今日の臨床サポート

食道癌

著者: 小澤壯治 多摩丘陵病院 外科・消化器外科

監修: 木下芳一 兵庫県立姫路循環器病センター/製鉄記念広畑病院

著者校正/監修レビュー済:2021/09/22
参考ガイドライン:
  1. 日本食道学会:食道癌診療ガイドライン 2017年版
患者向け説明資料

概要・推奨   

  1. 多量飲酒および喫煙は食道扁平上皮癌の危険因子であり、その発生に強い関連性がある。またアルコール摂取と喫煙を併せるとその危険率はさらに上昇する。
  1. 食道表在癌では色素内視鏡検査やnarrow band imaging(NBI)観察を含む内視鏡検査、拡大内視鏡検査、食道造影検査、超音波内視鏡検査(EUS)などを行い、総合的に診断を行う。狭窄が強く、内視鏡検査が不十分である場合は食道造影検査、EUS、CT、MRI検査にて診断する(推奨度2)。
  1. 食道癌の病期診断において、術前深達度がT1b以深の症例では術前にFDG-PET検査を施行することが推奨される(推奨度2)。
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  1. 低侵襲性、根治性、遠隔治療成績などに関して現時点では研究段階ではあるが、胸腔鏡、腹腔鏡下食道切除再建術や縦隔鏡、腹腔鏡を用いた内視鏡補助下経食道裂孔的非開胸食道抜去術などが報告されている(推奨度2)。食道癌に対する胸腔鏡手術は全国的に普及しており、2016年には約55%の症例に胸腔鏡下手術が行われ、年々増加している[1]
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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:
小澤壯治 : 特に申告事項無し[2021年]
監修:木下芳一 : 講演料(アストラゼネカ,武田,大塚,第一三共)[2021年]

改訂のポイント:
  1. 定期レビューを行った(修正なし)。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 食道癌は、世界中で8番目に多い癌で男性(男女比約6:1)に多い。
  1. 60~70歳代に好発し、占居部位は胸部中部食道が最も多い(48.0%)。
  1. 組織学的に扁平上皮癌と腺癌が2大組織型である。
  1. わが国の食道癌の大半が扁平上皮癌(89.5%:2012年食道学会全国調査)で腺癌は6.0%であった[2]
  1. 食道扁平上皮癌は飲酒、喫煙が危険因子となる。
  1. アセトアルデヒドの代謝酵素活性の低い(アルデヒド脱水素酵素2型 [ALDH2] へテロ欠損型)人がアルコールを常飲すると、体内にアルデヒドが蓄積し扁平上皮癌のリスクを高める。
  1. 食道腺癌の発生には、胃酸の食道への逆流(Gastroesophageal reflux、GER)に起因するバレット食道が危険因子となる。
  1. 食道癌の病期分類は治療方針の決定や予後予測に重要であり、T因子(癌の壁深達度)、N因子(リンパ節転移)、M因子(遠隔臓器転移)により決まる。
  1. 食道癌の治療は病期により内視鏡的治療、外科治療、化学療法、放射線治療を単独もしくは組み合わせて行う。
  1. 食道表在癌の多くが無症状である。
  1. 食道癌の約20%に同時性異時性の他臓器重複癌を認め、胃癌、咽頭癌の順で多い。
  1. ヨード染色に加え、NBI(narrow band Imaging)を用いた消化管内視鏡検査が早期癌の発見に有用である。
 
  1. 食道腺癌(バレット食道腺癌)に関しては、わが国では十分な症例数がなく、適切な手術方法や郭清範囲のコンセンサスは得られていないが、現時点では扁平上皮癌と同等に扱うことが勧められている(推奨度2J)。
  1. まとめ:わが国では症例数が少ないため、食道腺癌(バレット食道腺癌)における術式、郭清範囲に関するRCTはない。海外では、食道腺癌に対する術式に関するRCT(開胸開腹食道切除vs 経裂孔的食道切除)の報告があり、術後合併症において経裂孔による手技が優り、生存率において有意差はないものの、開胸群で優る傾向があった[3]
  1. 説明:食道腺癌における頸部・上縦隔リンパ節郭清の意義については議論が分かれるところである[4][5][6]。症例数は少ないものの、わが国の報告では食道腺癌は扁平上皮癌と同等のリンパ節転移を認めるとする報告が多い[7][8]。食道癌取扱い規約第11版ではリンパ節転移、遠隔臓器転移、壁内転移について扁平上皮癌と同じ扱いにしている[9]
  1. 結論:食道腺癌(バレット食道腺癌)に対する術式にについて、わが国では症例を蓄積し、リンパ節郭清範囲を含めた検討が必要である。
 
  1. 多量飲酒および喫煙は食道扁平上皮癌の危険因子であり、その発生に強い関連性がある。またアルコール摂取と喫煙を併せるとその危険率はさらに上昇する(推奨度2O)。
  1. まとめ:多量飲酒および喫煙と食道扁平上皮癌の発生に関して、複数のコホート研究がある[10][11][12]
  1. 代表事例:アルコールの代謝産物であるアルデヒドを分解するアルデヒド脱水素酵素2(ALDH2)には遺伝子多型があり、ALDH2不活型は大酒家における食道癌のリスクファクターと報告されている[13]
  1. 結論:多量飲酒および喫煙は食道扁平上皮癌の危険因子である。
問診・診察のポイント  
  1. 食道扁平上皮癌では飲酒、喫煙が危険因子となり、食道腺癌ではGERに基づくバレット食道が発生母地となるため、リスクファクターの問診が重要となる。また、食道は頸部・胸部・腹部の広い解剖学的範囲に存在する臓器であり、周囲臓器も占居部位によりさまざまであるため、出現する可能性のある症状も多彩となる。筋層以深に浸潤する食道癌は大部分が有症状で、腫瘍の増大による内腔の狭窄による狭窄感40%、嚥下困難18%などが主症状として出現する。さらに、進行度や発生部位、患者の全身状態により個々の症例への治療方針が大きく異なるが、外科的手術治療はその中心を占める。一般的に手術侵襲が大きくなるため、その適応には重要臓器を中心とした全身状態の把握が必須となる。

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文献 

著者: Committee for Scientific Affairs, The Japanese Association for Thoracic Surgery, Hideyuki Shimizu, Shunsuke Endo, Shoji Natsugoe, Yuichiro Doki, Yasutaka Hirata, Junjiro Kobayashi, Noboru Motomura, Kiyoharu Nakano, Hiroshi Nishida, Morihito Okada, Yoshikatsu Saiki, Aya Saito, Yukio Sato, Kazuo Tanemoto, Yasushi Toh, Hiroyuki Tsukihara, Shinji Wakui, Hiroyasu Yokomise, Munetaka Masuda, Kohei Yokoi, Yutaka Okita
雑誌名: Gen Thorac Cardiovasc Surg. 2019 Apr;67(4):377-411. doi: 10.1007/s11748-019-01068-9.
Abstract/Text
PMID 30877649  Gen Thorac Cardiovasc Surg. 2019 Apr;67(4):377-411. doi・・・
著者: Yuji Tachimori, Soji Ozawa, Hodaka Numasaki, Ryu Ishihara, Hisahiro Matsubara, Kei Muro, Tsuneo Oyama, Yasushi Toh, Harushi Udagawa, Takashi Uno, Registration Committee for Esophageal Cancer of the Japan Esophageal Society
雑誌名: Esophagus. 2019 Jul;16(3):221-245. doi: 10.1007/s10388-019-00674-z. Epub 2019 May 16.
Abstract/Text
PMID 31098822  Esophagus. 2019 Jul;16(3):221-245. doi: 10.1007/s10388-・・・
著者: Jan B F Hulscher, Johanna W van Sandick, Angela G E M de Boer, Bas P L Wijnhoven, Jan G P Tijssen, Paul Fockens, Peep F M Stalmeier, Fiebo J W ten Kate, Herman van Dekken, Huug Obertop, Hugo W Tilanus, J Jan B van Lanschot
雑誌名: N Engl J Med. 2002 Nov 21;347(21):1662-9. doi: 10.1056/NEJMoa022343.
Abstract/Text BACKGROUND: Controversy exists about the best surgical treatment for esophageal carcinoma.
METHODS: We randomly assigned 220 patients with adenocarcinoma of the mid-to-distal esophagus or adenocarcinoma of the gastric cardia involving the distal esophagus either to transhiatal esophagectomy or to transthoracic esophagectomy with extended en bloc lymphadenectomy. Principal end points were overall survival and disease-free survival. Early morbidity and mortality, the number of quality-adjusted life-years gained, and cost effectiveness were also determined.
RESULTS: A total of 106 patients were assigned to undergo transhiatal esophagectomy, and 114 to undergo transthoracic esophagectomy. Demographic characteristics and characteristics of the tumor were similar in the two groups. Perioperative morbidity was higher after transthoracic esophagectomy, but there was no significant difference in in-hospital mortality (P=0.45). After a median follow-up of 4.7 years, 142 patients had died--74 (70 percent) after transhiatal resection and 68 (60 percent) after transthoracic resection (P=0.12). Although the difference in survival was not statistically significant, there was a trend toward a survival benefit with the extended approach at five years: disease-free survival was 27 percent in the transhiatal-esophagectomy group, as compared with 39 percent in the transthoracic-esophagectomy group (95 percent confidence interval for the difference, -1 to 24 percent [the negative value indicates better survival with transhiatal resection]), whereas overall survival was 29 percent as compared with 39 percent (95 percent confidence interval for the difference, -3 to 23 percent).
CONCLUSIONS: Transhiatal esophagectomy was associated with lower morbidity than transthoracic esophagectomy with extended en bloc lymphadenectomy. Although median overall, disease-free, and quality-adjusted survival did not differ statistically between the groups, there was a trend toward improved long-term survival at five years with the extended transthoracic approach.

