_.26_Interferon_alfa|Octreotide & Interferon alfa]]
−
border-color:black;
+
|style="background-color:#d73027"|Inferior TTP
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[#Octreotide_.28Sandostatin.29_2|Octreotide LAR]]
 
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1003825 Raymond et al. 2011]
+
|}
−
|<span
+
<div class="toccolours" style="background-color:#b3e2cd">
−
style="background:#00CD00;
+
====Endocrine therapy====
−
padding:3px 6px 3px 6px;
+
*[[Octreotide (Sandostatin)]] 0.1 mg SC twice per day
−
border-color:black;
+
'''Continued indefinitely'''
−
border-width:2px;
+
</div>
−
border-style:solid;">Phase III</span>
+
<div class="toccolours" style="background-color:#fff2ae">
−
|[[#Sunitinib_.28Sutent.29|Sunitinib]]
+
====Dose and schedule modifications====
 +
*Patients with persistent carcinoid symptoms could receive increased doses up to 0.2 mg SC three times per day
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, low-dose {{#subobject:512195|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
!style="width: 25%"|Study
 +
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1009290 Yao et al. 2011 (RADIANT-3)]
+
|[https://doi.org/10.3109/02841869309083916 Janson & Oberg 1993]
−
|<span
+
|style="background-color:#91cf61"|Non-randomized
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[#Everolimus_.28Afinitor.29|Everolimus]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
''No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.''
+
====Endocrine therapy====
−
 
+
*[[Octreotide (Sandostatin)]] 0.05 mg SC twice per day
 +
'''Continued indefinitely'''
 +
</div></div>
 
===References===
 
===References===
−
# Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. [http://jco.ascopubs.org/content/27/28/4656.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19704057 PubMed]
+
# Kvols LK, Moertel CG, O'Connell MJ, Schutt AJ, Rubin J, Hahn RG. Treatment of the malignant carcinoid syndrome: evaluation of a long-acting somatostatin analogue. N Engl J Med. 1986 Sep 11;315(11):663-6. [https://doi.org/10.1056/NEJM198609113151102 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2427948/ PubMed]
−
# Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):501-13. [http://www.nejm.org/doi/full/10.1056/NEJMoa1003825 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21306237 PubMed]
+
# Janson ET, Oberg K. Long-term management of the carcinoid syndrome: treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. [https://doi.org/10.3109/02841869309083916 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7686765/ PubMed]
−
# Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Öberg K; RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. [http://www.nejm.org/doi/full/10.1056/NEJMoa1009290 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21306238 PubMed]
+
# Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003 Jun;90(6):687-93. [https://doi.org/10.1002/bjs.4149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12808615/ PubMed]
 +
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [https://doi.org/10.1093/annonc/mdh216 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15151956/ PubMed]
  
−
==Streptozocin & Doxorubicin {{#subobject:5c625d|Regimen=1}}==
+
==Octreotide LAR monotherapy {{#subobject:3fde03|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 30 mg {{#subobject:38d708|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2009.22.8510 Rinke et al. 2009 (PROMID)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-150-1 <span style="color:white;">ESMO-MCBS (2)</span>]'''
 
|-
 
|-
−
|[[#toc|back to top]]
+
|} -->
−
|}
+
|2001-2008
−
 
+
|style="background-color:#1a9851"|Phase 3 (E-esc)
−
===Regimen {{#subobject:a9c7ed|Variant=1}}===
+
|[[Neuroendocrine_tumor_-_null_regimens#Placebo|Placebo]]
−
{| border="1" style="text-align:center;" !align="left"  
+
|style="background-color:#1a9850"|Superior TTP (primary endpoint)<br>Median TTP: 14.3 vs 6 mo<br>(HR 0.34, 95% CI 0.20-0.59)<br><br>Did not meet secondary endpoint of OS<sup>1</sup><br>Median OS: 84.7 vs 83.7 mo<br>(HR 0.83, 95% CI 0.47-1.46)
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJM199202203260804 Moertel et al. 1992]
+
|[https://doi.org/10.1016/S0140-6736(11)61742-X Pavel et al. 2011 (RADIANT-2)]
−
|<span
+
|2007-2010
−
style="background:#00CD00;
+
|style="background-color:#1a9851"|Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[#Everolimus_.26_Octreotide|Octreotide LAR & Everolimus]]
−
border-color:black;
+
|style="background-color:#fc8d59"|Seems to have inferior PFS
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|Chlorozotocin<br> [[Neuroendocrine_tumors#Streptozocin_.26_Fluorouracil|Streptozocin & Fluorouracil]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''<sup>1</sup>Reported efficacy for OS in PROMID is based on the 2016 update.''<br>
−
*[[Streptozocin (Zanosar)]] 500 mg/m2 IV once per day on days 1 to 5
+
''Note: RADIANT-2 did not meet its primary endpoint, based on a pre-specified p-value cutoff of 0.0246.''
−
*[[Doxorubicin (Adriamycin)]] 50 mg/m2 IV once per day on days 1 & 22
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Endocrine therapy====
−
'''6-week cycles, given until progression of disease'''
+
*[[Octreotide LAR (Sandostatin LAR)]] 30 mg IM once on day 1, with potentially higher doses if needed for symptom control
−
 
