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| [[Pancreatic neuroendocrine tumor case study one|Case#1]] | | [[Pancreatic neuroendocrine tumor case study one|Case#1]] |
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| __NOTOC__
| | ==Related chapters== |
| {{Pancreatic neuroendocrine tumor}}
| | * [[Pancreatic cancer]] |
| {{PleaseHelp}}
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| ==References==
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| {{Reflist|2}}
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| ==Staging==
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| The 2010 WHO classification of tumors of the digestive system grades all the [[neuroendocrine tumor]]s into three categories, based on their degree of [[Grading (tumors)|cellular differentiation]] (from well-differentiated "NET G1" through to poorly-differentiated "NET G3"). The NCCN recommends use of the same AJCC-UICC staging system as pancreatic adenocarcinoma. Using this scheme, the stage by stage outcomes for PanNETs are dissimilar to pancreatic exocrine cancers.<ref name="NCI_FIG1">National Cancer Institute. Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ®) Incidence and Mortality [http://www.cancer.gov/cancertopics/pdq/treatment/isletcell/HealthProfessional/page1]</ref> A different TNM system for PanNETs has been proposed by The European Neuroendocrine Tumor Society.
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| <gallery class="center" caption="Pancreatic neuroendocrine tumor staging ([[American Joint Committee on Cancer|AJCC]])">
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| File:Pancrea2.png|Stage T1
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| File:Pancrea3.png|Stage T2
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| File:Pancrea4.png|Stage T3
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| File:Pancrea5.png|Stage T4
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| File:Pancrea5.png|Involvement of nearby lymph nodes – Stage N1
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| File:Pancrea7.png|Metastasis – stage M1
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| </gallery>
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| ==Treatment==
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| {{Main|Neuroendocrine tumor}}
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| In general, treatment for PanNET encompasses the same array of options as other [[neuroendocrine tumor]]s, as discussed in that main article.<!--duplication of that content here is probably unnecessary – see the main article link--> However, there are some specific differences, which are discussed here.
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| In functioning PanNETs, [[octreotide]] is usually recommended prior to biopsy or surgery but is generally avoided in [[insulinoma]]s to avoid profound [[hypoglycemia]].
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| PanNETs in [[MEN1]] are often multiple, and thus require different treatment and surveillance strategies.
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| Some PanNETs are more responsive to [[chemotherapy]] than are gastroenteric [[carcinoid]] tumors. Several agents have shown activity. In well differentiated PanNETs, chemotherapy is generally reserved for when there are no other treatment options. Combinations of several medicines have been used, such as [[doxorubicin]] with [[streptozocin]] and [[fluorouracil]] (5-FU) and capecitabine with temozolomide. Although marginally effective in well-differentiated PETs, [[cisplatin]] with [[etoposide]] has some activity in poorly differentiated neuroendocrine cancers (PDNECs), particularly if the PDNEC has an extremely high [[Ki-67 (protein)|Ki-67]] score of over 50%.
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| Several [[targeted therapy]] agents have been approved in PanNETs by the [[Food and Drug Administration|FDA]] based on improved [[progression-free survival]] (PFS):
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| * [[everolimus]] (Afinitor) is labeled for treatment of progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced or metastatic disease. The safety and effectiveness of everolimus in carcinoid tumors have not been established. | |
| * [[sunitinib]] (Sutent) is labeled for treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease. Sutent also has approval from the European Commission for the treatment of 'unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors with disease progression in adults'. A phase III study of sunitinib treatment in well differentiated pNET that had worsened within the past 12 months (either advanced or metastatic disease) showed that sunitinib treatment improved [[progression-free survival]] (11.4 months vs. 5.5 months), [[overall survival]], and the [[objective response rate]] (9.3% vs. 0.0%) when compared with placebo.