Copyright 2002 Massachusetts Medical Society
PMID 12444180  N Engl J Med. 2002 Nov 21;347(21):1662-9. doi: 10.1056/・・・
著者: J Rüdiger Siewert, M Feith, M Werner, H J Stein
雑誌名: Ann Surg. 2000 Sep;232(3):353-61.
Abstract/Text OBJECTIVE: To assess the outcome of surgical therapy based on a topographic/anatomical classification of adenocarcinoma of the esophagogastric junction.
SUMMARY BACKGROUND DATA: Because of its borderline location between the stomach and esophagus, the choice of surgical strategy for patients with adenocarcinoma of the esophagogastric junction is controversial.
METHODS: In a large single-center series of 1,002 consecutive patients with adenocarcinoma of the esophagogastric junction, the choice of surgical approach was based on the location of the tumor center or tumor mass. Treatment of choice was esophagectomy for type I tumors (adenocarcinoma of the distal esophagus) and extended gastrectomy for type II tumors (true carcinoma of the cardia) and type III tumors (subcardial gastric cancer infiltrating the distal esophagus). Demographic data, morphologic and histopathologic tumor characteristics, and long-term survival rates were compared among the three tumor types, focusing on the pattern of lymphatic spread, the outcome of surgery, and prognostic factors in patients with type II tumors.
RESULTS: There were marked differences in sex distribution, associated intestinal metaplasia in the esophagus, tumor grading, tumor growth pattern, and stage distribution between the three tumor types. The postoperative death rate was higher after esophagectomy than extended total gastrectomy. On multivariate analysis, a complete tumor resection (R0 resection) and the lymph node status (pN0) were the dominating independent prognostic factors for the entire patient population and in the three tumor types, irrespective of the surgical approach. In patients with type II tumors, the pattern of lymphatic spread was primarily directed toward the paracardial, lesser curvature, and left gastric artery nodes; esophagectomy offered no survival benefit over extended gastrectomy in these patients.
CONCLUSION: The classification of adenocarcinomas of the esophagogastric junction into type I, II, and III tumors shows marked differences between the tumor types and provides a useful tool for selecting the surgical approach. For patients with type II tumors, esophagectomy offers no advantage over extended gastrectomy if a complete tumor resection can be achieved.

PMID 10973385  Ann Surg. 2000 Sep;232(3):353-61.
著者: Xavier Benoît D'Journo, Christophe Doddoli, Pierre Michelet, Anderson Loundou, Delphine Trousse, Roger Giudicelli, Pierre Antoine Fuentes, Pascal Alexandre Thomas
雑誌名: Eur J Cardiothorac Surg. 2005 Apr;27(4):697-704. doi: 10.1016/j.ejcts.2004.12.022.
Abstract/Text OBJECTIVE: Controversy continues over the optimal extent of lymphadenectomy for the surgical treatment of Adenocarcinoma of the oesophagus.
METHODS: From 1996 to 2003, 102 transthoracic en-bloc esophagectomy were performed for adenocarcinoma. Based on the 1994 consensus conference of the International Society of Disease of Esophagus, 35 patients underwent standard lymphadenectomy whereas 67 underwent extended lymphadenectomy. Mortality, morbidity and long-term survival were reviewed in each group.
RESULTS: Extended lymphadenectomy increased the number of resected lymph nodes and improved the healthy/invaded lymph node ratio. It allowed to detect skip nodal metastasis in 36.4% of the N+ patients. Morbidity was higher following extended lymphadenectomy, with respect to pulmonary complications, and blood transfusions requirement (P=0.04). However, operative mortality was similar in both groups (9 vs. 11%). Overall disease-free survival was 28% at 5 years. Median of survival was higher in N0 than in N+ patients (55 months vs. 20 months; P=0.02). Extended lymphadenectomy was associated with an improving of disease-free survival when compared to standard lymphadenectomy (41 vs. 10% at 5 years; P<0.05), especially in the subgroup of patients with a N0 disease (median of survival 44 months vs. 17 months; P=0.001). Based on multivariable analyses, predictive factors of recurrence affecting disease free-survival were the pT status (P=0.02), standard lymphadenectomy (P=0.05) and extracapsular lymph node involvement (0.04).
CONCLUSIONS: These results indicate that extended 2-field lymphadenectomy is an important component of the surgical treatment of patients with adenocarcinoma of the oesophagus. It increases the likelihood of proper staging and affects patient outcome, while it does not enhance the operative mortality. However, extended lymphadenectomy increases non-fatal morbidity, especially the incidence of pulmonary complications and the need for blood transfusion.

PMID 15784377  Eur J Cardiothorac Surg. 2005 Apr;27(4):697-704. doi: 1・・・
著者: Nasser Altorki, Michael Kent, Cathy Ferrara, Jeffrey Port
雑誌名: Ann Surg. 2002 Aug;236(2):177-83. doi: 10.1097/01.SLA.0000021583.51164.F4.
Abstract/Text OBJECTIVE: To determine the prevalence of occult cervical nodal metastases in patients with squamous cell cancer and adenocarcinoma of the esophagus, and to determine the impact of esophagectomy with three-field lymph node dissection on survival and recurrence rates.
SUMMARY BACKGROUND DATA: Although esophagectomy with three-field lymph node dissection is commonly practiced in Japan, its role in the surgical management of esophageal cancer in the United States, especially in patients with esophageal adenocarcinoma, is essentially unknown.
METHODS: This is a prospective observational study of esophagectomy with three-field lymphadenectomy. Eighty patients underwent resection between August 1994 and April 2001. Clinicopathological information and follow-up data were collected on all patients until death or June 2001.
RESULTS: Hospital mortality and morbidity rates were 5% and 46%, respectively. Metastases to the recurrent laryngeal and/or deep cervical nodes occurred in 36% of patients irrespective of cell type (adenocarcinoma 37%, squamous 34%) or location within the esophagus (lower third 32%, middle third 60%). Overall 5-year and disease-free survival rates were 51% and 46%, respectively. Sixty-nine percent presented with nodal metastases. The 5-year survival rate for node-negative patients was 88%; that for those with nodal metastases was 33%. The 5-year survival rate in patients with positive cervical nodes was 25% (squamous 40%, adenocarcinoma 15%).
CONCLUSIONS: Esophagectomy with three-field lymph node dissection can be performed with a low mortality and reasonable morbidity. Unsuspected metastases to the recurrent laryngeal and/or cervical nodes are present in 36% of patients regardless of cell type or location within the esophagus. Thirty percent of patients were upstaged, mainly from stage III to stage IV. An overall 5-year survival rate of 51% suggests a true survival benefit beyond that achieved solely on the basis of stage migration.

PMID 12170022  Ann Surg. 2002 Aug;236(2):177-83. doi: 10.1097/01.SLA.0・・・
著者: J Steevens, L J Schouten, R A Goldbohm, P A van den Brandt
雑誌名: Gut. 2010 Jan;59(1):39-48. doi: 10.1136/gut.2009.191080.
Abstract/Text OBJECTIVE: Alcohol consumption and cigarette smoking may be differentially associated with oesophageal squamous cell carcinoma (OSCC), oesophageal adenocarcinoma (OAC), gastric cardia adenocarcinoma (GCA) and gastric non-cardia adenocarcinoma (GNCA). However, because this was based on retrospective studies, these hypotheses were examined in a prospective cohort.
METHODS: The prospective Netherlands Cohort Study consists of 120 852 participants who completed a baseline questionnaire on diet and other cancer risk factors in 1986. After 16.3 years of follow-up, 107 OSCC, 145 OAC, 164 GCA and 491 GNCA cases were available for analysis using Cox proportional hazards models and the case-cohort approach.
RESULTS: The multivariable adjusted incidence rate ratio (RR) for OSCC was 4.61 (95% CI 2.24 to 9.50) for > or = 30 g ethanol/day compared with abstainers (p trend <0.001), while no associations with alcohol were found for OAC, GCA or GNCA. Compared with never smokers, current smokers had RRs varying from 1.60 for GCA to 2.63 for OSCC, and were statistically significant or borderline statistically significant. Frequency, duration and pack-years of smoking were independently associated with risk of all four cancers. A positive interaction was found between alcohol consumption and smoking status regarding OSCC risk. The RR for current smokers who consumed >15 g/day of ethanol was 8.05 (95% CI 3.89 to 16.60; p interaction = 0.65), when compared with never smokers who consumed <5 g/day of ethanol.
CONCLUSIONS: This prospective study found alcohol consumption to be associated with increased risk of only OSCC. Cigarette smoking was associated with risk of all four cancers.

PMID 19828467  Gut. 2010 Jan;59(1):39-48. doi: 10.1136/gut.2009.191080・・・
著者: Kiyomi Sakata, Yoshiharu Hoshiyama, Seiji Morioka, Tsutomu Hashimoto, Tatsuya Takeshita, Akiko Tamakoshi, JACC Study Group
雑誌名: J Epidemiol. 2005 Jun;15 Suppl 2:S212-9.
Abstract/Text BACKGROUND: Using a large-scale cohort of about 110,000 people established in 45 areas throughout Japan from 1988 through 1990, the study attempted to uncover the joint effects of combined smoking and alcohol intake on esophageal cancer mortality.
METHODS: A cohort established from 1988 through 1990 included 46,465 men and 64,327 women aged 40 years and older and younger than 80. The number of female smokers and drinkers was low, and women were excluded from the analysis for that reason. In addition, 308 people with histories of malignant neoplasm, and 3,579 with unclear smoking and drinking data were also excluded, resulting in 42,578 people available for analysis. A follow-up of these individuals was conducted until 1999. Cox proportional hazards model was used for the analysis.
RESULTS: The joint effects of number of cigarettes and amount of alcohol consumed per day were compared with non-smokers and non-drinkers or those consuming less than one unit of alcohol per day. An increased synergistic esophageal cancer mortality risk (3.88) for both smoking and drinking was observed for those smoking 20 cigarettes or less per day and drinking one unit of alcohol or more but less than three units per day, with the risk rising (6.30) for those smoking at least 21 cigarettes and drinking at least three units of alcohol per day. Even in non-smokers with increased alcohol consumption, and in non-drinkers or those drinking at most one drink per day with increased smoking, no increased risk was observed.
CONCLUSIONS: In this cohort study of a Japanese population, increased esophageal cancer mortality risk was observed only when both factors of alcohol and tobacco intake were present simultaneously.

PMID 16127236  J Epidemiol. 2005 Jun;15 Suppl 2:S212-9.
著者: Seiji Ishiguro, Shizuka Sasazuki, Manami Inoue, Norie Kurahashi, Motoki Iwasaki, Shoichiro Tsugane, JPHC Study Group
雑誌名: Cancer Lett. 2009 Mar 18;275(2):240-6. doi: 10.1016/j.canlet.2008.10.020. Epub 2008 Nov 25.
Abstract/Text We examined the effect of alcohol consumption, cigarette smoking and flushing response on esophageal squamous cell carcinoma (ESCC) in a large-scale population-based cohort study. 44,970 middle-aged and older Japanese men were followed. A total of 215 cases of ESCC were newly diagnosed. Alcohol consumption and cigarette smoking are strongly associated with the incidence of ESCC. Heavy alcohol consumption increased the risk of ESCC especially among heavy smokers with the flushing response (HR = 3.41, 95% CI = 2.10-5.51). Strong effect modification was detected in heavy smokers. Our results suggest that heavy alcohol consumption together with heavy smoking may increase the risk of ESCC particularly in individuals with the flushing response.