+
'''28-day cycles'''
−
===References===
+
</div></div><br>
−
# Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. [http://www.nejm.org/doi/full/10.1056/NEJM199202203260804 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/1310159 PubMed]
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen variant #2, 40 mg {{#subobject:7c7215a|Variant=1}}===
−
==Streptozocin, Doxorubicin, Fluorouracil (FAS) {{#subobject:66b05e|Regimen=1}}==
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[[#toc|back to top]]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562767/ Wolin et al. 2015 (CSOM230C2303)]
−
|}
+
|2008-2012
−
FAS: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin, '''<u>S</u>'''treptozocin
+
|style="background-color:#1a9851"|Phase 3 (C)
−
 
+
|[[#Pasireotide_LAR_999|Pasireotide LAR]]
−
===Regimen {{#subobject:de76a2|Variant=1}}===
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of symptom control
−
Level of Evidence:
 
−
<span
 
−
style="background:#ff0000;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Retrospective</span>
 
−
 
 
−
*[[Fluorouracil (5-FU)]] 400 mg/m2 IV bolus once per day on days 1 to 5
 
−
*[[Streptozocin (Zanosar)]] 400 mg/m2 IV bolus once per day on days 1 to 5
 
−
*[[Doxorubicin (Adriamycin)]] 40 mg/m2 IV bolus once on day 1
 
−
 
 
−
'''28-day cycles, given until progression of disease, unacceptable toxicity, or patient intolerance'''
 
−
 
 
−
===References===
 
−
# Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, Yao JC. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004 Dec 1;22(23):4762-71. [http://jco.ascopubs.org/content/22/23/4762.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15570077 PubMed]
 
−
 
 
−
==Streptozocin & Fluorouracil {{#subobject:6f7b84|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen {{#subobject:e45011|Variant=1}}===
+
====Endocrine therapy====
−
{| border="1" style="text-align:center;" !align="left"  
+
*[[Octreotide LAR (Sandostatin LAR)]] 40 mg IM once on day 1
−
|'''Study'''
+
'''28-day cycles'''
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
</div></div><br>
−
|'''Comparator'''
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 60 mg {{#subobject:7c826a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJM199202203260804 Moertel et al. 1992]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ Strosberg et al. 2017 (NETTER-1)]
−
|<span
+
|2012-2016
−
style="background:#00CD00;
+
|style="background-color:#1a9851"|Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[#Lutetium_Lu_177_dotatate_.26_Octreotide_LAR|Lutetium Lu 177 dotatate & Octreotide LAR]]
−
border-color:black;
+
|style="background-color:#d73027"|Inferior PFS
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|Chlorozotocin<br> [[Neuroendocrine_tumors#Streptozocin_.26_Doxorubicin|Streptozocin & Doxorubicin]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Streptozocin (Zanosar)]] 500 mg/m2 IV once per day on days 1 to 5
+
====Endocrine therapy====
−
*[[Fluorouracil (5-FU)]] 400 mg/m2 IV bolus once per day on days 1 to 5
+
*[[Octreotide LAR (Sandostatin LAR)]] 60 mg IM once on day 1
−
 
+
'''28-day cycles'''
−
'''6-week cycles, given until progression of disease'''
+
</div></div>
−
 
 
 
===References===
 
===References===
−
# Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. [http://www.nejm.org/doi/full/10.1056/NEJM199202203260804 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/1310159 PubMed]
+
# '''Review:''' Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. [https://doi.org/10.1093/annonc/mdh216 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15151956/ PubMed]
 +
# '''PROMID:''' Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. [https://doi.org/10.1200/jco.2009.22.8510 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19704057/ PubMed] [https://clinicaltrials.gov/study/NCT00171873 NCT00171873]
 +
##'''Update:''' Rinke A, Wittenberg M, Schade-Brittinger C, Aminossadati B, Ronicke E, Gress TM, Müller HH, Arnold R; PROMID Study Group. Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors (PROMID): Results of Long-Term Survival. Neuroendocrinology. 2017;104(1):26-32. Epub 2016 Jan 6. [https://doi.org/10.1159/000443612 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26731483/ PubMed]
 +
# '''RADIANT-2:''' Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. 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 Dec 10;378(9808):2005-12. Epub 2011 Nov 25. [https://doi.org/10.1016/S0140-6736(11)61742-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22119496/ PubMed] [https://clinicaltrials.gov/study/NCT00412061 NCT00412061]
 +
## '''Update:''' Pavel ME, Baudin E, Öberg KE, Hainsworth JD, Voi M, Rouyrre N, Peeters M, Gross DJ, Yao JC. Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. 2017 Jul 1;28(7):1569-1575. [https://doi.org/10.1093/annonc/mdx193 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7360141/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28444114/ PubMed]
 +
# '''CSOM230C2303:''' Wolin EM, Jarzab B, Eriksson B, Walter T, Toumpanakis C, Morse MA, Tomassetti P, Weber MM, Fogelman DR, Ramage J, Poon D, Gadbaw B, Li J, Pasieka JL, Mahamat A, Swahn F, Newell-Price J, Mansoor W, Öberg K. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther. 2015 Sep 3;9:5075-86. [https://doi.org/10.2147/DDDT.S84177 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562767/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26366058/ PubMed] [https://clinicaltrials.gov/study/NCT00690430 NCT00690430]
 +
# '''NETTER-1:''' Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. [https://doi.org/10.1056/NEJMoa1607427 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895095/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28076709/ PubMed] [https://clinicaltrials.gov/study/NCT01578239 NCT01578239]
 +
## '''Update:''' Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. [https://doi.org/10.1016/s1470-2045(21)00572-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34793718/ PubMed]
  