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| ==Genetics==
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| [[DNA]] [[mutation]] analysis in well-differentiated pancreatic neuroendocrine tumors identified four important findings:<ref name="Jiao2011">{{cite journal |author= Jiao, Y.; Shi, C.; Edil, B. H.; De Wilde, R. F.; Klimstra, D. S.; Maitra, A.; Schulick, R. D.; Tang, L. H.; Wolfgang, C. L.; Choti, M. A.; Velculescu, V. E.; Diaz Jr, L. A.; Vogelstein, B.; Kinzler, K. W.; Hruban, R. H.; Papadopoulos, N.|title= DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors|journal= Science |volume= 331|issue=6021 |pages=1199–1203|year=2011 |pmid= 21252315|doi= 10.1126/science.1200609}}</ref><ref name=" McKenna2014">{{cite journal |author= McKenna, L. R.; Edil, B. H. |title= Update on pancreatic neuroendocrine tumors |journal= Gland surgery |volume= 3|issue=4 |pages=258–275|year=2014 |pmid=25493258|doi= 10.3978/j.issn.2227-684X.2014.06.03}}</ref>
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| * as expected, the [[gene]]s mutated in NETs, [[MEN1]], [[ATRX]], [[DAXX]], [[TSC2]], [[PTEN (gene)|PTEN]] and [[PIK3CA]],<ref name="Jiao2011" /> are different from the mutated genes previously found in [[pancreatic cancer|pancreatic]] [[adenocarcinoma]].<ref name="Jones2008">{{cite pmid|18772397}}</ref><ref name="Harada2009">{{cite pmid|19077451}}</ref>
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| * one in six well-differentiated pancreatic NETs have mutations in [[mTOR]] pathway genes, such as [[TSC2]], [[PTEN (gene)|PTEN]] and [[PIK3CA]].<ref name="Jiao2011" /> The sequencing discovery might allow selection of which NETs would benefit from mTOR inhibition such as with [[everolimus]], but this awaits validation in a [[clinical trial]].
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| * mutations affecting a new cancer pathway involving [[ATRX]] and [[DAXX]] genes were found in about 40% of pancreatic NETs.<ref name="Jiao2011" /> The proteins encoded by ATRX and DAXX participate in [[chromatin]] remodeling of [[telomere]]s; these mutations are associated with a [[telomerase]]-independent maintenance mechanism termed ALT (alternative lengthening of telomeres) that results in abnormally long telomeric ends of [[chromosomes]].
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| * [[ATRX]]/[[DAXX]] and [[MEN1]] mutations were associated with a better [[prognosis]].<ref name="Jiao2011" />
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| ==References==
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| {{Reflist|2|refs=
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| <--This reference list is organized alphanumerically by arbitrary ref name-->
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| <ref name="Afinitor-PI">http://www.pharma.us.novartis.com/product/pi/pdf/afinitor.pdf</ref>
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| <ref name="ASCOPost20110515Evero">Everolimus Approved for Pancreatic Neuroendocrine Tumors. The ASCO Post. May 15, 2011, Volume 2, Issue 8 http://ascopost.com/articles/may-15-2011/everolimus-approved-for-pancreatic-neuroendocrine-tumors/</ref>
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| <ref name="Benson2010">Benson AB, Myerson RJ, and Sasson AR. Pancreatic, neuroendocrine GI, and adrenal cancers. Cancer Management: A Multidisciplinary Approach 13th edition 2010. ISBN 978-0-615-41824-7 Text is available electronically (but may require free registration) at http://www.cancernetwork.com/cancer-management/pancreatic/article/10165/1802606</ref>
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| <ref name="Burns2012">{{cite journal| author=Burns WR, Edil BH| title=Neuroendocrine pancreatic tumors: guidelines for management and update| journal=Current treatment options in oncology| date=March 2012 |volume=13| issue=1| pages=24–34| pmid=22198808| doi=10.1007/s11864-011-0172-2}}</ref>
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| <ref name="EU2010">{{cite news|url=http://www.genengnews.com/gen-news-highlights/pfizer-scores-new-approval-for-sutent-in-europe/81244326/ |title=Pfizer Scores New Approval for Sutent in Europe |date=2 Dec 2010 }}</ref>
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| <ref name="Grant2005">{{cite journal| author=Grant C | title=Insulinoma| journal= Best Practice & Research Clinical Gastroenterology | date=2005|volume=19 | issue=5| pages=783–798 | pmid=16253900| doi=10.1016/j.bpg.2005.05.008}}</ref>