PMID 19036500  Cancer Lett. 2009 Mar 18;275(2):240-6. doi: 10.1016/j.c・・・
著者: A Yokoyama, T Ohmori, T Muramatsu, S Higuchi, T Yokoyama, S Matsushita, M Matsumoto, K Maruyama, M Hayashida, H Ishii
雑誌名: Int J Cancer. 1996 Nov 4;68(3):313-6. doi: 10.1002/(SICI)1097-0215(19961104)68:3<313::AID-IJC8>3.0.CO;2-4.
Abstract/Text In this study, 1,000 Japanese male alcoholics were consecutively screened by upper gastrointestinal endoscopy with esophageal iodine staining. Associations among cancer-detection rates, drinking and smoking habits, and aldehyde dehydrogenase-2 (ALDH2) genotypes were evaluated. A total of 53 patients (5.3%) had histologically confirmed cancer. Esophageal cancer was diagnosed in 36, gastric cancer in 17, and oropharyngolaryngeal cancer in 9 patients: 8 of the esophageal-cancer patients were multiple-cancer patients, with additional cancer(s) in the stomach and/or oropharyngolaryngeal region. Multiple logistic regression revealed that use of stronger alcoholic beverages (whisky or shochu) in contrast with lighter beverages (sake or beer) and smoking of 50 pack-years or more increased the risks for esophageal (odds ratio 3.2 and 2.8 respectively), oropharyngolaryngeal (4.8 and 5.1 respectively) and multiple cancer (10.5 and 11.8 respectively). The inactive form of ALDH2, encoded by the gene ALDH2*1/2*2 prevalent in Orientals, exposes them to higher blood levels of acetaldehyde, a recognized animal carcinogen, after drinking. This inactive ALDH2 was detected in 19/36 (52.8%) patients with esophageal cancer, in 5/9 (55.6%) patients with oropharyngolaryngeal cancer, and in 7/8 (87.5%) patients with multiple cancer. All of these gene frequencies far exceeded that in a large alcoholic cohort (80/655, 12.2%). The triple combination of the risk factors of the inactive ALDH2, stronger alcoholic beverages and heavy smoking was more commonly associated with multiple-cancer patients than with patients with esophageal cancer alone (62.5% vs. 7.1%). These results show that the 3 risk factors are important for the development of upper-aerodigestive-tract cancer in Japanese alcoholics. For these high-risk drinkers, regimented screening appears to be indicated.

PMID 8903472  Int J Cancer. 1996 Nov 4;68(3):313-6. doi: 10.1002/(SIC・・・
著者: Manabu Muto, Keiko Minashi, Tomonori Yano, Yutaka Saito, Ichiro Oda, Satoru Nonaka, Tai Omori, Hitoshi Sugiura, Kenichi Goda, Mitsuru Kaise, Haruhiro Inoue, Hideki Ishikawa, Atsushi Ochiai, Tadakazu Shimoda, Hidenobu Watanabe, Hisao Tajiri, Daizo Saito
雑誌名: J Clin Oncol. 2010 Mar 20;28(9):1566-72. doi: 10.1200/JCO.2009.25.4680. Epub 2010 Feb 22.
Abstract/Text PURPOSE: Most of the esophageal squamous cell carcinomas (ESCCs) and cancers of the head and neck (H&N) region are diagnosed at later stages. To achieve better survival, early detection is necessary. We compared the real-time diagnostic yield of superficial cancer in these regions between conventional white light imaging (WLI) and narrow band imaging (NBI) in high-risk patients.
PATIENTS AND METHODS: In a multicenter, prospective, randomized controlled trial, 320 patients with ESCC were randomly assigned to primary WLI followed by NBI (n = 162) or primary NBI followed by WLI (n = 158) in a back-to-back fashion. The primary aim was to compare the real-time detection rates of superficial cancer in the H&N region and the esophagus between WLI and NBI. The secondary aim was to evaluate the diagnostic accuracy of these techniques.
RESULTS: NBI detected superficial cancer more frequently than did WLI in both the H&N region and the esophagus (100% v 8%, P < .001; 97% v 55%, P < .001, respectively). The sensitivity of NBI for diagnosis of superficial cancer was 100% and 97.2% in the H&N region and the esophagus, respectively. The accuracy of NBI for diagnosis of superficial cancer was 86.7% and 88.9% in these regions, respectively. The sensitivity and accuracy were significantly higher using NBI than WLI in both regions (P < .001 and P = .02 for the H&N region; P < .001 for both measures for the esophagus, respectively).
CONCLUSION: NBI could be the standard examination for the early detection of superficial cancer in the H&N region and the esophagus.

PMID 20177025  J Clin Oncol. 2010 Mar 20;28(9):1566-72. doi: 10.1200/J・・・
著者: B E Chatterton, I Ho Shon, A Baldey, N Lenzo, A Patrikeos, B Kelley, D Wong, J E Ramshaw, A M Scott
雑誌名: Eur J Nucl Med Mol Imaging. 2009 Mar;36(3):354-61. doi: 10.1007/s00259-008-0959-y. Epub 2008 Oct 18.
Abstract/Text OBJECTIVES: The aims of this study were (1) to determine the incremental information provided by (18)F-FDG positron emission tomography (PET) in staging patients with oesophageal cancer, and (2) to determine the impact of PET staging on post-PET clinical management of oesophageal cancer, and on prognosis.
METHODS: In a multicentre, single-arm open study, patients with proved oesophageal cancer without definite distant metastases and regarded as suitable for potentially curative treatment were examined by PET. Clinicians were requested to supply a management plan before and another plan after being supplied with the PET scan results. Patients were followed for at least 1 year for outcome analysis.
RESULTS: A total of 129 patients (104 men, mean age 67 y) were recruited. PET detected additional sites of disease in 53 patients (41%). Significant changes in management (high or medium impact) were observed in 38% of patients, primarily as a result of identifying additional sites of disease and/or confirming previously equivocal regional and distant metastases. Progression-free survival was significantly shorter in patients found to have additional lesions on PET (p < 0.05), but was not related to SUV(max).
CONCLUSION: These findings demonstrate the significant impact of PET on the clinical management of patients with newly diagnosed oesophageal carcinoma, and on prognostic stratification of these patients.

PMID 18931839  Eur J Nucl Med Mol Imaging. 2009 Mar;36(3):354-61. doi:・・・
著者: H L van Westreenen, M Westerterp, G W Sloof, H Groen, P M M Bossuyt, P L Jager, E F Comans, H M van Dullemen, P Fockens, J Stoker, E J van der Jagt, J J B van Lanschot, J T M Plukker
雑誌名: Br J Surg. 2007 Dec;94(12):1515-20. doi: 10.1002/bjs.5708.
Abstract/Text BACKGROUND: The detection of distant metastases in patients with oesophageal cancer may be improved with [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET), preventing unnecessary surgical explorations. The aim of this study was to assess the additional value of FDG-PET after a state-of-the-art preoperative staging protocol.
METHODS: All patients in this prospective cohort study were staged with multidetector computed tomography, endoscopic ultrasonography and external ultrasonography of the neck, both combined with selective fine-needle aspiration cytology. Patients considered eligible for curative surgery after these investigations underwent FDG-PET.
RESULTS: FDG-PET revealed suspicious hot spots in 30 (15.1 per cent) of 199 patients. Metastases were confirmed in eight (4.0 per cent). In six of these, distant metastases were confirmed before surgery, but exploratory surgery was necessary for histological confirmation in the other two. All eight upstaged patients had clinical stage III-IV disease before FDG-PET (6.6 per cent of 122 with stage III-IV disease). In seven patients (3.5 per cent) hot spots appeared to be synchronous neoplasms, mainly colonic polyps. However, those in the remaining 15 (7.5 per cent) were false positive, leading to unnecessary additional investigations.
CONCLUSION: FDG-PET improves the selection of patients with oesophageal cancer for potentially curative surgery, especially in stages III-IV. However, the diagnostic benefit is limited after state-of-the-art staging, and so broad implementation in daily clinical practice is questionable.

Copyright (c) 2007 British Journal of Surgery Society Ltd.
PMID 17902092  Br J Surg. 2007 Dec;94(12):1515-20. doi: 10.1002/bjs.57・・・
著者: C Katada, M Muto, K Momma, M Arima, H Tajiri, C Kanamaru, H Ooyanagi, H Endo, T Michida, N Hasuike, I Oda, T Fujii, D Saito
雑誌名: Endoscopy. 2007 Sep;39(9):779-83. doi: 10.1055/s-2007-966761.
Abstract/Text BACKGROUND AND STUDY AIMS: Endoscopic mucosal resection (EMR) is now commonly indicated for esophageal squamous cell carcinoma (ESCC) within the lamina propria mucosa. However, EMR for ESCC that has invaded the muscularis mucosa is controversial because the risk of lymph node metastasis is not negligible. We conducted a multicenter retrospective cohort study to investigate the incidence of lymph node metastasis and survival after EMR for ESCC invading the muscularis mucosa.
PATIENTS AND METHODS: A total of 104 patients with 111 lesions invading the muscularis mucosa, were retrospectively studied at eight institutes. No patients exhibited evidence of metastasis of lymph nodes or distant organs prior to EMR. Overall and cause-specific survival rates were calculated from the date of EMR to the date of death or the most recent follow-up visit. Survival curves were plotted according to the Kaplan-Meier method.
RESULTS: In total, 86 patients (82.7%) who did not receive further treatment such as chemotherapy, irradiation therapy, chemoradiotherapy, or esophagectomy after EMR were followed up. Only two patients (1.9%) developed lymph node metastasis after EMR. With a median follow-up period of 43 months (range, 8-134 months), overall and cause-specific survival rates at 5 years after EMR were 79.5% and 95.0%, respectively.
CONCLUSIONS: EMR for ESCC that invades the muscularis mucosa has curative potential as a minimally invasive treatment option.