−
==Sunitinib (Sutent) {{#subobject:ee13d2|Regimen=1}}==
+
==Octreotide & Interferon alfa {{#subobject:dea906|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:b5051e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[[#toc|back to top]]
+
|[https://doi.org/10.1002/bjs.4149 Kölby et al. 2003]
−
|}
+
|1991-1998
−
 
+
|style="background-color:#1a9851"|Randomized Phase 2 (E-esc)
−
===Regimen {{#subobject:80d0ef|Variant=1}}===
+
|[[#Octreotide_monotherapy|Octreotide LAR]]
−
{| border="1" style="text-align:center;" !align="left"
+
|style="background-color:#1a9850"|Superior TTP
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1003825 Raymond et al. 2011]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455764/ Yao et al. 2017 (SWOG S0518)]
−
|<span
+
|2007-2012
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[#Octreotide_.26_Bevacizumab_999|Octreotide & Bevacizumab]]
−
border-color:black;
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[#Placebo_2|Placebo]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''Note: Kölby et al. 2003 did not specifically say whether [[Interferon alfa-2b (Intron-A)]] or [[Interferon alfa-2a (Roferon-A)]] was used.''
−
*[[Sunitinib (Sutent)]] 37.5 mg PO once per day
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Endocrine therapy====
−
'''Given until progression of disease, unacceptable toxicity, or patient death'''
+
*[[Octreotide (Sandostatin)]] 0.1 mg SC twice per day
−
 
+
**Patients with persistent carcinoid symptoms could receive increased doses up to 0.2 mg SC three times per day
 +
====Immunotherapy====
 +
*[[Interferon alfa-2b (Intron-A)]] 3,000,000 units (route not specified) once per day, 3 days per week
 +
**Increased as needed based on symptoms up to 5,000,000 units (route not specified) once per day, 5 days per week
 +
</div></div>
 
===References===
 
===References===
−
# Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):501-13. [http://www.nejm.org/doi/full/10.1056/NEJMoa1003825 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21306237 PubMed]
+
# Janson ET, Oberg K. Long-term management of the carcinoid syndrome: treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. [https://doi.org/10.3109/02841869309083916 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7686765/ PubMed]
−
 
+
# Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003 Jun;90(6):687-93. [https://doi.org/10.1002/bjs.4149 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12808615/ PubMed]
−
==Temozolomide (Temodar) {{#subobject:69ae1c|Regimen=1}}==
+
# '''SWOG S0518:''' Yao JC, Guthrie KA, Moran C, Strosberg JR, Kulke MH, Chan JA, LoConte N, McWilliams RR, Wolin EM, Mattar B, McDonough S, Chen H, Blanke CD, Hochster HS. Phase III Prospective Randomized Comparison Trial of Depot Octreotide Plus Interferon Alfa-2b Versus Depot Octreotide Plus Bevacizumab in Patients With Advanced Carcinoid Tumors: SWOG S0518. J Clin Oncol. 2017 May 20;35(15):1695-1703. Epub 2017 Apr 6. [https://doi.org/10.1200/JCO.2016.70.4072 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455764/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28384065/ PubMed] [https://clinicaltrials.gov/study/NCT00569127 NCT00569127]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
==Temozolomide monotherapy {{#subobject:5db4de|Regimen=1}}==
−
|-
+
<div class="toccolours" style="background-color:#eeeeee">
−
|[[#toc|back to top]]
+
===Regimen {{#subobject:7e3904|Variant=1}}===
−
|}
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
 
+
!style="width: 25%"|Study
−
===Regimen {{#subobject:6aac4c|Variant=1}}===
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
Level of Evidence:
 
−
<span
 
−
style="background:#EEEE00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
−
 
