膵・消化管神経内分泌腫瘍（NEN）診療ガイドライン（2019）第2版、金原出版株式会社.
WHO Classification of tumours Editorial Board, ed. WHO Classification of tumours, 5th ed. Vol 1, Digestive system Tumours. World Health Organization. 2019.
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
Epidemiological trends of pancreatic and gastrointestinal neuroendocrine tumors in Japan: a nationwide survey analysis.
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.
Toshihiko Masui, Tetsuhide Ito, Izumi Komoto, Shinji Uemoto, JNETS Project Study Group
Recent epidemiology of patients with gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NEN) in Japan: a population-based study.
BMC Cancer. 2020 Nov 14;20(1):1104. doi: 10.1186/s12885-020-07581-y. Epub 2020 Nov 14.
Abstract/Text
BACKGROUND: The worldwide prevalence and incidence of neuroendocrine neoplasms (NEN) have been increasing recently, although few studies have analyzed data on the current situation of NENs in Japan. Here, the Japan Neuroendocrine Tumor Society (JNETS) planned to investigate the recent incidence and distribution of these tumors using data from the national cancer registry started in 2016. This study examined the incidence and distribution of primary sites as well as rate of advanced disease from this population-based registry.
METHODS: A retrospective, population-based study using data from the national cancer registry in Japan (NCR) was conducted to evaluate patients with gastro-entero-pancreatic NEN (GEP-NEN) in 2016. Associated population data were used to determine annual age-adjusted incidences.
RESULTS: A total of 6735 individuals were diagnosed with GEP-NEN in Japan in 2016. Annual onset incidence was 0.70/100,000 for pancreatic NEN and 2.84/100,000 for gastrointestinal NEN. NEN in the ileum accounted for only 1% of total GEP-NENs in Japan. Most NENs in the esophagus or lungs were neuroendocrine carcinomas (NECs), while the majority of those in the duodenum, ileum, appendix and rectum were grade 1 neuroendocrine tumors (NETs). Median age at initial diagnosis was in between 60 to 65. Tumors in the duodenum, appendix and rectum were mostly limited to local, while those in the esophagus, stomach and colon tended to show distant metastasis. In Japan, initial treatment for GEP-NENs was resection even if the tumor was NEC.
CONCLUSIONS: This is the first report of a national registry-based incidence and distribution of GEP-NEN in Japan. These data will serve as an important first step to determining the exact etiology and trends for this pathology in Japan.
G Rindi, O Luinetti, M Cornaggia, C Capella, E Solcia
Three subtypes of gastric argyrophil carcinoid and the gastric neuroendocrine carcinoma: a clinicopathologic study.
Gastroenterology. 1993 Apr;104(4):994-1006. doi: 10.1016/0016-5085(93)90266-f.
Abstract/Text
BACKGROUND: Enterochromaffinlike (ECL) cell carcinoids recently observed in rats stimulated new interest in gastric endocrine tumors arising in humans.
METHODS: Paraffin-embedded sections of 55 endocrine tumor cases were stained with H&E, mucin tests were performed, and immunoperoxidase was used for detecting endocrine markers; 23 cases were also investigated ultrastructurally.
RESULTS: Forty-five argyrophil carcinoids, 9 neuroendocrine carcinomas, and 1 gastrinoma were identified. Three clinicopathologic subtypes of carcinoids were characterized: (1) twenty-eight cases, none metastatic, arose in a background of body-fundus atrophic gastritis and hypergastrinemia; (2) seven cases, 2 locally metastatic, were associated with hypertrophic gastropathy and hypergastrinemia due to multiple endocrine neoplasia/Zollinger-Ellison syndrome; and (3) ten were sporadic cases, 7 of which were deeply invasive, 6 metastatic, and 5 histologically atypical. All carcinoids showed histochemical and ultrastructural patterns of ECL cells. The 9 neuroendocrine carcinomas, all deeply invasive and metastatic, were composed of anaplastic, small- to intermediate-sized cells with high mitotic index and focal necrosis.
CONCLUSIONS: Gastrin-promoted carcinoids represent a benign or low grade tumor disease, whereas sporadic carcinoids and neuroendocrine carcinomas are life-threatening neoplasms, independent of gastrin promotion.
Mitsuaki Ishioka, Toshiaki Hirasawa, Hiroshi Kawachi, Kaoru Nakano, Junko Kunieda, Shoichi Yoshimizu, Yusuke Horiuchi, Akiyoshi Ishiyama, Toshiyuki Yoshio, Tomohiro Tsuchida, Junko Fujisaki
Enterochromaffin-like cell neuroendocrine tumor associated with parietal cell dysfunction.
Gastrointest Endosc. 2019 Nov;90(5):841-845.e1. doi: 10.1016/j.gie.2019.06.029. Epub 2019 Jul 2.
Abstract/Text
Baruch Brenner, Laura H Tang, Jinruh Shia, David S Klimstra, David P Kelsen
Small cell carcinomas of the gastrointestinal tract: clinicopathological features and treatment approach.
Semin Oncol. 2007 Feb;34(1):43-50. doi: 10.1053/j.seminoncol.2006.10.022.
Abstract/Text
Small cell undifferentiated carcinoma (SmCC) of the gastrointestinal tract (GIT) is a rare and highly aggressive malignancy. To date, fewer than 1,000 cases have been reported, with an estimated prevalence of 0.1% to 1% of all gastrointestinal (GI) tumors. Data on the disease are scarce due to its rarity and the fact that most authors have focused on one site within the GIT. In light of the limited data and its perceived similarity to SmCC of the lung, the disease has usually been treated as the latter. Nevertheless, recent clinicopathologic and molecular data imply several differences between the two entities, questioning the extent to which extrapolations from one to the other can be made. We review the available data on GI SmCC with emphasis on outlining its clinicopathologic features and the recommended treatment approach.
Yuichi Sato, Satoru Hashimoto, Ken-Ichi Mizuno, Manabu Takeuchi, Shuji Terai
Management of gastric and duodenal neuroendocrine tumors.
World J Gastroenterol. 2016 Aug 14;22(30):6817-28. doi: 10.3748/wjg.v22.i30.6817.
