今日の臨床サポート

インスリノーマ

著者: 山田穂高1) 自治医科大学附属さいたま医療センター

著者: 濱本博美2) はまもと内科クリニック

監修: 野田光彦 国際医療福祉大学市川病院 糖尿病・代謝・内分泌内科

著者校正/監修レビュー済:2021/10/27
参考ガイドライン:
  1. 日本神経内分泌腫瘍研究会(JNETS):膵・消化管神経内分泌腫瘍(NEN)診療ガイドライン 第2版
患者向け説明資料

概要・推奨   

  1. 日本人における第2回全国疫学調査の結果、膵神経内分泌腫瘍のうち、機能性腫瘍で最も多いのはインスリノーマである。
  1. インスリノーマの診断における絶食試験は、72時間ではなく48時間でも十分に有用性をみることができる(推奨度1)。
  1. 空腹時の血糖が55mg/dL以下の低血糖患者の場合には、まず血中インスリン値(IRI)、Cペプチド、プロインスリンを測定することが推奨される(推奨度1)。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要と
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧に
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となり
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
山田穂高 : #N/A[2021年]
濱本博美 : 特に申告事項無し[2021年]
監修:野田光彦 : 特に申告事項無し[2021年]

改訂のポイント:
  1. ソマトスタチンアナログのランレオチドが2017年に消化管・膵NETに対して保険承認された。

病態・疫学・診察

疾患情報  
  1. インスリノーマとはインスリンを過剰産生する膵臓の腫瘍である。その結果として、低血糖発作を誘発する疾患である。
  1. 膵神経内分泌腫瘍は人口10万人あたり有病患者数2.69人、人口10万人あたり1年の新規発症率1.27人である。機能性腫瘍は34.5%で、そのうちインスリノーマが20.9%を占め、最も頻度が高い(低血糖の定義が一定でなく、また低血糖で医療機関を受診する患者数が把握されていないため、低血糖に占める頻度は不明)。
  1. 男女比1:1.4で、女性にやや多い。
  1. 年齢的には8~82歳まで各年齢層に分布しており、患者平均年齢は45歳である。
  1. 90%が良性、単発性である。
  1. 多発性内分泌腫瘍(MEN)1型を0.8%で合併し、その場合は多発性が多く、悪性の頻度が高くなるため注意を要する。
  1. 発生部位は頭、体部、尾部に均等に分布し、大きさは腫瘍径2cm未満の腫瘍が80~90%を占める。
  1. 治療は腫瘍核出術が基本となる。
  1. 古典的にはWhippleの3徴(①空腹時の中枢神経症状 ②症状出現時の血糖が50mg/dL未満 ③ブドウ糖投与による症状消失)が有名で、約8割の患者でみられる。
  1. 50mg/dL以下の低血糖がいまだ捉えられていない場合は絶食試験を行う。原法は72時間であるが、インスリノーマであれば48時間までに94.5%で低血糖発作が再現されるため、48時間でもよい。
  1. インスリン自律分泌の指標としてFajans index(IRI[血中インスリン値]/BS>0.3)、Turner index(IRI×100/(BS-30)>200、田港らの(100-BS)×(IRI-3)>280が用いられる。簡易的に、血糖が55 mg/dL以下のときにIRI 3μU/mL以上、Cペプチド0.6 ng/mL以上、プロインスリン5.0 pmol/L以上でもよい。近年、IRI測定精度向上のため、プロインスリンの分泌が過剰なタイプはIRI測定時に交差しなくなり、IRIが見かけ上低値になることがあるが、その場合もCペプチドやプロインスリン値は上記基準を満たすことが多い。
 
  1. 日本人における第2回全国疫学調査の結果、膵神経内分泌腫瘍のうち、機能性腫瘍で最も多いのはインスリノーマである。
  1. 日本における第2回全国疫学調査の結果、2010年の1年間に受療した膵神経内分泌腫瘍は3,379人で、そのうち機能性腫瘍は34.5%であった。機能性腫瘍のなかではインスリノーマの占める割合が20.9%と最も高く、MEN1合併率は0.8%であった[1]
 