 
−
*[[Temozolomide (Temodar)]] 100 or 150 mg/m2 PO once per day on days 1 to 5; then [[Temozolomide (Temodar)]] dose may be increased in the following cycle(s) as tolerated up to 200 mg/m2 PO once per day on days 1 to 5
 
−
 
 
−
'''28-day cycles, given until progression of disease or unacceptable toxicity'''
 
−
 
 
−
Supportive medications:
 
−
*Tropisetron (Navoban) (dose/route/schedule not specified) routinely used as an antiemetic
 
−
 
 
−
===References===
 
−
# Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007 May 15;13(10):2986-91. [http://clincancerres.aacrjournals.org/content/13/10/2986.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17505000 PubMed]
 
−
 
 
−
==Temozolomide & Bevacizumab {{#subobject:ce7fe6|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
 
|-
 
|-
−
|[[#toc|back to top]]
+
|[http://clincancerres.aacrjournals.org/content/13/10/2986.long Ekeblad et al. 2007]
−
|}
+
| style="background-color:#ffffbe" |Retrospective
−
 
 
−
===Regimen {{#subobject:be3718|Variant=1}}===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#EEEE00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
−
 
 
−
*[[Temozolomide (Temodar)]] 150 mg/m2 PO once per day on days 1 to 7, 15 to 21
 
−
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1 & 15
 
−
 
 
−
'''28-day cycles, given until progression of disease or unacceptable toxicity'''
 
−
 
 
−
Supportive medications:
 
−
*[[Trimethoprim/Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO once every Monday, Wednesday, and Friday; allergic patients received alternate Pneumocystis carinii (PCP) prophylaxis
 
−
*[[Acyclovir (Zovirax)]] 400 mg PO TID as prophylaxis against varicella zoster
 
−
 
 
−
===References===
 
−
# Chan JA, Stuart K, Earle CC, Clark JW, Bhargava P, Miksad R, Blaszkowsky L, Enzinger PC, Meyerhardt JA, Zheng H, Fuchs CS, Kulke MH. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol. 2012 Aug 20;30(24):2963-8. doi: 10.1200/JCO.2011.40.3147. Epub 2012 Jul 9. [http://jco.ascopubs.org/content/30/24/2963.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22778320 PubMed]
 
−
 
 
−
==Temozolomide & Capecitabine {{#subobject:738284|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
''Note: Temozolomide dose is only increased if tolerated at the prior dose.''
−
===Regimen, Strosberg et al. 2011 {{#subobject:fc2dd9|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Temozolomide (Temodar)]] as follows:
−
style="background:#ff0000;
+
**Cycle 1: 100 to 150 mg/m<sup>2</sup> PO once per day on days 1 to 5
−
padding:3px 6px 3px 6px;
+
**Cycle 2 onwards: 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
−
border-color:black;
+
====Supportive therapy====
−
border-width:2px;
+
*[[Tropisetron (Navoban)]] (dose/route/schedule not specified) routinely used as an antiemetic
−
border-style:solid;">Retrospective</span>
 
−
 
 
−
*[[Temozolomide (Temodar)]] 200 mg/m2 PO once per day at bedtime on days 10 to 14
 
−
*[[Capecitabine (Xeloda)]] 750 mg/m2 PO BID on days 1 to 14
 
−
 
 
 
'''28-day cycles'''
 
'''28-day cycles'''
−
 
+
</div></div>
−
Supportive medications:
 
−
*Ondansetron (Zofran) 8 mg (route not specified) prior to each dose of temozolomide
 
−
 
 
−
===References===
 
−
# Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, Helm J, Kvols L. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011 Jan 15;117(2):268-75. doi: 10.1002/cncr.25425. Epub 2010 Sep 7. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.25425/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20824724 PubMed]
 
−
 
 
−
==Temozolomide & Thalidomide {{#subobject:16afb7|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#toc|back to top]]
 
−
|}
 
−
 
 
−
===Regimen, Kulke et al. 2006 {{#subobject:ceca5a|Variant=1}}===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#EEEE00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
−
 
 
−
*[[Temozolomide (Temodar)]] 150 mg/m2 PO once per day on days 1 to 7, 15 to 21
 
−
*[[Thalidomide (Thalomid)]] 200 mg PO once per day on days 1 to 28
 
−
 
 
−
'''28-day cycles, given until progression of disease or unacceptable toxicity'''
 
−
 
 
−
===References===
 
−
# Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, Vincitore M, Michelini A, Fuchs CS. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006 Jan 20;24(3):401-6. [http://jco.ascopubs.org/content/24/3/401.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16421420 PubMed]
 
−
 
 
−
=Pheochromocytoma=
 
−
 
 
−
==Cyclophosphamide, Vincristine, Dacarbazine (CVD) {{#subobject:6ff914|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#toc|back to top]]
 
−
|}
 
−
CVD: '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>D</u>'''acarbazine
 
−
 
 
−
===Regimen, Averbuch et al. 1988 {{#subobject:5998d1|Variant=1}}===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#ff0000;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Pilot, <20 patients reported</span>
 