Abstract/Text
Gastrointestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, like all NETs. However, the incidence of GI-NETS has been increasing in recent years. Gastric NETs (G-NETs) and duodenal NETs (D-NETs) are the common types of upper GI-NETs based on tumor location. G-NETs are classified into three distinct subgroups: type I, II, and III. Type I G-NETs, which are the most common subtype (70%-80% of all G-NETs), are associated with chronic atrophic gastritis, including autoimmune gastritis and Helicobacter pylori associated atrophic gastritis. Type II G-NETs (5%-6%) are associated with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome (MEN1-ZES). Both type I and II G-NETs are related to hypergastrinemia, are small in size, occur in multiple numbers, and are generally benign. In contrast, type III G-NETs (10%-15%) are not associated with hypergastrinemia, are large-sized single tumors, and are usually malignant. Therefore, surgical resection and chemotherapy are generally necessary for type III G-NETs, while endoscopic resection and follow-up, which are acceptable for the treatment of most type I and II G-NETs, are only acceptable for small and well differentiated type III G-NETs. D-NETs include gastrinomas (50%-60%), somatostatin-producing tumors (15%), nonfunctional serotonin-containing tumors (20%), poorly differentiated neuroendocrine carcinomas (< 3%), and gangliocytic paragangliomas (< 2%). Most D-NETs are located in the first or second part of the duodenum, with 20% occurring in the periampullary region. Therapy for D-NETs is based on tumor size, location, histological grade, stage, and tumor type. While endoscopic resection may be considered for small nonfunctional D-NETs (G1) located in the higher papilla region, surgical resection is necessary for most other D-NETs. However, there is no consensus regarding the ideal treatment of D-NETs.
Hans Scherübl, Robert T Jensen, Guillaume Cadiot, Ulrich Stölzel, Günter Klöppel
Neuroendocrine tumors of the small bowels are on the rise: Early aspects and management.
World J Gastrointest Endosc. 2010 Oct 16;2(10):325-34. doi: 10.4253/wjge.v2.i10.325.
Abstract/Text
Neuroendocrine tumors of the small bowel are on the rise. In the US they have increased by 300%-500% in the last 35 years. At the same time their prognosis is much improved. Today, most neuroendocrine tumors (NETs) of the duodenum are detected "incidentally" and therefore recognized at an early stage. Duodenal NETs which are well differentiated, not larger than 10 mm and limited to the mucosa/submucosa can be endoscopically resected. The management of duodenal NETs ranging between 10 and 20 mm needs an interdisciplinary discussion. Endoscopic ultrasound is the method of choice to determine tumor size and depth of infiltration. Surgery is recommended for well-differentiated duodenal NET tumors greater than 20 mm, for localized sporadic gastrinomas (of any size) and for localized poorly differentiated NE cancers. Surgery is recommended for any ileal NET. Advanced ileal NETs with a carcinoid syndrome are treated with long-acting somatostatin analogs. This treatment significantly improves (progression-free) survival in patients with metastatic NETs of the ileum. For optimal NET management, tumor biology, type, localization and stage of the neoplasm, as well as the patient's individual circumstances have to be taken into account.
Waku Hatta, Tomoyuki Koike, Katsunori Iijima, Kiyotaka Asanuma, Naoki Asano, Hiroaki Musha, Yoshifumi Inomata, Toshikazu Sano, Hiroyuki Endo, Atsushi Ikehata, Toru Horii, Motoki Ohyauchi, Satoshi Yokosawa, Atsuko Kasajima, Fumiyoshi Fujishima, Hironobu Sasano, Naoki Nakaya, Tomohiro Nakamura, Tooru Shimosegawa
The Risk Factors for Metastasis in Non-Ampullary Duodenal Neuroendocrine Tumors Measuring 20 mm or Less in Diameter.
Digestion. 2017;95(3):201-209. doi: 10.1159/000459619. Epub 2017 Mar 18.
Abstract/Text
BACKGROUND/AIMS: The treatment strategy for non-ampullary duodenal neuroendocrine tumors (NAD-NETs) ≤20 mm in diameter has not been established. In this study, we aimed to evaluate the detailed characteristics of NAD-NETs ≤20 mm in diameter to clarify the risk factors of subsequent metastasis.
METHODS: The patients with NAD-NETs ≤20 mm in diameter who had been treated at 12 institutions between 1992 and 2013 were enrolled. Clinical records were retrieved, and histopathological findings of all cases were centrally reviewed by 2 pathologists.
RESULTS: We studied 49 patients with a mean follow-up period of 66.5 months. Thirty-five patients were initially treated with endoscopic resection (ER), and 14 with surgery. A univariate analysis revealed the ORs and 95% CIs of the risk factors for metastasis were lymphovascular invasion (12.5 [2.01-77.9]), multiple tumors (9.75 [1.46-65.4]), a tumor size of 11-20 mm (6.67 [1.21-36.6]), and World Health Organization grade G2 (7.13 [1.16-43.9]). Five-year overall and disease-specific survival rates were 86.1 and 97.2%, respectively.
CONCLUSION: This is the first study to demonstrate the risk factors of metastasis in NAD-NETs ≤20 mm in diameter. These findings may be helpful for determining the appropriate therapeutic approach and the clinical strategy of treatment following ER.
© 2017 S. Karger AG, Basel.
Reese W Randle, Shuja Ahmed, Naeem A Newman, Clancy J Clark
Clinical outcomes for neuroendocrine tumors of the duodenum and ampulla of Vater: a population-based study.
J Gastrointest Surg. 2014 Feb;18(2):354-62. doi: 10.1007/s11605-013-2365-4. Epub 2013 Oct 10.
Abstract/Text
BACKGROUND: Previous case series report that neuroendocrine tumors (NETs) of the ampulla of Vater have worse overall survival (OS) than NETs in the duodenum. We aimed to compare the OS of patients with ampullary NETs to patients with duodenal NETs.
METHODS: This retrospective comparative cohort study used the Surveillance, Epidemiology, and End Results (SEER) registry from 1988 to 2009. OS was evaluated using Kaplan-Meier estimates and Cox proportional hazard regression.
RESULTS: Ampullary NETs (n = 120) were larger (median size 18 vs. 10 mm, p < 0.001), higher grade (poorly and undifferentiated tumor 42 % vs. 12 %, p < 0.001), higher SEER historic stage (distant metastasis 16 % vs. 7 %, p < 0.001), and more often resected (78 % vs. 60 %, p < 0.001) than duodenal NETs (n = 1,360). Median OS was significantly worse for patients with ampullary NETs than with duodenal NETs (98 vs. 143 months, p = 0.037). Local resection was performed for 50.5 % of the resected ampullary NETs and resulted in similar OS compared to locally resected duodenal NETs (HR 1.37, 95 % CI 0.76-2.48, p = 0.291).