PMID 17703385  Endoscopy. 2007 Sep;39(9):779-83. doi: 10.1055/s-2007-9・・・
著者: Yuichi Shimizu, Hiroyuki Tsukagoshi, Masahiro Fujita, Masao Hosokawa, Mototsugu Kato, Masahiro Asaka
雑誌名: Gastrointest Endosc. 2002 Sep;56(3):387-90.
Abstract/Text BACKGROUND: Endoscopic mucosal resection is recommended for squamous cell carcinoma of the esophagus confined to the lamina propria. However, endoscopic mucosal resection is often performed in patients with tumors that invade the muscularis mucosa or upper submucosa to minimize surgical invasiveness, despite the increased risk of lymph node metastasis. This study prospectively evaluated long-term outcome in such patients.
METHODS: Twenty-six consecutive patients with squamous cell esophageal carcinoma invading the muscularis mucosa or submucosa who underwent endoscopic mucosal resection from June 1992 through March 2000 (extended endoscopic mucosal resection group) were studied. As control group, 44 consecutive patients with esophageal carcinoma invading the muscularis mucosae or upper third of the submucosa and no preoperative evidence of lymph node metastasis who underwent esophagectomy during the same period (surgical resection group) were studied.
RESULTS: Overall survival rates at 5 years in the extended endoscopic mucosal resection group and surgical resection group were, respectively, 77.4% and 84.5%. There was no significant difference between survival distributions. Cause-specific survival rates at 5 years in extended endoscopic mucosal resection and surgical resection groups were, respectively, 95.0% and 93.5%. Survival curves for the groups were similar.
CONCLUSION: Although patients were not randomized to extended endoscopic mucosal resection or surgical resection in this study, the results suggest that endoscopic mucosal resection may be safe and effective for management of squamous cell esophageal carcinoma invading the muscularis mucosae or upper submucosa.

PMID 12196777  Gastrointest Endosc. 2002 Sep;56(3):387-90.
著者: H Mizuta, I Nishimori, Y Kuratani, Y Higashidani, T Kohsaki, S Onishi
雑誌名: Dis Esophagus. 2009;22(7):626-31. doi: 10.1111/j.1442-2050.2009.00954.x. Epub 2009 Mar 6.
Abstract/Text Endoscopic submucosal dissection (ESD) has been utilized as an alternative treatment to endoscopic mucosal resection for superficial esophageal cancer. We aimed to evaluate the complications associated with esophageal ESD and elucidate predictive factors for post-ESD stenosis. The study enrolled a total of 42 lesions of superficial esophageal cancer in 33 consecutive patients who underwent ESD in our department. We retrospectively reviewed ESD-associated complications and comparatively analyzed regional and technical factors between cases with and without post-ESD stenosis. The regional factors included location, endoscopic appearance, longitudinal and circumferential tumor sizes, depth of invasion, and lymphatic and vessel invasion. The technical factors included longitudinal and circumferential sizes of mucosal defects, muscle disclosure and cleavage, perforation, and en bloc resection. Esophageal stenosis was defined when a standard endoscope (9.8 mm in diameter) failed to pass through the stenosis. The results showed no cases of delayed bleeding, three cases of insidious perforation (7.1%), two cases of endoscopically confirmed perforation followed by mediastinitis (4.8%), and seven cases of esophageal stenosis (16.7%). Monovalent analysis indicated that the longitudinal and circumferential sizes of the tumor and mucosal defect were significant predictive factors for post-ESD stenosis (P < 0.005). Receiver operating characteristic analysis showed the highest sensitivity and specificity for a circumferential mucosal defect size of more than 71% (100 and 97.1%, respectively), followed by a circumferential tumor size of more than 59% (85.7 and 97.1%, respectively). It is of note that the success rate of en bloc resection was 95.2%, and balloon dilatation was effective for clinical symptoms in all seven patients with post-ESD stenosis. In conclusion, the most frequent complication with ESD was esophageal stenosis, for which the sizes of the tumor and mucosal defect were significant predictive factors. Although ESD enables large en bloc resection of esophageal cancer, practically, in cases with a lesion more than half of the circumference, great care must be taken because of the high risk of post-ESD stenosis.

PMID 19302207  Dis Esophagus. 2009;22(7):626-31. doi: 10.1111/j.1442-2・・・
著者: Chikatoshi Katada, Manabu Muto, Tetsuro Manabe, Narikazu Boku, Atsushi Ohtsu, Shigeaki Yoshida
雑誌名: Gastrointest Endosc. 2003 Feb;57(2):165-9. doi: 10.1067/mge.2003.73.
Abstract/Text BACKGROUND: Although bleeding and perforation are generally recognized major complications of endoscopic mucosal resection, esophageal stricture after endoscopic mucosal resection has not been well studied. Factors associated with the occurrence and severity of esophageal stenosis after endoscopic mucosal resection were investigated.
METHODS: Two hundred sixteen superficial esophageal lesions in 137 consecutive patients who underwent endoscopic mucosal resection from February 1993 through March 2001 were retrospectively studied. The circumferential extent of the mucosal defect after endoscopic mucosal resection was classified into 4 groups: under one fourth, one fourth to one half, one half to three fourths, and over three fourths. The longitudinal length of the mucosal defect was also evaluated. Stenosis was diagnosed when a standard endoscope (11-mm diameter) could not be passed through the stricture.
RESULTS: Esophageal stenosis developed after endoscopic mucosal resection of 13 lesions (6.0%). In all these cases endoscopic mucosal resection resulted in a mucosal defect that involved over three fourths of the luminal circumference. In the subgroup of patients with mucosal defects involving over three fourths of the circumference, those with a mucosal defect over 30 mm long required more frequent balloon dilatation (mean 8 [4.3] times) and the stenosis was of longer duration (mean 16 [17.7] months) than those with defects 30 mm or less in length (respectively, 1 [0.6] times and 2 [1.9] months).
CONCLUSIONS: A circumferential mucosal defect involving over three fourths the circumference of the esophagus after endoscopic mucosal resection was significantly associated with the subsequent development of esophageal stenosis. In addition, mucosal defects longer than 30 mm were associated with greater severity of stenosis. When endoscopic mucosal resection is performed for superficial esophageal lesions, removal of excess mucosa should be avoided.

PMID 12556777  Gastrointest Endosc. 2003 Feb;57(2):165-9. doi: 10.1067・・・
著者: Yukinori Kurokawa, Manabu Muto, Keiko Minashi, Narikazu Boku, Haruhiko Fukuda, Gastrointestinal Oncology Study Group of Japan Clinical Oncology Group (JCOG)
雑誌名: Jpn J Clin Oncol. 2009 Oct;39(10):686-9. doi: 10.1093/jjco/hyp078. Epub 2009 Aug 24.
Abstract/Text Standard treatment for clinical stage I esophageal cancer with submucosal invasion (T1b) has been surgical resection. We conducted a Phase II trial to evaluate the efficacy and the safety of combined treatment of endoscopic mucosal resection (EMR) and chemoradiotherapy for clinical stage I (T1b) esophageal cancer. Patients diagnosed as having clinical stage I (T1b) esophageal cancer which is considered to be resectable by EMR are eligible. When pathological examination of the EMR specimen confirms T1b tumor with negative or positive resection margin, the patient undergoes chemoradiotherapy. The study continues until 82 patients with T1b tumor with negative resection margin are enrolled from 20 institutions. The primary endpoint is 3-year overall survival (OS) in pT1b cases with negative resection margin. The secondary endpoints are 3-year OS and progression-free survival in all eligible cases, OS in pT1a-MM cases with margin-negative, complications of EMR and adverse events of chemoradiotherapy. The data from this trial will be expected to provide a non-surgical treatment option to the patients with clinical stage I (T1b) esophageal cancer.

PMID 19703839  Jpn J Clin Oncol. 2009 Oct;39(10):686-9. doi: 10.1093/j・・・
著者: K Isono, H Sato, K Nakayama
雑誌名: Oncology. 1991;48(5):411-20.
Abstract/Text In order to determine the operative indications of three-field lymph node dissection of esophageal cancer, attempts were made to collect data concerning procedures performed between 1983 and 1989 in major institutions in Japan, and the results from institutions performing three-field or two-field lymph node dissection were compared. The treatment results of three-field lymph node dissection were better than those after two-field dissection, except for early or advanced cancer. The survival rate improved by the three-field as compared with the two-field lymph node dissection; however, since surgery was invasive, some complications such as recurrent nerve paralysis were frequent. The results show that the indication of three-field lymph node dissection has to be carefully determined for each patient.

PMID 1745490  Oncology. 1991;48(5):411-20.
著者: Y Tabira, N Kitamura, M Yoshioka, M Tanaka, K Nakano, N Toyota, T Mori
雑誌名: J Cardiovasc Surg (Torino). 1999 Oct;40(5):737-40.
Abstract/Text BACKGROUND: Significance of three-field lymhpadenectomy for carcinoma of the thoracic esophagus was examined retrospectively based on depth of tumor infiltration, lymph nodal involvements and long-term survival.
METHODS: One hundred and fifty-two consecutive patients who underwent curative esophagectomy for thoracic carcinoma invading to submucosa (pT1) or deeper layers of the esophageal wall from 1983 to 1996 were examined. Sixty-six patients underwent three-field lymphadenectomy (3F) and 86 underwent two-field lymphadenectomy (2F). Survival curves were compared between 3F and 2F after stratifications according to depth of tumor infiltration, the number of positive nodes (0, 1 to 4, 5 or more), and positive intrathoracic recurrent nerve-chain nodes.
RESULTS: Overall 5-year survival rate for 3F was 43.8%, while it was 30.2% for 2F (p = 0.07). In 41 patients with pT1 cancers, the 5-year survival rate for 3F was 55.7%, while it was 41.4% for 2F (p = NS). In patients with cancers invading to muscularis propria (pT2), the 5-year survival rate for 3F was 49.4%, while it was 30.7% for 2F (p = 0.06). In patients with tumors invading to adventitia, there was no significant difference. In patients with one to four positive nodes, the 5-year survival rates for 3F was 50.1%, while it was 24.1% for 2F (p = 0.01). There was no significant difference in the subgroups with no positive nodes and five or more. In subgroups with positive recurrent nerve-chain nodes, the 5-year survival rate for 3F was 27.9%, while it was 0% for 2F (p = 0.01).
CONCLUSIONS: Significance of three-field lymphadenectomy was found in patients with one to four positive nodes or positive intrathoracic recurrent nerve-chain nodes.

PMID 10597014  J Cardiovasc Surg (Torino). 1999 Oct;40(5):737-40.
著者: H Akiyama, M Tsurumaru, H Udagawa, Y Kajiyama
雑誌名: Ann Surg. 1994 Sep;220(3):364-72; discussion 372-3.
Abstract/Text OBJECTIVE: The authors documented the localization and frequency of lymphatic spread in squamous cell carcinoma of the thoracic esophagus and evaluated the influence of radical systematic lymph node dissection on patient survival.
SUMMARY BACKGROUND DATA: From accumulated surgical experience, it was suggested that some of the patients with lymph nodal involvement from cancer could be cured by its clearance. However, it is only recently that cancer of the esophagus has been evaluated in terms of analyzing lymphatic spread and results of lymphadenectomy.
METHODS: Among 1298 patients admitted to the Toranomon Hospital between 1973 and 1993, 913 (70.3%) had resections, including curative and palliative procedures. For this study, 717 patients with TNM RO (resection with no residual tumor at operation in TNM classification) were analyzed. Survival was compared between groups of patients with less extensive thoracoabdominal (two-field) dissections and extensive collothoracoabdominal (three-field) dissections.
RESULTS: Comparative study revealed that 5-year survival rate for TNM RO patients after free-field dissection (55.0%) was significantly better (log rank test, p = 0.0013) than the rate after two-field dissection (38.3%). The results were particularly significant in subgroups with stage III and IV (because of nodal factor). Overall 5-year survival rate after all resections was 42.4%.
CONCLUSIONS: The role of radical lymph node dissection in cancer of the thoracic esophagus evaluated. Long-term survival was compared between two groups with two- and three-field dissection. It was concluded that survival rate was significantly better in patients with extensive three-field dissection.