−
 
 
−
*[[Cyclophosphamide (Cytoxan)]] 750 mg/m2 IV once on day 1
 
−
*[[Vincristine (Oncovin)]] 1.4 mg/m2 IV once on day 1
 
−
*[[Dacarbazine (DTIC)]] 600 mg/m2 IV once per day on days 1 & 2
 
−
 
 
−
'''21-day cycles'''
 
−
 
 
−
===References===
 
−
# Averbuch SD, Steakley CS, Young RC, Gelmann EP, Goldstein DS, Stull R, Keiser HR. Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med. 1988 Aug 15;109(4):267-73. [http://annals.org/article.aspx?articleid=702515 link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/3395037 PubMed]
 
−
 
 
−
==<sup>131</sup>I-Metaiodobenzylguanidine (<sup>131</sup>I-MIBG)==
 
−
Also known as m-[131I]iodobenzylguanidine ([131I]MIBG).
 
−
 
 
−
===Regimen #1, Rose et al. 2003 {{#subobject:f474b2|Variant=1}}===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#ff0000;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Pilot, <20 patients reported</span>
 
−
 
 
−
''Patients underwent stem cell harvest prior to treatment in case autologous stem cell infusion was needed.''
 
−
*<sup>131</sup>I-Metaiodobenzylguanidine (<sup>131</sup>I-MIBG) 12 to 18 mCi/kg (maximum single dose of 850 mCi) IV over 2 hours once on day 1
 
−
 
 
−
'''"Repeat 131I-MIBG treatments were administered on a case-by-case basis in an effort to improve the overall response"'''
 
−
 
 
−
Supportive medications:
 
−
*Intravenous fluids started 12 hours before 131I-MIBG administration.
 
−
*Potassium iodide (KI) 6 mg/kg PO once at least 2 hours prior to 131I-MIBG, then potassium iodide (KI) 0.88 mg/kg PO Q4H x 7 days, then potassium iodide (KI) 1 mg/kg PO (frequency not specified) "for 45 days after the infusion."
 
−
*Potassium perchlorate 8 mg/kg once at least 2 hours prior to 131I-MIBG, then potassium perchlorate 2 mg/kg PO Q6H x 5 days.
 
−
 
 
−
===Regimen #2, Krempf et al. 1991 {{#subobject:53e027|Variant=1}}===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#ff0000;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Pilot, <20 patients reported</span>
 
−
 
 
−
*m-[131I]iodobenzylguanidine ([131I]MIBG) 740 megabequerel/mg every 3 months
 
−
 
 
 
===References===
 
===References===
−
# Krempf M, Lumbroso J, Mornex R, Brendel AJ, Wemeau JL, Delisle MJ, Aubert B, Carpentier P, Fleury-Goyon MC, Gibold C et al. Use of m-[131I]iodobenzylguanidine in the treatment of malignant pheochromocytoma. J Clin Endocrinol Metab. 1991 Feb;72(2):455-61. [http://jcem.endojournals.org/content/72/2/455.long link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/1991814 PubMed]
+
# '''Retrospective:''' Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007 May 15;13(10):2986-91. [http://clincancerres.aacrjournals.org/content/13/10/2986.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17505000/ PubMed]
−
# Rose B, Matthay KK, Price D, Huberty J, Klencke B, Norton JA, Fitzgerald PA. High-dose 131I-metaiodobenzylguanidine therapy for 12 patients with malignant pheochromocytoma. Cancer. 2003 Jul 15;98(2):239-48. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.11518/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12872341 PubMed]
+
[[Category:Neuroendocrine tumor regimens]]
 +
[[Category:Disease-specific pages]]
 +
[[Category:Endocrine cancers]]

Revision as of 17:47, 23 June 2024

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Section editor
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If you are interested in this role, please contact us at [email protected].

Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: This page is now exclusively focused on those tumors commonly called carcinoids, which may or may not be associated with the carcinoid syndrome; there are now separate pages for pancreatic NET and other endocrine cancers. Neuroendocrine tumors of unknown primary and poorly differentiated (high-grade) neuroendocrine carcinomas are usually treated with a small cell lung cancer regimen; see this page for histology-specific options.