CONCLUSIONS: While ampullary NETs are more advanced at presentation and have worse OS than duodenal NETs, long-term survival is possible with proximal small bowel NETs. For locally resected NETs, OS is similar between ampullary and duodenal NETs.
Gianfranco Delle Fave, Dik J Kwekkeboom, Erik Van Cutsem, Guido Rindi, Beata Kos-Kudla, Ulrich Knigge, Hironobu Sasano, Paola Tomassetti, Ramon Salazar, Philippe Ruszniewski, Barcelona Consensus Conference participants
ENETS Consensus Guidelines for the management of patients with gastroduodenal neoplasms.
Neuroendocrinology. 2012;95(2):74-87. doi: 10.1159/000335595. Epub 2012 Feb 15.
Abstract/Text
Manisha H Shah, Whitney S Goldner, Thorvardur R Halfdanarson, Emily Bergsland, Jordan D Berlin, Daniel Halperin, Jennifer Chan, Matthew H Kulke, Al B Benson, Lawrence S Blaszkowsky, Jennifer Eads, Paul F Engstrom, Paul Fanta, Thomas Giordano, Jin He, Martin J Heslin, Gregory P Kalemkerian, Fouad Kandeel, Sajid A Khan, Wajih Zaheer Kidwai, Pamela L Kunz, Boris W Kuvshinoff, Christopher Lieu, Venu G Pillarisetty, Leonard Saltz, Julie Ann Sosa, Jonathan R Strosberg, Craig A Sussman, Nikolaos A Trikalinos, Nataliya A Uboha, Jonathan Whisenant, Terence Wong, James C Yao, Jennifer L Burns, Ndiya Ogba, Griselda Zuccarino-Catania
NCCN Guidelines Insights: Neuroendocrine and Adrenal Tumors, Version 2.2018.
J Natl Compr Canc Netw. 2018 Jun;16(6):693-702. doi: 10.6004/jnccn.2018.0056.
Abstract/Text
The NCCN Guidelines for Neuroendocrine and Adrenal Tumors provide recommendations for the management of adult patients with neuroendocrine tumors (NETs), adrenal gland tumors, pheochromocytomas, and paragangliomas. Management of NETs relies heavily on the site of the primary NET. These NCCN Guidelines Insights summarize the management options and the 2018 updates to the guidelines for locoregional advanced disease, and/or distant metastasis originating from gastrointestinal tract, bronchopulmonary, and thymus primary NETs.
Copyright © 2018 by the National Comprehensive Cancer Network.
Catherine G Tran, Scott K Sherman, Mohammed O Suraju, Apoorve Nayyar, Henning Gerke, Rami G El Abiad, Chandrikha Chandrasekharan, Po Hien Ear, Thomas M O'Dorisio, Joseph S Dillon, Andrew M Bellizzi, James R Howe
Management of Duodenal Neuroendocrine Tumors: Surgical versus Endoscopic Mucosal Resection.
Ann Surg Oncol. 2021 Sep 13;. doi: 10.1245/s10434-021-10774-9. Epub 2021 Sep 13.
Abstract/Text
BACKGROUND: Management of duodenal neuroendocrine tumors (DNETs) is not standardized, with smaller lesions (< 1-2 cm) generally treated by endoscopic mucosal resection (EMR) and larger DNETs by surgical resection (SR). This study reviewed how patients were selected for treatment and compared outcomes.
PATIENTS AND METHODS: Patients with DNETs undergoing resection were identified through institutional databases, and clinicopathologic data recorded. χ2 and Wilcoxon tests compared variables. Survival was determined by Kaplan-Meier, and Cox regression tested association with survival.
RESULTS: Among 104 patients, 64 underwent EMR and 40 had SR. Patients selected for SR had larger tumor size, younger age, and higher T, N, and M stage. There was no difference in progression-free (PFS) or overall survival (OS) between SR and EMR. In 1-2 cm DNETs, there was no difference in PFS between SR and EMR [median not reached (NR), P = 0.1]; however, longer OS was seen in SR (median NR versus 112 months, P = 0.03). In 1-2 cm DNETs, SR patients were more likely to be node-positive and younger. After adjustment for age, resection method did not correlate with survival. Comparison of surgically resected DNETs versus jejunoileal NETs revealed longer PFS (median NR versus 73 months, P < 0.001) and OS (median NR versus 119 months, P = 0.004) DISCUSSION: In 1-2 cm DNETs, there was no difference in survival between EMR and SR after adjustment for age. Recurrences could be salvaged, suggesting that EMR is a reasonable strategy. Compared with jejunoileal NETs, DNETs treated by SR had improved PFS and OS.
© 2021. Society of Surgical Oncology.
Gwang Ha Kim, Jin Il Kim, Seong Woo Jeon, Jeong Seop Moon, Il-Kwun Chung, Sam-Ryong Jee, Heung Up Kim, Geom Seog Seo, Gwang Ho Baik, Yong Chan Lee, Korean College of Helicobacter and Upper Gastrointestinal Research
Endoscopic resection for duodenal carcinoid tumors: a multicenter, retrospective study.
J Gastroenterol Hepatol. 2014 Feb;29(2):318-24. doi: 10.1111/jgh.12390.
Abstract/Text
BACKGROUND AND AIM: Gastrointestinal carcinoid tumors < 10 mm in diameter and limited to the submucosal layer demonstrate a low frequency of lymph node and distant metastasis, and are suitable for endoscopic treatment. The aim of this study was to assess the efficacy, safety, and long-term prognosis of endoscopic resections for the treatment of duodenal carcinoid tumors.
METHODS: This study included a total of 41 duodenal carcinoid tumors in 38 patients between January 2006 and December 2011. The indications for endoscopic resection were lesions ≤ 10 mm in diameter, confined to the submucosal layer, and without lymph node or distant metastasis. Endoscopic resection was accomplished using endoscopic mucosal resection (EMR), EMR with a ligation device (EMR-L), EMR after circumferential precutting, or endoscopic submucosal dissection (ESD).