PMID 8092902  Ann Surg. 1994 Sep;220(3):364-72; discussion 372-3.
著者: T Nozoe, Y Kakeji, H Baba, Y Maehara
雑誌名: Dis Esophagus. 2005;18(4):226-9. doi: 10.1111/j.1442-2050.2005.00482.x.
Abstract/Text Significance of extended radical surgical treatment including three-field lymph node dissection for squamous cell carcinoma (SCC) of the esophagus remains debatable. The aim of the current study was to reconsider the merits and demerits obtained by three-field lymph node dissection for esophageal carcinoma and also to attempt to elucidate an appropriate surgical strategy for submucosal SCC of the thoracic esophagus. Thirty-one patients with SCC of the thoracic esophagus who had been treated with esophagectomy and two-field (thoracic and abdominal) lymph node dissection without preoperative therapies were enrolled. Five-year survival rate was 75.0% and the incidence proportion of postoperative complication was 9.7%. These data regarding postoperative outcome of patients were by no means inferior to those in the previous reports referring the prognosis of patients with esophageal carcinoma who had been treated with three-field lymph node dissection. Authors would like to mention that two-field lymph node dissection associated with reduced incidence of postoperative complications might be enough to treat the submucosal SCC of the thoracic esophagus.

PMID 16128778  Dis Esophagus. 2005;18(4):226-9. doi: 10.1111/j.1442-20・・・
著者: Nobuhiro Sato, Keisuke Koeda, Kenichiro Ikeda, Yusuke Kimura, Kiichi Aoki, Takeshi Iwaya, Yuji Akiyama, Kaoru Ishida, Kazuyoshi Saito, Shigeatsu Endo
雑誌名: Ann Surg. 2002 Aug;236(2):184-90. doi: 10.1097/01.SLA.0000022025.67985.53.
Abstract/Text OBJECTIVE: To investigate whether preoperative corticosteroid administration plays a role in attenuating postoperative morbidity.
SUMMARY BACKGROUND DATA: There is as yet no consensus on the beneficial effects of steroids in alleviating surgical stress.
METHODS: A total of 66 patients undergoing surgery for thoracic esophageal cancer were randomly categorized preoperatively into two groups of 33 patients each. One group was administered an intravenous infusion of methylprednisolone (10 mg/kg body weight) 30 minutes before the surgery (MP group), while the other group received a placebo infusion (control group). The primary endpoint was organ system failure during the first 7 days after surgery. Comparisons of surgery-related complications, cytokine responses, and blood counts were also made between the two groups.
RESULTS: The percentage of patients in the MP group who had one or more organ system failures was 33%, significantly lower than the corresponding percentage of 61% in the control group. The surgery-related complication rate and long-term survival rate were similar in the two groups. The peak plasma levels of interleukin (IL)-1 receptor antagonist, IL-6, and IL-8 were significantly lower in the MP group than in the control group. Changes in the plasma levels of IL-10 were significantly larger in the MP group. No significant differences in the circulating lymphocyte and neutrophil counts were observed between the groups.
CONCLUSIONS: The results suggest that prophylactic administration of corticosteroids is associated with a decrease in postoperative morbidity in patients undergoing invasive surgery. The laboratory data suggest that corticosteroids may attenuate surgical stress-induced inflammatory responses both directly by suppressing the release of proinflammatory cytokines and via inducing IL-10 synthesis.

PMID 12170023  Ann Surg. 2002 Aug;236(2):184-90. doi: 10.1097/01.SLA.0・・・
著者: Masahiko Yano, Masaaki Taniguchi, Toshimasa Tsujinaka, Yoshiyuki Fujiwara, Takushi Yasuda, Hitoshi Shiozaki, Morito Monden
雑誌名: Hepatogastroenterology. 2005 Mar-Apr;52(62):481-5.
Abstract/Text BACKGROUND/AIMS: This study examined whether or not preoperative administration of methylprednisolone reduces perioperative systemic inflammatory response and thus can offer clinical benefit to patients.
METHODOLOGY: Forty patients with thoracic esophageal cancer who were scheduled for esophagectomy with lymphadenectomy were randomly allocated to either of the following two groups: 20 patients received methylprednisolone (500 mg/body) in saline 2 hours before surgery and another 20 patients received a placebo (saline alone). The effects on the early clinical course were assessed by rectal intramucosal pH (pHi) as a marker of systemic oxygenation, water balance, serum cytokine levels and the incidence of postoperative complications. The effects on the late clinical course were examined by comparing patient survival time.
RESULTS: Rectal pHi value, water balance, blood balance and body weight change did not significantly differ between the two groups. Serum proinflammatory cytokine (interleukin-6 and interleukin-8) levels were significantly higher in the control group than the methylprednisolone group 2 hours after surgery. Serum C-reactive protein was also significantly higher in the control group on postoperative day 2 and 3. No significant differences were seen in the incidence of postoperative complications. Survival curves for the two groups did not statistically differ.
CONCLUSIONS: Preoperative methylprednisolone significantly reduces inflammatory cytokine response immediately after surgery for esophageal cancer, but its clinical benefit remains unclear.

PMID 15816462  Hepatogastroenterology. 2005 Mar-Apr;52(62):481-5.
著者: Edgard Engelman, Cécile Maeyens
雑誌名: J Gastrointest Surg. 2010 May;14(5):788-804. doi: 10.1007/s11605-010-1168-0. Epub 2010 Mar 13.
Abstract/Text BACKGROUND: Eight clinical trials involving the administration of preoperative i.v. methylprednisolone have been undertaken in order to decrease the considerable inflammatory response to esophageal resection, in an effort to decrease the supposedly associated morbidity and mortality
METHOD: A meta-analysis was performed for eight clinical end-points. Due to quality problems in seven of the eight included studies, a Bayesian meta-analysis using a skeptical prior derived from the results of the classical analysis was also performed.
RESULTS: The end-points including any organ dysfunction (OR = 0.30), respiratory complication (OR = 0.41), sepsis (OR = 0.37), liver dysfunction (OR = 18), cardiovascular dysfunction (OR = 0.28), and surgical anastomotic leak (OR = 0.42) were significantly decreased by methylprednisolone pretreatment. Following the Bayesian analysis, despite the use of skeptical priors, there is a 95% probability to obtain a relative risk reduction of at least 23% to 54%, depending of the end-point, by methylprednisolone pretreatment.
CONCLUSION: We are in the presence of a potential benefit that cannot be accepted at face value due to the quality problems of the included studies. But in the presence of a remaining potential benefit after a Bayesian analysis starting from a skeptical prior, the best option would be the planning of a large multicenter prospective randomized study.

PMID 20229072  J Gastrointest Surg. 2010 May;14(5):788-804. doi: 10.10・・・
著者: T Akaishi, I Kaneda, N Higuchi, Y Kuriya, J Kuramoto, T Toyoda, A Wakabayashi
雑誌名: J Thorac Cardiovasc Surg. 1996 Dec;112(6):1533-40; discussion 1540-1.
Abstract/Text OBJECTIVE: Total esophagectomy with en bloc mediastinal lymphadenectomy for cancer carries a substantial morbidity and mortality rate. To investigate the feasibility of thoracoscopic technique, we carried out an extensive laboratory study. Encouraged by our excellent results, we conducted a clinical trial.
METHODS: From September 1994 to September 1995, 39 patients thoracic esophageal cancer lesions not invading surrounding organs underwent total esophagectomy with mediastinal lymphadenectomy by means of thoracoscopy. Ages ranged from 47 to 86 years. The procedures were conventional except for the thoracic portion, which was performed as a thoracoscopic procedure with six trocar holes instead of thoracotomy. All harvested lymph nodes were counted for each station. Spirometric data and plethysmographically determined vital capacity were measured before and after operation for all patients.
RESULTS: All procedures were accomplished as scheduled, and none was converted to open thoracotomy. The operating time was 200 +/- 41 minutes (mean +/- standard deviation). Estimated blood loss was 270 +/- 157 ml. The harvested lymph nodes numbered 19.7 +/- 11.1 per patient. Seventeen patients (45%) had positive lymph nodes. There were no in-hospital deaths within 30 days. Twenty-two patients did not require postoperative ventilatory support. Vital capacity decreased to 85% +/- 11% of the preoperative values, and forced expiratory volume in 1 second decreased to 82% +/- 16%.
CONCLUSIONS: Thoracoscopic mediastinal lymphadenectomy is technically feasible, and its completeness is comparable to that of the open technique. The decline in pulmonary function is significantly less than that seen in our previous experience with the open technique.

PMID 8975845  J Thorac Cardiovasc Surg. 1996 Dec;112(6):1533-40; disc・・・
著者: H Osugi, M Takemura, M Higashino, N Takada, S Lee, H Kinoshita
雑誌名: Br J Surg. 2003 Jan;90(1):108-13. doi: 10.1002/bjs.4022.
Abstract/Text BACKGROUND: A direct comparison of open operation and video-assisted thoracoscopic surgery (VATS) for radical oesophagectomy has yet to be published.
METHODS: Medical records of 149 patients with oesophageal squamous cell carcinoma who underwent oesophagectomy and three-field lymphadenectomy were reviewed. Seventy-seven patients had the thoracic procedure performed via a 5-cm minithoracotomy and four ports (VATS group); the others were operated on by conventional posterolateral thoracotomy (open group).
RESULTS: The mean number of retrieved mediastinal nodes, blood loss and morbidity were similar in the VATS and open groups (33.9 versus 32.8 nodes, 284 versus 310 g, and 32 versus 38 per cent respectively). The thoracic procedure took longer in patients having VATS than in the control group (227 versus 186 min; P = 0.031). Vital capacity reduction was less with VATS than in the open group (15 versus 22 per cent; P = 0.016). The 3- and 5-year survival rates were similar: 70 and 55 per cent respectively for VATS compared with 60 and 57 per cent for the open procedure.
CONCLUSION: VATS provides comparable results to open radical oesophagectomy, with less surgical trauma.