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| <ref name="Heaphy2011">{{cite journal| author=Heaphy CM, De Wilde RF, Jiao Y, et al | date=2011| title=Altered Telomeres in Tumors with ATRX and DAXX Mutations| journal=Science |volume=333| issue=6041| pages= 425| doi=10.1126/science.1207313 | pmid=3174141 | pmid=21719641}}</ref>
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| <ref name="Jensen2008">{{cite journal| author=Jensen RT, Berna MJ, Bingham DB, Norton JA | title=Inherited pancreatic endocrine tumor syndromes: Advances in molecular pathogenesis, diagnosis, management, and controversies| journal= Cancer | date=2008|volume=113| issue=7 Suppl| pages= 1807–1843| pmid=18798544|pmc=2574000| doi=10.1002/cncr.23648}}</ref>
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| <ref name="Klimstra2010">The PanNET denomination is in line with current [[WHO]] guidelines. Historically, PanNETs have also been referred to by a variety of terms, and are still often called "islet cell tumors" or "pancreatic endocrine tumors". See: {{cite journal |author=Klimstra DS, Modlin IR, Coppola D, et al. |title=The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems |journal=Pancreas |volume=39 |issue=6 |pages=707–12 | date=August 2010 |pmid=20664470 |doi=10.1097/MPA.0b013e3181ec124e |url=http://www.seen.es/docs/apartados/470/The_Pathologic_Classification_of_Neuroendocrine.2.pdf}}</ref>
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| <ref name="NCCN_NET201501">{{cite web|title=Neuroendocrine tumors, NCCN Guidelines Version 1.2015|website=NCCN Guidelines|publisher=National Comprehensive Cancer Network, Inc. |url=http://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf|accessdate=December 25, 2014|date=November 11, 2014}}</ref>
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| <ref name="NCIPET">National Cancer Institute. Cancer Drug Information. FDA Approval for Sunitinib Malate. Pancreatic Neuroendocrine Tumors http://www.cancer.gov/cancertopics/druginfo/fda-sunitinib-malate</ref>
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| <ref name=Oberg-2012>{{cite journal |author=Öberg K, Knigge U, Kwekkeboom D, Perren A |title=Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up |journal=Annals of Oncology: Official Journal of the European Society for Medical Oncology / ESMO |volume=23 Suppl 7 |issue= |pages=vii124–30 | date=October 2012 |pmid=22997445 |doi=10.1093/annonc/mds295 |url=http://annonc.oxfordjournals.org/content/23/suppl_7/vii124.long#T2}} ([http://annonc.oxfordjournals.org/content/23/suppl_7/vii124/T5.expansion.html Table 5] outlines the proposed TNM staging system for PanNETs.)</ref>
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| <ref name="PDQ">Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ) Health Professional Version. National Cancer Institute. March 7, 2014. [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0032521/can]</ref>
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| <ref name="Ramage2005">{{cite journal |author=Ramage JK, Davies AH, Ardill J, et al.|title=Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours |journal=Gut |volume=Suppl 4 |issue= suppl_4|pages=iv1–16 |date=Jun 2005 |series=54 |pmid=15888809|pmc=1867801|doi=10.1136/gut.2004.053314|url=http://gut.bmj.com/cgi/content/full/54/suppl_4/iv1}}</ref>
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| <ref name= "Raymond2011">{{cite journal | author = Raymond E, Dahan L, Raoul JL, et al. | year = 2011 | title = Sunitinib malate for the treatment of pancreatic neuroendocrine tumors | url = | journal = N Engl J Med | volume = 364 | issue = 6| pages = 501–13 | pmid = 21306237 | doi=10.1056/NEJMoa1003825}}</ref>
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| <ref name="Sutent-PI">http://labeling.pfizer.com/ShowLabeling.aspx?id=607</ref>
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| <ref name="Tejani2014">{{cite journal| author=Tejani MA, Saif MW (2014). "Pancreatic neuroendocrine tumors: Does chemotherapy work?". JOP : Journal of the pancreas 15 (2): 132–4. doi:10.6092/1590-8577/2301 (inactive 2014-12-26). PMID 24618436}}</ref>
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| ==External links== | | ==External links== |
| * {{DMOZ|Health/Conditions_and_Diseases/Cancer/Gastrointestinal/Pancreatic/Neuroendocrine/}} | | * {{DMOZ|Health/Conditions_and_Diseases/Cancer/Gastrointestinal/Pancreatic/Neuroendocrine/}} |