RESULTS: EMR was performed in 18 tumors, EMR-L in 16, EMR after circumferential precutting in 3, and ESD in 4. En-bloc resection was performed in 39 tumors (95%), and endoscopic complete resection was achieved in 40 (98%); pathological complete resection was achieved in 17 tumors (41%). The endoscopic complete resection rate did not differ according to the resection method, but the pathological complete resection rate was higher for ESD than for EMR and EMR-L. Intraprocedural bleeding was noted in five cases, with no occurrence of perforation. Recurrence was not observed during the mean follow-up period of 17 months (range 1-53 months).
CONCLUSION: Endoscopic resection appears to be a safe and effective treatment for duodenal carcinoid tumors measuring ≤ 10 mm in diameter and confined to the submucosal layer.
© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.
Helcio Pedrosa Brito, Isabela Trindade Torres, Karine Corcione Turke, Artur Adolfo Parada, Jaques Waisberg, Ricardo Vieira Botelho
Comparison of endoscopic resection techniques for duodenal neuroendocrine tumors: systematic review.
Endosc Int Open. 2021 Aug;9(8):E1214-E1221. doi: 10.1055/a-1487-5594. Epub 2021 Jul 16.
Abstract/Text
Background and study aims Regardless of size, duodenal neuroendocrine tumors (dNETs) should be considered potentially malignant. A complete resection without complications is essential to increase safety procedures. The aim of this review was to describe effectiveness and possible complications of endoscopic techniques resection for resectioning dNETs in patients with tumors ≤ 20 mm in diameter. Methods An electronic bibliographic search was conducted using MEDLINE (via PubMed), Embase, Cochrane Central, and Google Scholar virtual databases. The types of intervention were endoscopic mucosal resection alone (EMR) or with cap (EMR-C), with a ligation device (EMR-L), with previous elevation of the tumor (EMR-I) or with endoscopic submucosal dissection (ESD); argon plasm coagulation (APC), and polypectomy. The outcome measures adopted were presence of free margin associated with tumor resection, tumor recurrence, complications (bleeding and perforation), and length of the procedure. Results Ten publications were included with the result of 224 dNET resections. EMR alone and polypectomy resulted in the most significantly compromised margin. The most frequent complication was bleeding (n = 21), followed by perforation (n = 8). Recurrence occurred in 13 cases, the majority of those under EMR or EMR-I. Conclusions EMR-C or EMR-I should be preferred for resectioning of dNETs. Polypectomy should not be indicated for resection of dNETs due to the high occurrence of incomplete resections. EMR alone must be avoided due a higher frequency of compromised margin and recurrent surgery. ESD was associated with no recurrence, however, but an increased occurrence of bleeding and perforation.
The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
John T Mullen, Huamin Wang, James C Yao, Jeffrey H Lee, Nancy D Perrier, Peter W T Pisters, Jeffrey E Lee, Douglas B Evans
Carcinoid tumors of the duodenum.
Surgery. 2005 Dec;138(6):971-7; discussion 977-8. doi: 10.1016/j.surg.2005.09.016.
Abstract/Text
BACKGROUND: Carcinoid tumors of the duodenum are rare, and their natural history has not been defined. Consequently, there is no consensus on the optimal extent of surgical treatment.
METHODS: The authors reviewed the records of all patients with primary carcinoid tumors of the duodenum treated at their institution from 1969 through 2004. Patients with primary periampullary tumors and gastrinomas were excluded.
RESULTS: Twenty-four patients had a pathologic diagnosis of duodenal carcinoid tumor. The majority (89%) of tumors measured less than 2 cm in diameter, and most (85%) were limited to the mucosa or submucosa. Lymph node metastases were identified in the surgical specimen in 7 (54%) of 13 patients in whom lymph nodes were examined, including 2 patients with tumors smaller than 1 cm and limited to the submucosa. At a mean follow-up of 46 months, the disease-specific survival rate was 100%, and only 2 patients have had recurrences in regional lymph nodes. No patient has had distant metastases or the carcinoid syndrome.
CONCLUSIONS: Carcinoid tumors of the duodenum are indolent. The presence of regional lymph node metastases cannot be predicted reliably on the basis of tumor size or depth of invasion, and their impact on survival is uncertain.
H R Makhlouf, A P Burke, L H Sobin
Carcinoid tumors of the ampulla of Vater: a comparison with duodenal carcinoid tumors.
Cancer. 1999 Mar 15;85(6):1241-9. doi: 10.1002/(sici)1097-0142(19990315)85:6<1241::aid-cncr5>3.0.co;2-4.
Abstract/Text
BACKGROUND: Although ampullary carcinoid tumors (ACs) are often categorized clinically as duodenal carcinoid tumors (DCs), there are distinct clinical and pathologic differences.
METHODS: Clinical, histopathologic, and immunohistochemical features of 12 ACs were compared with those of 53 DCs that did not involve the ampulla.
RESULTS: Patients with AC were ages 28-74 years (mean, 54.9 years); 8 were males and 4 were females. Five were white and three were black; the race of four patients was not known. The size of ACs ranged from 0.2 to 5.0 cm in greatest dimension. There were no significant differences between AC patients and DC patients with respect to male predominance, race, tumor size, and mitotic rate. The insular growth pattern was more common in AC; the cribriform type was more common in DC. Four of 12 ACs contained psammoma bodies, versus none of 53 DCs (P = 0.001). The rate of metastasis was similar in patients with AC (4 of 12, 33%) compared with DC patients (14 of 53, 26%). In DC patients, involvement of the muscularis propria, a size greater than 2 cm, and mitotic activity were significantly correlated with metastatic risk. In AC patients, tumor size and mitotic activity had no correlation with metastatic potential. One AC had features of an atypical carcinoid tumor; there were none in the duodenal group. One-half of patients with AC presented with jaundice versus 7% of patients with DC (P = 0.005). Three patients (25%) with AC had von Recklinghausen disease versus 0 of 53 patients with DC (P = 0.003). Immunohistochemically, tumor cells expressed somatostatin in 67%, serotonin and cholecystokinin in 17%, insulin in 25%, and glucagon and gastrin in 0% of ACs. In contrast, 56% of DCs expressed gastrin (P < 0.001).
CONCLUSIONS: Carcinoid tumors of the ampulla differ clinically, histologically, and immunohistochemically from carcinoid tumors elsewhere in the duodenum.
Shin Hwang, Sung-Gyu Lee, Young-Joo Lee, Duck-Jong Han, Song-Cheol Kim, Sea-Hyun Kwon, Je-Ho Ryu, Jung-Ik Park, Hyo-Jun Lee, Ga-Won Choi, Eun-Sil Yu
Radical surgical resection for carcinoid tumors of the ampulla.