14 regimens on this page
20 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

CommNETS/NANETS

ESMO

French Intergroup

NANETS

NCCN

All lines of therapy

Capecitabine & Temozolomide

Regimen

Study Dates of enrollment Evidence
Jeong et al. 2021 (Asan-ONCHBP-2017-002) 2017-2021 Phase 2

Chemotherapy

28-day cycles

References

  1. Asan-ONCHBP-2017-002: Jeong H, Shin J, Jeong JH, Kim KP, Hong SM, Kim YI, Ryu JS, Ryoo BY, Yoo C. Capecitabine plus temozolomide in patients with grade 3 unresectable or metastatic gastroenteropancreatic neuroendocrine neoplasms with Ki-67 index <55%: single-arm phase II study. ESMO Open. 2021 Jun;6(3):100119. link to original article link to PMC article PubMed NCT03079440

Doxorubicin & Fluorouracil

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sun et al. 2005 1981-1990 Phase 2/3 (C) Fluorouracil & Streptozocin Seems to have inferior OS

Chemotherapy

  • Doxorubicin (Adriamycin) by the following symptom-based criteria:
    • No jaundice: 40 mg/m2 IV push once on day 1
    • Jaundiced: 25 mg/m2 IV push once on day 1
  • Fluorouracil (5-FU) 400 mg/m2 IV push once per day on days 1 to 5

35-day cycles

References

  1. ECOG E1281: Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG; ECOG. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005 Aug 1;23(22):4897-904. link to original article contains dosing details in manuscript PubMed

Everolimus monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Yao et al. 2015 (RADIANT-4) 2012-04 to 2013-08 Phase 3 (E-RT-esc) Placebo Superior PFS (primary endpoint)
Median PFS: 11 vs 3.9 mo
(HR 0.48, 95% CI 0.35-0.67)

Might have superior OS (secondary endpoint)
Median OS: NYR vs NYR
(HR 0.64, 95% CI 0.40-1.05) 		Equivalent HRQoL

Targeted therapy

Continued indefinitely

References

  1. RADIANT-4: Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H, Voi M, Pacaud LB, Rouyrre N, Sachs C, Valle JW, Fave GD, Van Cutsem E, Tesselaar M, Shimada Y, Oh DY, Strosberg J, Kulke MH, Pavel ME; RAD001 in Advanced Neuroendocrine Tumours Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016 Mar 5;387(10022):968-977. Epub 2015 Dec 17. link to original article contains dosing details in abstract link to PMC article PubMed NCT01524783
    1. HRQoL analysis: Pavel ME, Singh S, Strosberg JR, Bubuteishvili-Pacaud L, Degtyarev E, Neary MP, Carnaghi C, Tomasek J, Wolin E, Raderer M, Lahner H, Valle JW, Pommier R, Van Cutsem E, Tesselaar MET, Fave GD, Buzzoni R, Hunger M, Eriksson J, Cella D, Ricci JF, Fazio N, Kulke MH, Yao JC. Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1411-1422. Epub 2017 Aug 30. link to original article PubMed

Everolimus & Octreotide

Regimen variant #1

Study Dates of enrollment Evidence
Yao et al. 2008 2005-2006 Phase 2

Targeted therapy

Endocrine therapy

28-day cycles


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yao et al. 2008 2005-2006 Phase 2
Pavel et al. 2011 (RADIANT-2) 2007-2010 Phase 3 (E-esc) Octreotide LAR Seems to have superior PFS (primary endpoint)
Median PFS: 16.4 vs 11.3 mo
(HR 0.77, 95% CI 0.59-1.00)

Note: RADIANT-2 did not meet its primary endpoint, based on a pre-specified p-value cutoff of 0.0246.

Targeted therapy

Endocrine therapy

28-day cycles

References

  1. Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008 Sep 10;26(26):4311-8. link to original article contains dosing details in manuscript link to PMC article PubMed
  2. RADIANT-2: Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. 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 Dec 10;378(9808):2005-12. Epub 2011 Nov 25. link to original article contains dosing details in manuscript PubMed NCT00412061
    1. Update: Pavel ME, Baudin E, Öberg KE, Hainsworth JD, Voi M, Rouyrre N, Peeters M, Gross DJ, Yao JC. Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. 2017 Jul 1;28(7):1569-1575. link to original article link to PMC article PubMed

Fluorouracil & Streptozocin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Engstrom et al. 1984 (ECOG E5275) 1976-1981 Phase 3 (E-esc) Doxorubicin Did not meet co-primary endpoints of ORR/OS
Sun et al. 2005 1981-1990 Phase 2/3 (E-switch-ic) Doxorubicin & Fluorouracil Seems to have superior OS

Chemotherapy

10-week cycles

References

  1. ECOG E5275: Engstrom PF, Lavin PT, Moertel CG, Folsch E, Douglass HO Jr. Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol. 1984 Nov;2(11):1255-9. link to original article contains dosing details in manuscript PubMed
  2. ECOG E1281: Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG; ECOG. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005 Aug 1;23(22):4897-904. link to original article contains dosing details in manuscript PubMed

Interferon alfa-2b monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Oberg et al. 1983 NR Non-randomized, fewer than 20 pts
Faiss et al. 2003 1995-1998 Phase 3 (E-de-esc) 1. Lanreotide Did not meet primary endpoint of ORR at 12 mo
2. Lanreotide & Interferon alfa-2b Did not meet primary endpoint of ORR at 12 mo

Note: Treatment details are from Faiss et al. 2003.