  1. 一般的にインスリノーマの発症年齢は幅広く、やや女性に多く、腫瘍径は小さいものが多い。
  1. 海外の報告[2]では、平均発症年齢は45歳(範囲:8~82歳)で、女性に多く(男女比1:1.4)、腫瘍径2cm未満の腫瘍が80~90%を占め、膵臓の頭部、体部、尾部に等しく分布する。
 
  1. インスリノーマの診断における絶食試験は、72時間ではなく48時間でも十分に有用性をみることができる(推奨度1S)。
  1. インスリノーマの絶食試験における低血糖発作までの時間をみたシステマティックレビューがある[3]
  1. それによると、127例のインスリノーマ患者において、絶食試験の12時間までに42.5%、24時間までに66.9%、48時間までに94.5%に低血糖発作が再現され、試験を終了できた。
  1. このことから、絶食試験において72時間は必要ではなく、48時間で行うことが推奨される。
 
  1. 空腹時の血糖が55 mg/dL以下の低血糖患者の場合には、まず血中インスリン値(IRI)、Cペプチド、プロインスリンを測定することが推奨される(推奨度1G)。
  1. インスリノーマの場合、血糖が55 mg/dL以下のときにIRI 3μU/mL以上、Cペプチド0.6 ng/mL以上、プロインスリン5.0 pmol/L以上となることから、まずIRI、Cペプチド、プロインスリンを測定することが推奨される。なお、IRIが3μU/mL未満の場合でも、ほかの2つを満たすことが多い。また低血糖時にグルカゴンを静脈注射すると25 mg/dL以上の血糖上昇がみられる。
問診・診察のポイント  
  1. 臨床症状としては低血糖に伴う自律神経症状と中枢神経症状が出現する。自律神経症状は発汗(30~69%)、倦怠感(28~56%)、食欲亢進・肥満(14~50%)、振戦(12~14%)、動悸(5~12%)などである。中枢神経症状は意識障害(67~80%)、複視や物が霞んで見えるなどの視覚異常(42~59%)、健忘症(47%)、性格変化(16~38%)、てんかん(16~17%)などである。自律神経症状が先行することが多いが、自律神経障害がある場合や低血糖発作を繰り返す場合には自律神経症状の自覚症状を欠き(無自覚性低血糖)、中枢神経症状のみを呈する場合もある[4]。非特異的症状として嘔気や嘔吐、腹痛が数%報告されている。
  1. これらの出現から診断に至るまでの期間は、6カ月以内は26%しかなく、6カ月~5年が50%、20年以上要した例も1.9%存在する。

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文献 

著者: Tetsuhide Ito, Hisato Igarashi, Kazuhiko Nakamura, Hironobu Sasano, Takuji Okusaka, Koji Takano, Izumi Komoto, Masao Tanaka, Masayuki Imamura, Robert T Jensen, Ryoichi Takayanagi, Akira Shimatsu
雑誌名: J Gastroenterol. 2015 Jan;50(1):58-64. doi: 10.1007/s00535-014-0934-2. Epub 2014 Feb 6.
Abstract/Text BACKGROUND: Although neuroendocrine tumors (NETs) are rare, the number of patients with NET is increasing. However, in Japan, there have been no epidemiological studies on NET since 2005; thus, the prevalence of NET remains unknown.
METHODS: We reported the epidemiology of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [pancreatic neuroendocrine tumors (PNETs) and gastrointestinal neuroendocrine tumors (GI-NETs)] in Japan in 2005. Here, we conducted the second nationwide survey on patients with GEP-NETs who received treatment in 2010.
RESULTS: A total of 3,379 patients received treatment for PNETs in 2010, representing a 1.2-fold increase in the number of patients from 2005 to 2010. The prevalence was estimated to be 2.69/100,000, with an annual onset incidence of 1.27/100,000 in 2010. Non-functioning tumor (NF)-PNETs comprised 65.5% of cases followed by insulinoma (20.9%) and gastrinoma (8.2%). Interestingly, the number of patients with NF-PNETs increased ~1.8 fold since 2005. A total of 19.9% of patients exhibited distant metastasis at initial diagnosis; 4.3% had complications with multiple endocrine neoplasia type 1 (MEN-1), and only 4.0% had NF-PNETs associated with MEN-1. Meanwhile, an estimated 8,088 patients received treatment for GI-NETs, representing a ~1.8-fold increase since 2005. The prevalence was estimated to be 6.42/100,000, with an annual onset incidence of 3.51/100,000. The locations of GI-NETs varied: foregut, 26.1%; midgut, 3.6%; and hindgut, 70.3%. Distant metastasis and complications with MEN-1 were observed in 6.0 and 0.42% at initial diagnosis, respectively. The frequency of carcinoid syndrome in patients with GI-NETs was 3.2%.
CONCLUSION: We clarified the epidemiological changes in GEP-NETs from 2005 to 2010 in Japan.