J Gastrointest Surg. 2008 Apr;12(4):713-7. doi: 10.1007/s11605-007-0389-3. Epub 2007 Nov 9.
Abstract/Text
Ampullary carcinoid tumors are extremely rare. The present study describes the clinicopathological features and outcomes for 10 ampullary carcinoid patients who underwent radical resection from 1998 to 2005. During this study period, 294 patients underwent pancreatoduodenectomy for ampullary neoplasms in our institution. The mean patient age was 58.0 +/- 13.4 years, and seven were male. Initial clinical manifestations were jaundice in four patients, nonspecific gastrointestinal symptoms in five, and completely asymptomatic in one. Standard pancreatoduodenectomy was performed in three patients, and pylorus-preserving pancreatoduodenectomy in seven, and there were no major complications. The mean tumor size and volume were 2.1 +/- 1.3 cm and 4.1 +/- 6.9 ml, respectively. Synaptophysin staining was positive in ten patients and chromogranin staining positive in eight. R0 resection was achieved in all ten patients. Overall and disease-free survival rates were 90 and 80% at 1 year, and 64 and 56% at 3 years, respectively. The liver was the most common site of initial metastasis after curative resection. Univariate analyses revealed that a maximal tumor diameter > or =2 cm and tumor extension beyond the ampulla were risk factors for tumor recurrence. In conclusion, while the majority of ampullary carcinoids are indolent, this tumor is associated with a relatively poor prognosis. We believe that radical resection, with the aim of complete tumor removal and cure, is the treatment of choice.
Wilson M Clements, Stephen P Martin, Grant Stemmerman, Andrew M Lowy
Ampullary carcinoid tumors: rationale for an aggressive surgical approach.
J Gastrointest Surg. 2003 Sep-Oct;7(6):773-6. doi: 10.1016/s1091-255x(03)00114-8.
Abstract/Text
Two cases of ampullary carcinoid tumor are reported. These tumors are among the most rare of GI tract carcinoids and appear to have a distinct presentation and biological behavior from carcinoids arising in the duodenum. The existing literature is reviewed with attention to the implications for surgical management of this rare disease.
D K Bartsch, J Waldmann, V Fendrich, L Boninsegna, C L Lopez, S Partelli, M Falconi
Impact of lymphadenectomy on survival after surgery for sporadic gastrinoma.
Br J Surg. 2012 Sep;99(9):1234-40. doi: 10.1002/bjs.8843.
Abstract/Text
BACKGROUND: The study was undertaken to determine prognostic factors and the value of systematic lymphadenectomy on survival in sporadic gastrinoma.
METHODS: Patients with sporadic gastrinoma who underwent initial surgery during a 21-year period in two tertiary referral centres were analysed retrospectively with respect to clinical characteristics, operative procedures and outcome.
RESULTS: Forty-eight patients with a median age of 52 (range 22-73) years were analysed. Some 18 patients had pancreatic and 26 had duodenal gastrinomas, whereas the primary tumour remained unidentified in four patients. After a median postoperative follow-up of 83 (range 3-296) months, 20 patients had no evidence of disease, 13 patients were alive with disease, 11 patients had died from the disease and four had died from unrelated causes. In 41 patients who underwent potentially curative surgery, systematic lymphadenectomy with excision of more than ten lymph nodes resulted in a higher rate of biochemical cure after surgery than no or selective lymphadenectomy (13 of 13 versus 18 of 28 patients; P = 0·017), with a trend towards prolonged disease specific survival (P = 0·062) and disease-free survival (P = 0·120), and a reduced risk of death (0 of 13 versus 7 of 24 patients; P = 0·037). Negative prognostic factors for disease specific survival were pancreatic location (P = 0·029), tumour size equal to or larger than 25 mm (P = 0·003), Ki-67 index more than 5 per cent (P < 0·001), preoperative gastrin level 3000 pg/ml or more (P = 0·003) and liver metastases (P < 0·001). Sex, age, type of surgery and presence of lymph node metastases had no influence on disease free or disease specific survival.
CONCLUSION: In sporadic gastrinoma, systematic lymphadenectomy during initial surgery may reduce the risk of persistent disease and improve survival.
Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
Francesco Giovinazzo, Giovanni Butturini, Daniela Monsellato, Giuseppe Malleo, Giovanni Marchegiani, Claudio Bassi
Lymph nodes metastasis and recurrences justify an aggressive treatment of gastrinoma.
Updates Surg. 2013 Mar;65(1):19-24. doi: 10.1007/s13304-013-0201-8. Epub 2013 Feb 16.
Abstract/Text
In the current study, short- and long-term outcomes after aggressive surgical treatment for gastrinoma were evaluated. From August 1990 to August 2009, 20 patients diagnosed with Zollinger Ellison syndrome were reviewed. Eleven pancreaticoduodenectomies, three total pancreatectomies, four lymph node dissections, four enucleations and two palliative procedures were performed. Four (27.8 %) patients had disease associated with MEN1 syndrome, 13 (72.2 %) had sporadic gastrinomas (SG) and 3 had disease of unknown primary origin. No in-hospital mortality was observed. After radical resection, lymph node metastasis was present in 82 % of the cases. Eight percent of patients who underwent radical resection developed recurrence compared with 100 % of those who underwent enucleoresection (p = 0.03). Average time to recurrence in patients with sporadic gastrinoma was 66.7 months (confidence interval (CI) 62.9-70.5) in those treated with enucloeresection compared to 181.1 months (CI 124.3-237.8) in the radical resection group (p = 0.007). One recurrence was observed in the MEN1 group. Based on post-operative mortality, recurrence and lymph node metastasis, our data suggest that patients with gastrinoma should undergo abdominal exploration with aggressive resection of the primary tumour and regional lymph nodes in place of conservative treatment.
D L Fraker, J A Norton, H R Alexander, D J Venzon, R T Jensen
Surgery in Zollinger-Ellison syndrome alters the natural history of gastrinoma.
Ann Surg. 1994 Sep;220(3):320-8; discussion 328-30. doi: 10.1097/00000658-199409000-00008.
Abstract/Text
OBJECTIVE: The authors assessed the impact of gastrinoma resection on the subsequent development of hepatic metastases in Zollinger-Ellison syndrome.