Copyright 2003 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd
PMID 12520585  Br J Surg. 2003 Jan;90(1):108-13. doi: 10.1002/bjs.4022・・・
著者: Bernard M Smithers, David C Gotley, Ian Martin, Janine M Thomas
雑誌名: Ann Surg. 2007 Feb;245(2):232-40. doi: 10.1097/01.sla.0000225093.58071.c6.
Abstract/Text OBJECTIVE: We report patient outcomes from esophageal resection with respect to morbidity and cancer survival comparing open thoracotomy and laparotomy (Open), with a thoracoscopic/laparotomy approach (Thoracoscopic-Assisted) and a total thoracoscopic/laparoscopic approach (Total MIE).
METHODS: From a prospective database of all patients managed with cancer of the esophagus or esophagogastric junction, patients who had a resection using one of three techniques were analyzed to assess postoperative variables, adequacy of cancer clearance, and survival.
RESULTS: The number of patients for each procedure was as follows: Open, 114; Thoracoscopic-Assisted, 309; and Total MIE, 23. The groups were comparable with respect to preoperative variables. The differences in the postoperative variables were: less median blood loss in the Thoracoscopic-Assisted (400 mL) and Total MIE (300 mL) groups versus Open (600 mL); longer time for Total MIE (330 minutes) versus Thoracoscopic-Assisted (285 minutes) and Open (300 minutes); longer median time in hospital for Open (14 days) versus Thoracoscopic-Assisted (13 days), Total MIE (11 days) and less stricture formation in the Open (6.1%) versus Thoracoscopic-Assisted (21.6%), Total MIE (36%). There were no differences in lymph node retrieval for each of the approaches. Open had more stage III patients (65.8%) versus Thoracoscopic-Assisted (34.4%), Total MIE (52.1%). There was no difference in survival when the groups were compared stage for stage for overall median or 3-year survival.
CONCLUSION: Minimally invasive techniques to resect the esophagus in patients with cancer were confirmed to be safe and comparable to an open approach with respect to postoperative recovery and cancer survival.

PMID 17245176  Ann Surg. 2007 Feb;245(2):232-40. doi: 10.1097/01.sla.0・・・
著者: James D Luketich, Miguel Alvelo-Rivera, Percival O Buenaventura, Neil A Christie, James S McCaughan, Virginia R Litle, Philip R Schauer, John M Close, Hiran C Fernando
雑誌名: Ann Surg. 2003 Oct;238(4):486-94; discussion 494-5. doi: 10.1097/01.sla.0000089858.40725.68.
Abstract/Text OBJECTIVE: To assess our outcomes after minimally invasive esophagectomy (MIE).
SUMMARY BACKGROUND DATA: Esophagectomy has traditionally been performed by open methods. Results from most series include mortality rates in excess of 5% and hospital stays frequently greater than 10 days. MIE has the potential to improve these results, but only a few small series have been reported. This report summarizes our experience of 222 cases.
METHODS: From 1996 to 2002, MIE was performed in 222 patients. Indications for operation included high-grade dysplasia (n = 47) and cancer (n = 175). Neoadjuvant chemotherapy was used in 78 (35.1%) and radiation in 36 (16.2%). Initially, a laparoscopic transhiatal approach was used (n = 8), but subsequently our approach evolved to include thoracoscopic mobilization (n = 214).
RESULTS: There were 186 men and 36 women. Median age was 66.5 years (range, 39-89). Nonemergent conversion to open procedure was required in 16 patients (7.2%). MIE was successfully completed in 206 (92.8%) patients. The median intensive care unit stay was 1 day (range, 1-30); hospital stay was 7 days (range, 3-75). Operative mortality was 1.4% (n = 3). Anastomotic leak rate was 11.7% (n = 26). At a mean follow-up of 19 months (range, 1-68), quality of life scores were similar to preoperative values and population norms. Stage specific survival was similar to open series.
CONCLUSIONS: MIE offers results as good as or better than open operation in our center with extensive minimally invasive and open experience. In this single institution experience, we observed a lower mortality rate (1.4%) and shorter hospital stay (7 days) than most open series. Given these results, we are now developing an intergroup trial (ECOG 2202) to assess MIE in a multicenter setting.

PMID 14530720  Ann Surg. 2003 Oct;238(4):486-94; discussion 494-5. doi・・・
著者: Urs Zingg, Alexander McQuinn, Dennis DiValentino, Adrian J Esterman, Justin R Bessell, Sarah K Thompson, Glyn G Jamieson, David I Watson
雑誌名: Ann Thorac Surg. 2009 Mar;87(3):911-9. doi: 10.1016/j.athoracsur.2008.11.060.
Abstract/Text BACKGROUND: Minimally invasive esophagectomy (MIE) compared with open esophagectomy (OE) has been shown to have clinical advantages, but selection bias is present.
METHODS: All patients undergoing MIE or OE for cancer between 1999 and 2007 were eligible for analysis. To minimize selection bias, only patients who also met the selection criteria for the thoracoscopic approach were included in the open esophagectomy group.
RESULTS: Fifty-six patients underwent MIE and 98 OE. No significant differences in demographics or pathologic data between groups occurred, with the exception of thoracic epidural analgesia (OE 98%, MIE 71.1%, p < 0.001), and neoadjuvant treatment (OE 50.5%, MIE 71.4%, p = 0.016). Morbidity and in-hospital death were not significantly different. Duration of surgery was longer in MIE (250 vs 209 minutes, p < 0.001) and blood loss less (320 mL vs 857 mL, p < 0.001). Intensive care unit stay was shorter in MIE (3.0 vs 6.8 days, p = 0.022). The relative risk (RR) for in-hospital death was 0.57 (p = 0.475) if the patients underwent MIE. After adjusting for thoracic epidural analgesia, the RR was 0.29 (p = 0.213) for the MIE group. The RR for surgical morbidity was 1.47 (p = 0.154) for patients undergoing MIE. Neoadjuvant treatment increased the RR for surgical morbidity to 1.78 (p = 0.028). No difference between the two groups concerning survival occurred.
CONCLUSIONS: The MIE is comparable with the OE. In MIE, neoadjuvant treatment increased the risk of surgical morbidity. Thoracic epidural analgesia in MIE reduced the risk of in-hospital death and should be considered for all patients undergoing esophagectomy.

PMID 19231418  Ann Thorac Surg. 2009 Mar;87(3):911-9. doi: 10.1016/j.a・・・
著者: H Osugi, M Takemura, M Higashino, N Takada, S Lee, M Ueno, Y Tanaka, K Fukuhara, Y Hashimoto, Y Fujiwara, H Kinoshita
雑誌名: Surg Endosc. 2003 Mar;17(3):515-9. doi: 10.1007/s00464-002-9075-4. Epub 2002 Oct 29.
Abstract/Text BACKGROUND: The efficacy of thoracoscopic radical esophagectomy for cancer of the thoracic esophagus and the learning curve required have yet to be clearly established.
METHODS: Eighty treatment-naive patients with esophageal cancer without contiguous spread underwent esophageal mobilization and extensive mediastinal lymphadenectomy through a 5-cm minithoracotomy and four trocar ports. The outcomes in the first 34 patients (group 1) and the last 46 patients (group 2) were compared.
RESULTS: There were no differences in background or clinicopathologic factors between the two groups. The duration of the thoracoscopic procedure and blood loss were less (p <0.0001), the incidence of postoperative pulmonary infection was less (p = 0.0127), and the number of mediastinal nodes retrieved was greater (p = 0.0076) in group 2. Multivariate analysis demonstrated that surgical experience (number of cases performed) predicted the risk of pulmonary infection (p = 0.0331).
CONCLUSION: Video-assisted thoracoscopic radical esophagectomy can be performed with safety and efficacy comparable to those of open esophagectomy. Morbidity decreases with the surgeon's experience.

PMID 12399847  Surg Endosc. 2003 Mar;17(3):515-9. doi: 10.1007/s00464-・・・
著者: Nobutoshi Ando, Hoichi Kato, Hiroyasu Igaki, Masayuki Shinoda, Soji Ozawa, Hideaki Shimizu, Tsutomu Nakamura, Hiroshi Yabusaki, Norio Aoyama, Akira Kurita, Kenichiro Ikeda, Tatsuo Kanda, Toshimasa Tsujinaka, Kenichi Nakamura, Haruhiko Fukuda
雑誌名: Ann Surg Oncol. 2012 Jan;19(1):68-74. doi: 10.1245/s10434-011-2049-9. Epub 2011 Aug 31.
Abstract/Text BACKGROUND: Patients with esophageal carcinoma receiving postoperative chemotherapy showed superior disease-free survival than those receiving surgery alone in a Japan Clinical Oncology Group trial (JCOG9204). The purpose of this study was to evaluate optimal perioperative timing-that is, before or after surgery-for providing chemotherapy in patients with locally advanced esophageal squamous cell carcinoma.
METHODS: Eligible patients with clinical stage II or III, excluding T4, squamous cell carcinoma were randomized to undergo surgery followed (group 1) or preceded (group 2) by chemotherapy consisting of two courses of cisplatin plus 5-fluorouracil. The primary end point was progression-free survival.
RESULTS: We randomized 330 patients, with 166 assigned to group 1 and 164 to group 2, between May 2000 and May 2006. The planned interim analysis was conducted after completion of patient accrual. Progression-free survival did not reach the stopping boundary, but overall survival in group 2 was superior to that of group 1 (P = 0.01). Therefore, the Data and Safety Monitoring Committee recommended early publication. Updated analyses showed the 5-year overall survival to be 43% in group 1 and 55% in group 2 (hazard ratio 0.73, 95% confidence interval 0.54-0.99, P = 0.04), where the median follow-up of censored patients was 61.6 months. Concerning operative morbidity, renal dysfunction after surgery in group 2 was slightly higher than in group 1.
CONCLUSIONS: Preoperative chemotherapy with cisplatin plus 5-fluorouracil can be regarded as standard treatment for patients with stage II/III squamous cell carcinoma.