Immunotherapy

7-day cycles

Subsequent treatment

References

  1. Oberg K, Funa K, Alm G. Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med. 1983 Jul 21;309(3):129-33. linkt to original article PubMed
  2. Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. link to original article contains dosing details in manuscript PubMed

Lanreotide monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Faiss et al. 2003 1995-1998 Phase 3 (E-de-esc) 1. Interferon alfa-2b Did not meet primary endpoint of ORR at 12 mo
2. Lanreotide & Interferon alfa-2b Did not meet primary endpoint of ORR at 12 mo

Endocrine therapy

Continued indefinitely

Subsequent treatment

References

  1. Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. link to original article contains dosing details in manuscript PubMed

Lanreotide LAR monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Vinik et al. 2016 (ELECT) 2009-05 to 2013-05 Phase 3 (E-esc) Placebo Decreased need for short-acting octreotide rescue (primary endpoint)

Endocrine therapy

28-day cycle for 4 cycles

References

  1. ELECT: Vinik AI, Wolin EM, Liyanage N, Gomez-Panzani E, Fisher GA; ELECT Study Group. Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment (ELECT): A Randomized, Double-Blind, Placebo-Controlled Trial. Endocr Pract. 2016 Sep;22(9):1068-80. Epub 2016 May 23. link to original article contains dosing details in manuscript PubMed NCT00774930

Lanreotide & Interferon alfa-2b

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Faiss et al. 2003 1995-1998 Phase 3 (E-esc) 1. Interferon alfa-2b Did not meet primary endpoint of ORR at 12 mo
2. Lanreotide Did not meet primary endpoint of ORR at 12 mo

Endocrine therapy

Immunotherapy

References

  1. Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. link to original article contains dosing details in manuscript PubMed

Lutetium Lu 177 dotatate & Octreotide LAR

FDA-recommended dose

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brabander et al. 2017 (ERASMUS) 2000-2015 Case series (RT)
Strosberg et al. 2017 (NETTER-1) 2012-2016 Phase 3 (E-RT-esc) Octreotide LAR; high-dose Superior PFS (primary endpoint)
Median PFS: NYR vs 8.4 mo
(HR 0.21, 95% CI 0.13-0.33)

Radioconjugate therapy

8-week cycle for 4 cycles

Endocrine therapy

  • Octreotide LAR (Sandostatin LAR) as follows:
    • Cycles 1 to 4: 30 mg IM once on day 2, given approximately 24 hours after lutetium Lu 177 dotatate
    • Cycle 5 onwards: 30 mg IM once on day 1

8-week cycle for 4 cycles, then monthly cycles

References

  1. NETTER-1: Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01578239
    1. Update: Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. link to original article PubMed
  2. ERASMUS: Brabander T, van der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA, de Herder WW, van Eijck CHJ, Franssen GJH, Krenning EP, Kwekkeboom DJ. Long-Term Efficacy, Survival, and Safety of [177Lu-DOTA0,Tyr3]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors. Clin Cancer Res. 2017 Aug 15;23(16):4617-4624. Epub 2017 Apr 20. link to original article PubMed

Octreotide monotherapy

Regimen variant #1

Study Evidence
Oberg et al. 2004 Consensus guideline

Note: per the consensus guideline, a "reasonable starting dose" was 0.15 mg SC three times per day.

Endocrine therapy

  • Octreotide (Sandostatin) 0.1 to 0.5 mg SC given 2 to four times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms

Continued indefinitely


Regimen variant #2

Study Evidence
Kvols et al. 1986 Phase 2

Endocrine therapy

Continued indefinitely


Regimen variant #3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kölby et al. 2003 1991-1998 Randomized Phase 2 (C) Octreotide & Interferon alfa Inferior TTP

Endocrine therapy

Continued indefinitely

Dose and schedule modifications

  • Patients with persistent carcinoid symptoms could receive increased doses up to 0.2 mg SC three times per day


Regimen variant #4, low-dose

Study Evidence
Janson & Oberg 1993 Non-randomized

Endocrine therapy

Continued indefinitely

References

  1. Kvols LK, Moertel CG, O'Connell MJ, Schutt AJ, Rubin J, Hahn RG. Treatment of the malignant carcinoid syndrome: evaluation of a long-acting somatostatin analogue. N Engl J Med. 1986 Sep 11;315(11):663-6. link to original article contains dosing details in manuscript PubMed
  2. Janson ET, Oberg K. Long-term management of the carcinoid syndrome: treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. link to original article contains dosing details in abstract PubMed
  3. Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003 Jun;90(6):687-93. link to original article contains dosing details in manuscript PubMed
  4. Review: Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. link to original article contains dosing details in manuscript PubMed

Octreotide LAR monotherapy

Regimen variant #1, 30 mg

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rinke et al. 2009 (PROMID) 2001-2008 Phase 3 (E-esc) Placebo Superior TTP (primary endpoint)
Median TTP: 14.3 vs 6 mo
(HR 0.34, 95% CI 0.20-0.59)

Did not meet secondary endpoint of OS1
Median OS: 84.7 vs 83.7 mo
(HR 0.83, 95% CI 0.47-1.46)
Pavel et al. 2011 (RADIANT-2) 2007-2010 Phase 3 (C) Octreotide LAR & Everolimus Seems to have inferior PFS

1Reported efficacy for OS in PROMID is based on the 2016 update.
Note: RADIANT-2 did not meet its primary endpoint, based on a pre-specified p-value cutoff of 0.0246.