SUMMARY BACKGROUND DATA: The symptoms of acid hypersecretion can be controlled medically in Zollinger-Ellison syndrome with high-dose pharmacologic therapy. The current role of surgery is curative excision of the gastrinoma. Because biochemical cure is obtained only in a portion of the patients and the neoplastic disease may be indolent in this syndrome, the ability of surgical resection of gastrinoma to alter or improve the subsequent development of hepatic metastases and mortality has not been defined.
METHODS: One hundred twenty-four patients with the biochemical diagnosis of Zollinger-Ellison syndrome and no hepatic metastases on initial imaging studies were evaluated. Ninety-eight patients underwent surgical exploration for curative gastrinoma resections while 26 patients were managed medically. Long-term follow-up regarding development of hepatic metastases and survival were evaluated.
RESULTS: Surgical exploration with gastrinoma excision resulted in a significantly decreased incidence of hepatic metastases 3% (3/98) compared with patients managed medically 23% (6/26) with comparable follow-up (p < 0.003). Two deaths due to metastatic gastrinoma occurred in the nonoperative group compared with no disease-specific deaths in the surgical group (p = 0.085).
CONCLUSIONS: For the patient with Zollinger-Ellison syndrome without metastatic disease, surgical exploration with attempted curative gastrinoma resection is recommended because it may alter the natural history of this syndrome.
Jeffrey A Norton, Douglas L Fraker, H R Alexander, Fathia Gibril, David J Liewehr, David J Venzon, Robert T Jensen
Surgery increases survival in patients with gastrinoma.
Ann Surg. 2006 Sep;244(3):410-9. doi: 10.1097/01.sla.0000234802.44320.a5.
Abstract/Text
OBJECTIVE: To determine whether the routine use of surgical exploration for gastrinoma resection/cure in 160 patients with Zollinger-Ellison syndrome (ZES) altered survival compared with 35 ZES patients who did not undergo surgery.
SUMMARY BACKGROUND DATA: The role of routine surgical exploration for resection/cure in patients with ZES has been controversial since the original description of this disease in 1955. This controversy continues today, not only because medical therapy for acid hypersecretion is so effective, but also in large part because no studies have shown an effect of tumor resection on survival.
METHODS: Long-term follow-up of 160 ZES patients who underwent routine surgery for gastrinoma/resection/cure was compared with 35 patients who had similar disease but did not undergo surgery for a variety of reasons. All patients had preoperative CT, MRI, ultrasound; if unclear, angiography and somatostatin receptor scintigraphy since 1994 to determine resectability. At surgery, all had the same standard ZES operation. All patients were evaluated yearly with imaging studies and disease activity studies.
RESULTS: The 35 nonsurgical patients did not differ from the 160 operated in clinical, laboratory, or tumor imaging results. The 2 groups did not differ in follow-up time since initial evaluation (range, 11.8-12 years). At surgery, 94% had a tumor removed, 51% were cured immediately, and 41% at last follow-up. Significantly more unoperated patients developed liver metastases (29% vs. 5%, P = 0.0002), died of any cause (54 vs. 21%, P = 0.0002), or died a disease-related death (23 vs. 1%, P < 0.00001). Survival plots showed operated patients had a better disease-related survival (P = 0.0012); however, there was no difference in non-disease-related survival. Fifteen-year disease-related survival was 98% for operated and 74% for unoperated (P = 0.0002).
CONCLUSIONS: These results demonstrate that routine surgical exploration increases survival in patients with ZES by increasing disease-related survival and decreasing the development of advanced disease. Routine surgical exploration should be performed in ZES patients.
Detlef K Bartsch, Volker Fendrich, Peter Langer, Ilhan Celik, Peter H Kann, Matthias Rothmund
Outcome of duodenopancreatic resections in patients with multiple endocrine neoplasia type 1.
Ann Surg. 2005 Dec;242(6):757-64, discussion 764-6. doi: 10.1097/01.sla.0000189549.51913.d8.
Abstract/Text
OBJECTIVE: To evaluate the outcome of an aggressive surgical approach for duodenopancreatic neuroendocrine tumors (PETs) associated with multiple endocrine neoplasia type 1 (MEN1).
SUMMARY BACKGROUND DATA: The management of PETs is still controversial in the setting of the autosomal dominant inherited MEN1 syndrome.
METHODS: MEN1 patients that had either biochemical evidence of functioning PETs or visualized nonfunctioning PETs larger than 1 cm in size on imaging were operated. Since 1997, patients were followed annually by biochemical testing and imaging studies.
RESULTS: Twenty-six genetically confirmed MEN1 patients underwent duodenopancreatic resection for functioning (n = 17) or nonfunctioning (n = 9) PETs. Ten (38%) patients had malignant PETs as characterized by the presence of lymph node (10 patients) and/or distant metastases (2 patients). The surgical approach was selected based on the type, location, and size of PETs. Four Zollinger-Ellison syndrome (ZES) patients required pylorus preserving pancreaticoduodenectomy (PPPD) as initial or redo procedure, 20 patients underwent other duodenopancreatic resections, and 2 patients had simple enucleations of PETs. After median 83 months (range, 5-241 months), 24 patients were alive and 2 patients died of an unrelated cause. All patients with insulinoma or vipoma and 7 of 11 patients with ZES were biochemically cured, including the ZES patients who underwent PPPD. However, 19 of 26 (73%) patients developed new small PETs (<1 cm) in the pancreatic remnant, but no patient had yet detectable metastases on imaging.
CONCLUSIONS: Early and aggressive surgery of PETs in MEN1 patients prevents the development of liver metastases, which are the most life-threatening determinant. PPPD might be the procedure of choice for MEN1-ZES, which has to be proven in large scale studies.
Masayuki Imamura, Izumi Komoto, Shuichi Ota, Takuya Hiratsuka, Shinji Kosugi, Ryuichiro Doi, Masaaki Awane, Naoya Inoue
Biochemically curative surgery for gastrinoma in multiple endocrine neoplasia type 1 patients.
World J Gastroenterol. 2011 Mar 14;17(10):1343-53. doi: 10.3748/wjg.v17.i10.1343.
Abstract/Text
AIM: To search for the optimal surgery for gastrinoma and duodenopancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1.