PMID 24499825  J Gastroenterol. 2015 Jan;50(1):58-64. doi: 10.1007/s00・・・
著者: Bassam Abboud, Joe Boujaoude
雑誌名: World J Gastroenterol. 2008 Feb 7;14(5):657-65.
Abstract/Text Insulinomas continue to pose a diagnostic challenge to physicians, surgeons and radiologists alike. Most are intrapancreatic, benign and solitary. Biochemical diagnosis is obtained and imaging techniques to localize lesions continue to evolve. Surgical resection is the treatment of choice. Despite all efforts, an occult insulinoma (occult insulinoma refers to a biochemically proven tumor with indeterminate anatomical site before operation) may still be encountered. New localization preoperative techniques decreases occult cases and the knowledge of the site of the mass before surgery allows to determine whether enucleation of the tumor or pancreatic resection is likely to be required and whether the tumor is amenable to removal via a laparoscopic approach. In absence of preoperative localization and intraoperative detection of an insulinoma, blind pancreatic resection is not recommended.

PMID 18205253  World J Gastroenterol. 2008 Feb 7;14(5):657-65.
著者: B Hirshberg, A Livi, D L Bartlett, S K Libutti, H R Alexander, J L Doppman, M C Skarulis, P Gorden
雑誌名: J Clin Endocrinol Metab. 2000 Sep;85(9):3222-6. doi: 10.1210/jcem.85.9.6807.
Abstract/Text Insulinoma causes fasting hypoglycemia due to inappropriate insulin secretion. Its diagnosis is based on demonstrating Whipple's triad during a supervised 72-h fast. For 75 yr, the 72-h fast has been the cornerstone for the diagnosis; however, it has never been critically assessed using newer assays for insulin, C peptide, and proinsulin. Thus, the aim of the current study is to assess the need for a full 72-h fast for the diagnosis of insulinoma. Patients with suspected hypoglycemia with documented glucose concentrations below 45 mg/dL were admitted to the NIH. Data obtained during the supervised fast of patients with pathologically proven insulinoma over a 30-yr period (1970-2000) were reviewed. We identified 127 patients with insulinoma. The average age of patients was 42.7 +/- 15.9 yr, with a predominance of females (62%). 107 patients had a benign tumor, 20 had malignant insulinoma, and 15 patients had multiple endocrine neoplasia type 1. The fast was terminated due to hypoglycemia in 44 patients (42.5%) by 12 h, 85 patients (66.9%) by 24 h, and 120 (94.5%) by 48 h. Seven patients fasted beyond 48 h despite subtle neuroglycopenic symptoms and glucose and insulin concentrations diagnostic of insulinoma. Immunoreactive proinsulin was elevated at the beginning of the fast in 90% of 42 patients. Proinsulin in noninsulinoma, in contrast to insulinoma, patients is usually suppressible; therefore, samples taken in the suppressed state have the greatest diagnostic value. We conclude that with the current available insulin and proinsulin assays, the diagnosis of insulinoma can be made within 48 h. Thus, the 48-h fast should replace the 72-h fast in textbooks and hospital protocols as the new diagnostic standard.