Endocrine therapy

28-day cycles


Regimen variant #2, 40 mg

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wolin et al. 2015 (CSOM230C2303) 2008-2012 Phase 3 (C) Pasireotide LAR Did not meet primary endpoint of symptom control

Endocrine therapy

28-day cycles


Regimen variant #3, 60 mg

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Strosberg et al. 2017 (NETTER-1) 2012-2016 Phase 3 (C) Lutetium Lu 177 dotatate & Octreotide LAR Inferior PFS

Endocrine therapy

28-day cycles

References

  1. Review: Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. link to original article contains dosing details in manuscript PubMed
  2. PROMID: Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. link to original article contains dosing details in manuscript PubMed NCT00171873
    1. Update: Rinke A, Wittenberg M, Schade-Brittinger C, Aminossadati B, Ronicke E, Gress TM, Müller HH, Arnold R; PROMID Study Group. Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors (PROMID): Results of Long-Term Survival. Neuroendocrinology. 2017;104(1):26-32. Epub 2016 Jan 6. link to original article PubMed
  3. RADIANT-2: Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. 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 Dec 10;378(9808):2005-12. Epub 2011 Nov 25. link to original article contains dosing details in manuscript PubMed NCT00412061
    1. Update: Pavel ME, Baudin E, Öberg KE, Hainsworth JD, Voi M, Rouyrre N, Peeters M, Gross DJ, Yao JC. Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. 2017 Jul 1;28(7):1569-1575. link to original article link to PMC article PubMed
  4. CSOM230C2303: Wolin EM, Jarzab B, Eriksson B, Walter T, Toumpanakis C, Morse MA, Tomassetti P, Weber MM, Fogelman DR, Ramage J, Poon D, Gadbaw B, Li J, Pasieka JL, Mahamat A, Swahn F, Newell-Price J, Mansoor W, Öberg K. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther. 2015 Sep 3;9:5075-86. link to original article link to PMC article contains dosing details in abstract PubMed NCT00690430
  5. NETTER-1: Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01578239
    1. Update: Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. Epub 2021 Nov 15. link to original article PubMed

Octreotide & Interferon alfa

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kölby et al. 2003 1991-1998 Randomized Phase 2 (E-esc) Octreotide LAR Superior TTP
Yao et al. 2017 (SWOG S0518) 2007-2012 Phase 3 (C) Octreotide & Bevacizumab Did not meet primary endpoint of PFS

Note: Kölby et al. 2003 did not specifically say whether Interferon alfa-2b (Intron-A) or Interferon alfa-2a (Roferon-A) was used.

Endocrine therapy

  • Octreotide (Sandostatin) 0.1 mg SC twice per day
    • Patients with persistent carcinoid symptoms could receive increased doses up to 0.2 mg SC three times per day

Immunotherapy

  • Interferon alfa-2b (Intron-A) 3,000,000 units (route not specified) once per day, 3 days per week
    • Increased as needed based on symptoms up to 5,000,000 units (route not specified) once per day, 5 days per week

References

  1. Janson ET, Oberg K. Long-term management of the carcinoid syndrome: treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. link to original article PubMed
  2. Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003 Jun;90(6):687-93. link to original article contains dosing details in manuscript PubMed
  3. SWOG S0518: Yao JC, Guthrie KA, Moran C, Strosberg JR, Kulke MH, Chan JA, LoConte N, McWilliams RR, Wolin EM, Mattar B, McDonough S, Chen H, Blanke CD, Hochster HS. Phase III Prospective Randomized Comparison Trial of Depot Octreotide Plus Interferon Alfa-2b Versus Depot Octreotide Plus Bevacizumab in Patients With Advanced Carcinoid Tumors: SWOG S0518. J Clin Oncol. 2017 May 20;35(15):1695-1703. Epub 2017 Apr 6. link to original article link to PMC article PubMed NCT00569127

Temozolomide monotherapy

Regimen

Study Evidence
Ekeblad et al. 2007 Retrospective

Note: Temozolomide dose is only increased if tolerated at the prior dose.

Chemotherapy

  • Temozolomide (Temodar) as follows:
    • Cycle 1: 100 to 150 mg/m2 PO once per day on days 1 to 5
    • Cycle 2 onwards: 200 mg/m2 PO once per day on days 1 to 5

Supportive therapy

28-day cycles

References

  1. Retrospective: Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007 May 15;13(10):2986-91. link to original article contains dosing details in manuscript PubMed
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