METHODS: Sixteen patients with genetically confirmed multiple endocrine neoplasia type 1 (MEN 1) and Zollinger-Ellison syndrome (ZES) underwent resection of both gastrinomas and duodenopancreatic neuroendocrine tumors (NETs) between 1991 and 2009. For localization of gastrinoma, selective arterial secretagogue injection test (SASI test) with secretin or calcium solution was performed as well as somatostatin receptor scintigraphy (SRS) and other imaging methods such as computed tomography (CT) or magnetic resonance imaging (MRI). The modus of surgery for gastrinoma has been changed over time, searching for the optimal surgery: pancreaticoduodenectomy (PD) was first performed guided by localization with the SAST test, then local resection of duodenal gastrinomas with dissection of regional lymph nodes (LR), and recently pancreas-preserving total duodenectomy (PPTD) has been performed for multiple duodenal gastrinomas.
RESULTS: Among various types of preoperative localizing methods for gastrinoma, the SASI test was the most useful method. Imaging methods such as SRS or CT made it essentially impossible to differentiate functioning gastrinoma among various kinds of NETs. However, recent imaging methods including SRS or CT were useful for detecting both distant metastases and ectopic NETs; therefore they are indispensable for staging of NETs. Biochemical cure of gastrinoma was achieved in 14 of 16 patients (87.5%); that is, 100% in 3 patients who underwent PD, 100% in 6 patients who underwent LR (although in 2 patients (33.3%) second LR was performed for recurrence of duodenal gastrinoma), and 71.4% in 7 patients who underwent PPTD. Pancreatic NETs more than 1 cm in diameter were resected either by distal pancreatectomy or enucleations, and no hepatic metastases have developed postoperatively. Pathological study of the resected specimens revealed co-existence of pancreatic gastrinoma with duodenal gastrinoma in 2 of 16 patients (13%), and G cell hyperplasia and/or microgastrinoma in the duodenal Brunner's gland was revealed in all of 7 duodenal specimens after PPTD.
CONCLUSION: Aggressive resection surgery based on accurate localization with the SASI test was useful for biochemical cure of gastrinoma in patients with MEN 1.
Thomas J Vogl, Nagy N N Naguib, Stefan Zangos, Katrin Eichler, Alborz Hedayati, Nour-Eldin A Nour-Eldin
Liver metastases of neuroendocrine carcinomas: interventional treatment via transarterial embolization, chemoembolization and thermal ablation.
Eur J Radiol. 2009 Dec;72(3):517-28. doi: 10.1016/j.ejrad.2008.08.008. Epub 2008 Oct 1.
Abstract/Text
UNLABELLED: The aim of this review article is to provide a practical clinical guideline for indication, technical aspects, protocol guideline and strategies for the interventional treatment of liver metastases from neuroendocrine tumors and focusing on the results of various protocols of management. The response to therapy, in the published articles, is calculated on the basis of the following clinical parameters; including symptomatic response (SR), biologic response (BR), morphological response (MR), progress free survival (PFS), and survival periods (SP). Transarterial chemoembolization (TACE) has been associated with SR rates of 60-95%, BR of 50-90%, MR of 33-80%, SR of 20-80 months, and a 5-year survival of between 50% and 65%. PFS was also between 18 and 24 months. In the transarterial embolization (TAE) group, SR was similar to the TACE group, MR was 32% and 82%, survival was between 18 and 88 months with a survival rate of 40-67%, and BR was between 50% and 69%. Radiofrequency ablation (RFA), either percutaneous or during surgery, has been associated with SR of 71-95% for a mean duration of 8-10 months, BR of 65%, and mean SP of 1.6 years after ablation. The mean survival following surgical resection for operable cases is 4.26 years+/-S.D.: 1.1.
CONCLUSION: The interventional protocols for the management of liver metastases from neuroendocrine tumors: for oligonodular liver metastatic deposits, local resection or RFA and/or LITT is recommended, while in multinodular diseases with higher tumor load, TACE or TAE is recommended.
Andrew Kennedy, Lourens Bester, Riad Salem, Ricky A Sharma, Rowan W Parks, Philippe Ruszniewski, NET-Liver-Metastases Consensus Conference
Role of hepatic intra-arterial therapies in metastatic neuroendocrine tumours (NET): guidelines from the NET-Liver-Metastases Consensus Conference.
HPB (Oxford). 2015 Jan;17(1):29-37. doi: 10.1111/hpb.12326. Epub 2014 Sep 4.
Abstract/Text
OBJECTIVES: Liver metastasis from a neuroendocrine tumour (NET) represents a significant clinical entity. A multidisciplinary group of experts was convened to develop state-of-the-art recommendations for its management.
METHODS: Peer-reviewed published reports on intra-arterial therapies for NET hepatic metastases were reviewed and the findings presented to a jury of peers. The therapies reviewed included transarterial embolization (TAE), transarterial chemoembolization (TACE) and radioembolization (RE). Two systems were used to evaluate the level of evidence in each publication: (i) the US National Cancer Institute (NCI) system, and (ii) the GRADE system.
RESULTS: Eighteen publications were reviewed. These comprised 11 reports on TAE or TACE and seven on RE. Four questions posed to the panel were answered and recommendations offered.
CONCLUSIONS: Studies of moderate quality support the use of TAE, TACE and RE in hepatic metastases of NETs. The quality and strength of the reports available do not allow any modality to be determined as superior in terms of imaging response, symptomatic response or impact on survival. Radioembolization may have advantages over TAE and TACE because it causes fewer side-effects and requires fewer treatments. Based on current European Neuroendocrine Tumor Society (ENETS) Consensus Guidelines, RE can be substituted for TAE or TACE in patients with either liver-only disease or those with limited extrahepatic metastases.
© 2014 The Authors. HPB published by John Wiley & Sons Ltd on behalf of the International Hepato-Pancreato-Biliary Association.
D L Chan, R Thompson, M Lam, N Pavlakis, J Hallet, C Law, S Singh, S Myrehaug
External Beam Radiotherapy in the Treatment of Gastroenteropancreatic Neuroendocrine Tumours: A Systematic Review.
Clin Oncol (R Coll Radiol). 2018 Jul;30(7):400-408. doi: 10.1016/j.clon.2018.03.006. Epub 2018 Mar 31.
Abstract/Text
AIMS: External beam radiotherapy (EBRT) is infrequently used to treat gastroenteropancreatic neuroendocrine tumours (GEPNETS), with little published data to date. We carried out a systematic review to assess the activity of EBRT for GEPNETS.
MATERIALS AND METHODS: Major databases were searched for papers including at least five patients treated with contemporary EBRT techniques. Eligible studies underwent dual independent review. The primary end points were response rate for lesions treated with definitive intent and recurrence-free survival for primary lesions treated with neoadjuvant or adjuvant intent.