PMID 21879261  Ann Surg Oncol. 2012 Jan;19(1):68-74. doi: 10.1245/s104・・・
著者: Nobutoshi Ando, Toshifumi Iizuka, Hiroko Ide, Kaoru Ishida, Masayuki Shinoda, Tadashi Nishimaki, Wataru Takiyama, Hiroshi Watanabe, Kaichi Isono, Norio Aoyama, Hiroyasu Makuuchi, Otsuo Tanaka, Hideaki Yamana, Shunji Ikeuchi, Toshiyuki Kabuto, Kagami Nagai, Yutaka Shimada, Yoshihide Kinjo, Haruhiko Fukuda, Japan Clinical Oncology Group
雑誌名: J Clin Oncol. 2003 Dec 15;21(24):4592-6. doi: 10.1200/JCO.2003.12.095.
Abstract/Text PURPOSE: We performed a multicenter randomized controlled trial to determine whether postoperative adjuvant chemotherapy improves outcome in patients with esophageal squamous cell carcinoma undergoing radical surgery.
PATIENTS AND METHODS: Patients undergoing transthoracic esophagectomy with lymphadenectomy between July 1992 and January 1997 at 17 institutions were randomly assigned to receive surgery alone or surgery plus chemotherapy including two courses of cisplatin (80 mg/m2 of body-surface area x 1 day) and fluorouracil (800 mg/m2 x 5 days) within 2 months after surgery. Adaptive stratification factors were institution and lymph node status (pN0 versus pN1). The primary end point was disease-free survival.
RESULTS: Of the 242 patients, 122 were assigned to surgery alone, and 120 to surgery plus chemotherapy. In the surgery plus chemotherapy group, 91 patients (75%) received both full courses of chemotherapy; grade 3 or 4 hematologic or nonhematologic toxicities were limited. The 5-year disease-free survival rate was 45% with surgery alone, and 55% with surgery plus chemotherapy (one-sided log-rank, P =.037). The 5-year overall survival rate was 52% and 61%, respectively (P =.13). Risk reduction by postoperative chemotherapy was remarkable in the subgroup with lymph node metastasis.
CONCLUSION: Postoperative adjuvant chemotherapy with cisplatin and fluorouracil is better able to prevent relapse in patients with esophageal cancer than surgery alone.

PMID 14673047  J Clin Oncol. 2003 Dec 15;21(24):4592-6. doi: 10.1200/J・・・
著者: Eric Van Cutsem, Vladimir M Moiseyenko, Sergei Tjulandin, Alejandro Majlis, Manuel Constenla, Corrado Boni, Adriano Rodrigues, Miguel Fodor, Yee Chao, Edouard Voznyi, Marie-Laure Risse, Jaffer A Ajani, V325 Study Group
雑誌名: J Clin Oncol. 2006 Nov 1;24(31):4991-7. doi: 10.1200/JCO.2006.06.8429.
Abstract/Text PURPOSE: In the randomized, multinational phase II/III trial (V325) of untreated advanced gastric cancer patients, the phase II part selected docetaxel, cisplatin, and fluorouracil (DCF) over docetaxel and cisplatin for comparison against cisplatin and fluorouracil (CF; reference regimen) in the phase III part.
PATIENTS AND METHODS: Advanced gastric cancer patients were randomly assigned to docetaxel 75 mg/m2 and cisplatin 75 mg/m2 (day 1) plus fluorouracil 750 mg/m2/d (days 1 to 5) every 3 weeks or cisplatin 100 mg/m2 (day 1) plus fluorouracil 1,000 mg/m2/d (days 1 to 5) every 4 weeks. The primary end point was time-to-progression (TTP).
RESULTS: In 445 randomly assigned and treated patients (DCF = 221; CF = 224), TTP was longer with DCF versus CF (32% risk reduction; log-rank P < .001). Overall survival was longer with DCF versus CF (23% risk reduction; log-rank P = .02). Two-year survival rate was 18% with DCF and 9% with CF. Overall response rate was higher with DCF (chi2 P = .01). Grade 3 to 4 treatment-related adverse events occurred in 69% (DCF) v 59% (CF) of patients. Frequent grade 3 to 4 toxicities for DCF v CF were: neutropenia (82% v 57%), stomatitis (21% v 27%), diarrhea (19% v 8%), lethargy (19% v 14%). Complicated neutropenia was more frequent with DCF than CF (29% v 12%).
CONCLUSION: Adding docetaxel to CF significantly improved TTP, survival, and response rate in gastric cancer patients, but resulted in some increase in toxicity. Incorporation of docetaxel, as in DCF or with other active drug(s), is a new therapy option for patients with untreated advanced gastric cancer.

PMID 17075117  J Clin Oncol. 2006 Nov 1;24(31):4991-7. doi: 10.1200/JC・・・
著者: Jan B Vermorken, Eva Remenar, Carla van Herpen, Thierry Gorlia, Ricard Mesia, Marian Degardin, John S Stewart, Svetislav Jelic, Jan Betka, Joachim H Preiss, Danielle van den Weyngaert, Ahmad Awada, Didier Cupissol, Heinz R Kienzer, Augustin Rey, Isabelle Desaunois, Jacques Bernier, Jean-Louis Lefebvre, EORTC 24971/TAX 323 Study Group
雑誌名: N Engl J Med. 2007 Oct 25;357(17):1695-704. doi: 10.1056/NEJMoa071028.
Abstract/Text BACKGROUND: Phase 2 studies suggest that the standard regimen of cisplatin and fluorouracil (PF) plus docetaxel (TPF) improves outcomes in squamous-cell carcinoma of the head and neck. We compared TPF with PF as induction chemotherapy in patients with locoregionally advanced, unresectable disease.
METHODS: We randomly assigned eligible patients between the ages of 18 and 70 years who had stage III or stage IV disease and no distant metastases to receive either TPF (docetaxel and cisplatin, day 1; fluorouracil by continuous infusion, days 1 to 5) or PF every 3 weeks for four cycles. Patients without progression of disease received radiotherapy within 4 to 7 weeks after completing chemotherapy. The primary end point was progression-free survival.
RESULTS: A total of 358 patients underwent randomization, with 177 assigned to the TPF group and 181 to the PF group. At a median follow-up of 32.5 months, the median progression-free survival was 11.0 months in the TPF group and 8.2 months in the PF group (hazard ratio for disease progression or death in the TPF group, 0.72; P=0.007). Treatment with TPF resulted in a reduction in the risk of death of 27% (P=0.02), with a median overall survival of 18.8 months, as compared with 14.5 months in the PF group. There were more grade 3 or 4 events of leukopenia and neutropenia in the TPF group and more grade 3 or 4 events of thrombocytopenia, nausea, vomiting, stomatitis, and hearing loss in the PF group. The rates of death from toxic effects were 2.3% in the TPF group and 5.5% in the PF group.
CONCLUSIONS: As compared with the standard regimen of cisplatin and fluorouracil, induction chemotherapy with the addition of docetaxel significantly improved progression-free and overall survival in patients with unresectable squamous-cell carcinoma of the head and neck. (ClinicalTrials.gov number, NCT00003888 [ClinicalTrials.gov].).

Copyright 2007 Massachusetts Medical Society.
PMID 17960012  N Engl J Med. 2007 Oct 25;357(17):1695-704. doi: 10.105・・・
著者: Marshall R Posner, Diane M Hershock, Cesar R Blajman, Elizabeth Mickiewicz, Eric Winquist, Vera Gorbounova, Sergei Tjulandin, Dong M Shin, Kevin Cullen, Thomas J Ervin, Barbara A Murphy, Luis E Raez, Roger B Cohen, Monica Spaulding, Roy B Tishler, Berta Roth, Rosana del Carmen Viroglio, Varagur Venkatesan, Ilya Romanov, Sanjiv Agarwala, K William Harter, Matthew Dugan, Anthony Cmelak, Arnold M Markoe, Paul W Read, Lynn Steinbrenner, A Dimitrios Colevas, Charles M Norris, Robert I Haddad, TAX 324 Study Group
雑誌名: N Engl J Med. 2007 Oct 25;357(17):1705-15. doi: 10.1056/NEJMoa070956.
Abstract/Text BACKGROUND: A randomized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil (TPF) with cisplatin and fluorouracil (PF), followed by chemoradiotherapy.
METHODS: We randomly assigned 501 patients (all of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were candidates for organ preservation) to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week. The primary end point was overall survival.
RESULTS: With a minimum of 2 years of follow-up (> or =3 years for 69% of patients), significantly more patients survived in the TPF group than in the PF group (hazard ratio for death, 0.70; P=0.006). Estimates of overall survival at 3 years were 62% in the TPF group and 48% in the PF group; the median overall survival was 71 months and 30 months, respectively (P=0.006). There was better locoregional control in the TPF group than in the PF group (P=0.04), but the incidence of distant metastases in the two groups did not differ significantly (P=0.14). Rates of neutropenia and febrile neutropenia were higher in the TPF group; chemotherapy was more frequently delayed because of hematologic adverse events in the PF group.
CONCLUSIONS: Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy. (ClinicalTrials.gov number, NCT00273546 [ClinicalTrials.gov].).

Copyright 2007 Massachusetts Medical Society.
PMID 17960013  N Engl J Med. 2007 Oct 25;357(17):1705-15. doi: 10.1056・・・
著者: Makoto Yamasaki, Hiroshi Miyata, Koji Tanaka, Osamu Shiraishi, Masaaki Motoori, Y F Peng, Takushi Yasuda, Masahiko Yano, Hitoshi Shiozaki, Masaki Mori, Yuichiro Doki
雑誌名: Oncology. 2011;80(5-6):307-13. doi: 10.1159/000329806. Epub 2011 Jul 18.
Abstract/Text OBJECTIVE: Esophageal squamous cell carcinoma (ESCC) is refractory to current therapeutic regimens and more effective therapies are imperative. To this end, we conducted a multicenter phase I/II trial of docetaxel, cisplatin, and fluorouracil (DCF) combination chemotherapy for ESCC.
METHODS: The study subjects were 46 patients with advanced or recurrent ESCC. Treatment included docetaxel at 60, 70, and 75 mg/m(2), cisplatin at 70 mg/m(2) on day 1, and daily fluorouracil at 700 mg/m(2) on days 1 through 5. The recommended dose of docetaxel was determined in phase I, while the response rate (RR) and progression-free survival rates were analyzed in phase II.
RESULTS: The recommended dose was determined to be 70 mg/m(2) in phase I. In phase II, the RR was 72.5%. Interim analysis showed median and 1-year progression-free survival of 14 months and 55.6%, respectively. Grade 3/4 toxicities of leukopenia and neutropenia occurred in 72.5 and 90% of patients, respectively. No treatment-related death was recorded. Surgical resection was subsequently performed in 20 patients after chemotherapy, and curative resection was achieved in 19.
CONCLUSION: DCF was tolerable and effective for advanced and recurrent ESCC. Such findings might encourage a change in the treatment strategy for ESCC.