PMID 10999812  J Clin Endocrinol Metab. 2000 Sep;85(9):3222-6. doi: 10・・・
著者: Kimberly A Placzkowski, Adrian Vella, Geoffrey B Thompson, Clive S Grant, Carl C Reading, J William Charboneau, James C Andrews, Ricardo V Lloyd, F John Service
雑誌名: J Clin Endocrinol Metab. 2009 Apr;94(4):1069-73. doi: 10.1210/jc.2008-2031. Epub 2009 Jan 13.
Abstract/Text OBJECTIVE: The objective of the study was to assess changes in the presentation and diagnostic and radiological evaluation of patients with surgically confirmed insulinoma at the Mayo Clinic 1987-2007.
METHODS: A retrospective analysis of patients with insulinoma was conducted. Patients with prior gastric bypass were excluded.
RESULTS: A total of 237 patients [135 women (57%)] were identified. Hypoglycemia was reported solely in the fasting state in 73%, the fasting and postprandial state in 21%, and exclusively postprandially in 6%. There was a predominance of men in the postprandial symptom group. Considering the period of study by quartile, outpatient evaluation increased from 35 to 83% and successful preoperative localization improved from 74 to 100% comparing the first to the fourth quartiles. Although the rates of localization by noninvasive techniques remained static at approximately 75%, the addition of invasive modalities has resulted in successful preoperative localization in all patients in the past 10 yr. The sensitivity and specificity of the established diagnostic criteria using insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and glucose response to iv glucagon were greater than 90% and greater than 70%, respectively.
CONCLUSIONS: Although fasting hypoglycemia is characteristic of patients with insulinoma, postprandial symptoms have been reported with increasing, albeit low, frequency. Trends in the evaluation and preoperative management include a shift to outpatient diagnostic testing, an emphasis on successful preoperative localization to avoid blind pancreatic exploration, and a validation of the diagnostic criteria for hyperinsulinemic hypoglycemia.

PMID 19141587  J Clin Endocrinol Metab. 2009 Apr;94(4):1069-73. doi: 1・・・
著者: G V Gill, O Rauf, I A MacFarlane
雑誌名: Postgrad Med J. 1997 Oct;73(864):640-1.
Abstract/Text A survey of UK patients receiving the drug diazoxide, revealed 40 patients with insulinoma on this treatment. Mean age (+/- SD) was 67 +/- 18 years, and 74% were female. Duration of treatment was 7 +/- 6 years (range 1-22). Most (55%) patients were treated with diazoxide because of tumour non-localisation (including failed previous surgery). Metastatic disease (20%) and poor surgical risk (10%) were other indications. Side-effects (notably fluid retention and hirsutism) were common (47%) but not troublesome. Treatment was highly effective--59% were symptom free and 38% had only occasional symptoms. Only one patient had frequent hypoglycaemia despite treatment. We conclude that diazoxide is effective in the management of insulinoma. Side-effects are common but not problematic. Treatment should be considered for all patients not cured by surgery, or unsuitable for surgical treatment.