RESULTS: Of 11 included studies (all retrospective), seven investigated pancreatic neuroendocrine tumours (PNETs, 100 patients, 14% grade 3) and four studies investigated extra-pancreatic neuroendocrine tumours (84 patients, 14% grade 3). Trials investigating PNETs administered a median of 50.4 Gy via three-dimensional conformal radiotherapy and intensity-modulated radiotherapy. EBRT was given with neoadjuvant or adjuvant intent in 56 patients, with a recurrence rate of 15%. For the 44 patients not undergoing surgery, the radiological response rate was 46%. Grade 3 + toxicity rates were 11% (acute) and 4% (late). Twelve patients with anorectal neuroendocrine carcinoma received 58 Gy to the primary tumour. Seventy-two patients were treated to sites of metastatic disease (34 bone, 27 brain, 11 soft tissue). Local and distant control were poorly reported. Overall survival ranged from 9 to 19 months. No studies in this group reported toxicity outcomes.
CONCLUSIONS: There are limited, retrospective data on the overall activity and safety of EBRT in GEPNETS. EBRT generally seems to be well tolerated in selected PNET patients with encouraging activity. Well-designed prospective studies in clearly defined populations are required to clarify the role of EBRT in neuroendocrine tumours.
Copyright © 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
V Ratanatharathorn, W E Powers, W T Moss, C A Perez
Bone metastasis: review and critical analysis of random allocation trials of local field treatment.
Int J Radiat Oncol Biol Phys. 1999 Apr 1;44(1):1-18. doi: 10.1016/s0360-3016(98)00510-0.
Abstract/Text
PURPOSE: Compare and contrast reports of random allocation clinical trials of local field radiation therapy of metastases to bone to determine the techniques producing the best results (frequency, magnitude, and duration of benefit), and relate these to the goals of complete relief of pain and prevention of disability for the remaining life of the patient.
METHODS AND MATERIALS: Review all published reports of random allocation clinical trials, and perform a systematic analysis of the processes and outcomes of the several trial reports.
RESULTS: All trials were performed on selected populations of patients with symptomatic metastases and most studies included widely diverse groups with regard to: (a) site of primary tumor, (b) location, extent, size, and nature of metastases, (c) duration of survival after treatment All trial reports lack sufficient detail for full and complete analysis. Much collected information is not now available for reanalysis and many important data sets were apparently never collected. Several of the variations in patient and tumor characteristics were found to be much more important than treatment dose in the outcome results. Treatment planning and delivery techniques were unsophisticated and probably resulted in a systematic delivery of less than the assigned dose to some metastases. In general the use and benefit of retreatment was greater in those patients who initially received lower doses but the basis and dose of retreatment was not documented. Follow-up of patients was varied with a large proportion of surviving patients lost to follow-up in several studies. The greatest difference in the reports is the method of calculation of results. The applicability of Kaplan-Meier actuarial analysis, censoring the lost and dead patients, as used in studies with loss to follow-up of a large number of patients is questionable. The censoring involved is "informative" (the processes of loss relate to the outcome) and not acceptable since it results in artificial elevation of the frequency of response. Overall, higher dose fractionated treatment regimens produced a better frequency, magnitude, and duration of response than lower dose single-fraction regimens. Relapse after initial response was frequent. The "median duration of relief" was much shorter than the "median duration of survival" post-treatment. Thus the "net pain relief" is far less than the goal of pain relief for the total duration of life after treatment.
CONCLUSIONS: The pain relief obtained in all studies is poor and our care practices need to be improved. Many patients never achieved complete relief and for most who did, the duration of relief was much less than their period of survival after treatment. Higher dose, fractionated treatments produced a greater frequency, magnitude, and duration of response with an improved "net pain relief." Additional trials with selection of comparable cases, good definition of extent of disease, exemplary treatment, and complete follow-up are required.
W M Sze, M D Shelley, I Held, T J Wilt, M D Mason
Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy--a systematic review of randomised trials.
Clin Oncol (R Coll Radiol). 2003 Sep;15(6):345-52. doi: 10.1016/s0936-6555(03)00113-4.
Abstract/Text
Recent randomised studies have reported that single fraction radiotherapy is as effective as multifraction radiotherapy in relieving pain caused by bone metastasis. However, there are concerns about the higher re-treatment rates and the efficacy of preventing future complications, such as pathological fracture and spinal cord compression, by single fraction radiotherapy. A systematic review of randomised studies, examining the effectiveness of single fraction radiotherapy versus multiple fraction radiotherapy for metastatic bone pain relief and prevention of bone complications, was conducted to help answer this controversy. Randomised studies comparing single fraction radiotherapy with multifraction radiotherapy on metastatic bone pain were identified. The analyses were performed using intention-to-treat principle. The results were pooled using meta-analysis to estimate the effect of treatment on pain response, re-treatment rate, pathological fracture rate and spinal cord compression rate. Twelve trials involving 3621 sites were included in the meta-analysis. The overall pain-response rates for single fraction radiotherapy and multifraction radiotherapy were 60% (1080/1814) and 59% (1060/1807), respectively, giving an odds ratio (OR) of 1.03 (95% confidence interval [CI] 0.90-1.19), indicating no difference between the two radiotherapy schedules. There was also no difference in complete pain response rates for single fraction radiotherapy (34% [508/1476]) and multifraction radiotherapy (32% [475/1473]), with an OR of 1.10 (950% CI 0.94-1.30). Patients treated by single fraction radiotherapy had a higher re-treatment rate, with 21.5% (267/1240) requiring re-treatment compared with 7.4% (91/1236) of patients in the multifraction radiotherapy arm (OR 3.44 [95% CI 2.67-4.43]). The pathological fracture rate was also higher in single fraction radiotherapy arm patients. Three per cent (37/1240) of patients treated by single fraction radiotherapy developed pathological fracture compared with 1.6% (20/1236) for those treated by multifraction radiotherapy (OR 1.82 [95% CI 1.06-3.11]). The spinal cord compression rates were similar for both arms (OR 1.41 [95% CI 0.72-2.75]). Single fraction radiotherapy was as effective as multifraction radiotherapy in relieving metastatic bone pain. However, the re-treatment rate and pathological fracture rate were higher after single fraction radiotherapy. Studies with quality of life and health economic end points are warranted to find out the optimal treatment option.