PMID 9497974  Postgrad Med J. 1997 Oct;73(864):640-1.
著者: Boaz Hirshberg, Craig Cochran, Monica C Skarulis, Steven K Libutti, H Richard Alexander, Bradford J Wood, Richard Chang, David E Kleiner, Phillip Gorden
雑誌名: Cancer. 2005 Jul 15;104(2):264-72. doi: 10.1002/cncr.21179.
Abstract/Text BACKGROUND: Malignant insulinoma occurs in a few patients with insulinoma. Due to the small sample of patients, there are little data regarding their clinical manifestation as well as the preferred treatment modalities. The aims of the current study were to summarize the National Institutes of Health experience during the last two decades and to conduct a critical review of the current literature.
METHODS: The authors identified 10 patients with metastatic insulinoma.
RESULTS: The patients presented with four patterns of clinical behavior. First, four patients presented with lymph node metastasis and, after surgical excision, maintained a prolonged tumor-free survival. Second, four patients presented with metastatic disease to the liver, which appeared years after the initial diagnosis and presumed curative surgery. Third, one patient presented with a large alpha-fetoprotein-secreting liver mass. Finally, 9 of the 10 patients had a prolonged survival. Various treatment modalities were used to control hypoglycemia. Short-term benefits were most often achieved with embolization and diazoxide. Less successful modalities included radiofrequency ablation, radical debulking surgery, verapamil therapy, octreotide therapy, and chemotherapy.
CONCLUSIONS: The current study, as well as others, suggested that metastatic insulinoma may have a variable natural history. After the initial surgical resection, the biology of the tumor, rather than any treatment modality, was most likely the major determinant of long-term survival.

PMID 15937909  Cancer. 2005 Jul 15;104(2):264-72. doi: 10.1002/cncr.21・・・
著者: Matthew H Kulke, Emily K Bergsland, James C Yao
雑誌名: N Engl J Med. 2009 Jan 8;360(2):195-7. doi: 10.1056/NEJMc0806740.
Abstract/Text
PMID 19129539  N Engl J Med. 2009 Jan 8;360(2):195-7. doi: 10.1056/NEJ・・・
著者: James C Yao, Manisha H Shah, Tetsuhide Ito, Catherine Lombard Bohas, Edward M Wolin, Eric Van Cutsem, Timothy J Hobday, Takuji Okusaka, Jaume Capdevila, Elisabeth G E de Vries, Paola Tomassetti, Marianne E Pavel, Sakina Hoosen, Tomas Haas, Jeremie Lincy, David Lebwohl, Kjell Öberg, RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group
雑誌名: N Engl J Med. 2011 Feb 10;364(6):514-23. doi: 10.1056/NEJMoa1009290.
Abstract/Text BACKGROUND: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.
METHODS: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus.
RESULTS: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks).
CONCLUSIONS: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).

PMID 21306238  N Engl J Med. 2011 Feb 10;364(6):514-23. doi: 10.1056/N・・・
著者: Eric Raymond, Laetitia Dahan, Jean-Luc Raoul, Yung-Jue Bang, Ivan Borbath, Catherine Lombard-Bohas, Juan Valle, Peter Metrakos, Denis Smith, Aaron Vinik, Jen-Shi Chen, Dieter Hörsch, Pascal Hammel, Bertram Wiedenmann, Eric Van Cutsem, Shem Patyna, Dongrui Ray Lu, Carolyn Blanckmeister, Richard Chao, Philippe Ruszniewski
雑誌名: N Engl J Med. 2011 Feb 10;364(6):501-13. doi: 10.1056/NEJMoa1003825.
Abstract/Text BACKGROUND: The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials.
METHODS: We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety.
RESULTS: The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue.
CONCLUSIONS: Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.).

PMID 21306237  N Engl J Med. 2011 Feb 10;364(6):501-13. doi: 10.1056/N・・・
著者: Martyn E Caplin, Marianne Pavel, Jarosław B Ćwikła, Alexandria T Phan, Markus Raderer, Eva Sedláčková, Guillaume Cadiot, Edward M Wolin, Jaume Capdevila, Lucy Wall, Guido Rindi, Alison Langley, Séverine Martinez, Joëlle Blumberg, Philippe Ruszniewski, CLARINET Investigators
雑誌名: N Engl J Med. 2014 Jul 17;371(3):224-33. doi: 10.1056/NEJMoa1316158.
Abstract/Text BACKGROUND: Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited.
METHODS: We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety.
RESULTS: Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group).
CONCLUSIONS: Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).

PMID 25014687  N Engl J Med. 2014 Jul 17;371(3):224-33. doi: 10.1056/N・・・

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