Copyright © 2011 S. Karger AG, Basel.
PMID 21778771  Oncology. 2011;80(5-6):307-13. doi: 10.1159/000329806. ・・・
著者: Shigeyuki Tamura, Motohiro Imano, Hiroya Takiuchi, Kenji Kobayashi, Haruhiko Imamoto, Hirofumi Miki, Yoshihiro Goto, Taro Aoki, Ying-Feng Peng, Toshimasa Tsujinaka, Hiroshi Furukawa, Osaka Gastrointestinal Cancer Chemotherapy Study Group
雑誌名: Anticancer Res. 2012 Apr;32(4):1403-8.
Abstract/Text BACKGROUND: The aims of this multiple-institution phase II study were to evaluate the efficacy and tolerability of docetaxel, cisplatin and 5-fluorouracil (DCF) for the therapy of patients with metastatic squamous cell carcinoma of the esophagus (SCCE).
PATIENTS AND METHODS: Eligible patients included those with previously untreated SCCE, score of ECOG 0-2 and adequate organ function. Patients received 60 mg/m(2) docetaxel and 70 mg/m(2) cisplatin on day 1, and 600 mg/m(2) 5-fluorouracil on days 1-5 every four weeks.
RESULTS: Twenty-nine (22 male, 7 female) patients with metastatic SCCE (M1a: 20, M1b: 9) were enrolled. Three cases achieved complete response and seven a partial response. In addition to these patients, three patients achieved good response and underwent surgical resection, giving an overall response rate of 34.5% (95% Confidene Interval=17.9-54.3) in confirmed cases and 44.8% (95% CI=26.4-64.3) in unconfirmed cases. Grade 3 or 4 hematological toxicities were as follows: leukopenia in 15 patients (52%), neutropenia in 22 patients (76%) and febrile neutropenia in 6 patients (21%), while grade 3 or 4 non-hematological toxicities were relatively rare.
CONCLUSION: This DCF regimen was well tolerated; the results of this study provide information on the potential of DCF for treatment of patients with metastatic SCCE.

PMID 22493377  Anticancer Res. 2012 Apr;32(4):1403-8.
著者: J S Cooper, M D Guo, A Herskovic, J S Macdonald, J A Martenson, M Al-Sarraf, R Byhardt, A H Russell, J J Beitler, S Spencer, S O Asbell, M V Graham, L L Leichman
雑誌名: JAMA. 1999 May 5;281(17):1623-7.
Abstract/Text CONTEXT: Carcinoma of the esophagus traditionally has been treated by surgery or radiation therapy (RT), but 5-year overall survival rates have been only 5% to 10%. We previously reported results of a study conducted from January 1986 to April 1990 of combined chemotherapy and RT vs RT alone when an interim analysis revealed significant benefit for combined therapy.
OBJECTIVE: To report the long-term outcomes of a previously reported trial designed to determine if adding chemotherapy during RT improves the survival rate of patients with esophageal carcinoma.
DESIGN: Randomized controlled trial conducted 1985 to 1990 with follow-up of at least 5 years, followed by a prospective cohort study conducted between May 1990 and April 1991.
SETTING: Multi-institution participation, ranging from tertiary academic referral centers to general community practices.
PATIENTS: Patients had squamous cell or adenocarcinoma of the esophagus, T1-3 N0-1 M0, adequate renal and bone marrow reserve, and a Karnofsky score of at least 50. Interventions Combined modality therapy (n = 134): 50 Gy in 25 fractions over 5 weeks, plus cisplatin intravenously on the first day of weeks 1, 5, 8, and 11, and fluorouracil, 1 g/m2 per day by continuous infusion on the first 4 days of weeks 1, 5, 8, and 11. In the randomized study, combined therapy was compared with RT only (n = 62): 64 Gy in 32 fractions over 6.4 weeks.
MAIN OUTCOME MEASURES: Overall survival, patterns of failure, and toxic effects.
RESULTS: Combined therapy significantly increased overall survival compared with RT alone. In the randomized part of the trial, at 5 years of follow-up the overall survival for combined therapy was 26% (95% confidence interval [CI], 15%-37%) compared with 0% following RT. In the succeeding nonrandomized part, combined therapy produced a 5-year overall survival of 14% (95% CI, 6%-23%). Persistence of disease (despite therapy) was the most common mode of treatment failure; however, it was less common in the groups receiving combined therapy (34/130 [26%]) than in the group treated with RT only (23/62 [37%]). Severe acute toxic effects also were greater in the combined therapy groups. There were no significant differences in severe late toxic effects between the groups. However, chemotherapy could be administered as planned in only 89 (68%) of 130 patients (10% had life-threatening toxic effects with combined therapy vs 2% in the RT only group).
CONCLUSION: Combined therapy increases the survival of patients who have squamous cell or adenocarcinoma of the esophagus, T1-3 N0-1 M0, compared with RT alone.

PMID 10235156  JAMA. 1999 May 5;281(17):1623-7.
著者: Rebecca K S Wong, Richard A Malthaner, Lisa Zuraw, R Bryan Rumble, Cancer Care Ontario Practice Guidelines Initiative Gastrointestinal Cancer Disease Site Group
雑誌名: Int J Radiat Oncol Biol Phys. 2003 Mar 15;55(4):930-42.
Abstract/Text PURPOSE: To make recommendations regarding combined radiotherapy (RT) and chemotherapy (RTCT), compared with RT alone, when a nonsurgical approach is used for patients with localized esophageal carcinoma.
MATERIALS AND METHODS: The Medline, Cancerlit, Cochrane Library databases, and abstracts published in the American Society of Clinical Oncology and the American Society for Therapeutic Radiology and Oncology proceedings were searched for evidence. Evidence was evaluated by two members of the Gastrointestinal Cancer Disease Site Group and methodologists.
RESULTS: Pooling seven randomized trials detected a statistically significant survival benefit at 1 year for concomitant RTCT compared with RT alone (1-year mortality odds ratio 0.61; 95% confidence interval 0.44-0.84; p <0.00001). Local control also significantly improved with concomitant RTCT compared with RT alone for the available data (odds ratio 0.52; 95% confidence interval 0.31-0.89; p = 0.004), but a significant increase in adverse effects, including life-threatening toxicities, was shown.
CONCLUSIONS: Concomitant RT and cisplatin-based CT is recommended over RT alone. Patients should be aware of the increased acute toxicity associated with this approach, and this recommendation should only be made after consideration of the potential risks and benefits and the patient's general condition. Sequential RTCT is not recommended as standard practice.

PMID 12605971  Int J Radiat Oncol Biol Phys. 2003 Mar 15;55(4):930-42.・・・
著者: Bruce D Minsky, Thomas F Pajak, Robert J Ginsberg, Thomas M Pisansky, James Martenson, Ritsuko Komaki, Gordon Okawara, Seth A Rosenthal, David P Kelsen
雑誌名: J Clin Oncol. 2002 Mar 1;20(5):1167-74.
Abstract/Text PURPOSE: To compare the local/regional control, survival, and toxicity of combined-modality therapy using high-dose (64.8 Gy) versus standard-dose (50.4 Gy) radiation therapy for the treatment of patients with esophageal cancer.
PATIENTS AND METHODS: A total of 236 patients with clinical stage T1 to T4, N0/1, M0 squamous cell carcinoma or adenocarcinoma selected for a nonsurgical approach, after stratification by weight loss, primary tumor size, and histology, were randomized to receive combined-modality therapy consisting of four monthly cycles of fluorouracil (5-FU) (1,000 mg/m(2)/24 hours for 4 days) and cisplatin (75 mg/m(2) bolus day 1) with concurrent 64.8 Gy versus the same chemotherapy schedule but with concurrent 50.4 Gy. The trial was stopped after an interim analysis. The median follow-up was 16.4 months for all patients and 29.5 months for patients still alive.
RESULTS: For the 218 eligible patients, there was no significant difference in median survival (13.0 v 18.1 months), 2-year survival (31% v 40%), or local/regional failure and local/regional persistence of disease (56% v 52%) between the high-dose and standard-dose arms. Although 11 treatment-related deaths occurred in the high-dose arm compared with two in the standard-dose arm, seven of the 11 deaths occurred in patients who had received 50.4 Gy or less.
CONCLUSION: The higher radiation dose did not increase survival or local/regional control. Although there was a higher treatment-related mortality rate in the patients assigned to the high-dose radiation arm, it did not seem to be related to the higher radiation dose. The standard radiation dose for patients treated with concurrent 5-FU and cisplatin chemotherapy is 50.4 Gy.

PMID 11870157  J Clin Oncol. 2002 Mar 1;20(5):1167-74.
著者: Hoichi Kato, Akihiro Sato, Haruhiko Fukuda, Yoshikazu Kagami, Harushi Udagawa, Akihiko Togo, Nobutoshi Ando, Otsuo Tanaka, Masayuki Shinoda, Hideaki Yamana, Satoshi Ishikura
雑誌名: Jpn J Clin Oncol. 2009 Oct;39(10):638-43. doi: 10.1093/jjco/hyp069. Epub 2009 Jun 23.
Abstract/Text OBJECTIVE: The study objective was to evaluate the efficacy and toxicity of chemoradiotherapy with 5-fluorouracil (5-FU) plus cisplatin in patients with Stage I esophageal squamous cell carcinoma (ESCC). The primary endpoint was proportion of complete response (%CR).
METHODS: Patients with Stage I (T1N0M0) ESCC, aged 20-75 years, without indication of endoscopic mucosal resection were eligible. Treatment consisted of cisplatin 70 mg/m(2) (day 1) and 5-FU 700 mg/m(2)/day (days 1-4) combined with 30 Gy radiotherapy (2 Gy/day, 5 days/week, days 1-21). The cycle was repeated twice with 1-week split. Salvage surgery was recommended for residual tumor or local recurrence.
RESULTS: From December 1997 to June 2000, 72 patients were enrolled. No ineligible patient or major protocol violation was observed. There were 63 CRs for %CR of 87.5% [95% confidence interval (CI): 77.6-94.1]. Six patients with residual tumor successfully underwent esophagectomy. There was no Grade 4 toxicity. Four-year survival proportion was 80.5% (95% CI: 71.3-89.7), and 4-year major relapse-free survival proportion was 68% (95% CI: 57.3-78.8) (mucosal recurrence removed by endoscopy was not counted as an event).
CONCLUSIONS: High CR proportion and survival proportion with mild toxicity suggest that this regimen could be considered as a candidate of new standard treatment to be compared with surgery in patients with Stage I ESCC.

PMID 19549720  Jpn J Clin Oncol. 2009 Oct;39(10):638-43. doi: 10.1093/・・・
著者: Ken Kato, Kei Muro, Keiko Minashi, Atsushi Ohtsu, Satoshi Ishikura, Narikazu Boku, Hiroya Takiuchi, Yoshito Komatsu, Yoshinori Miyata, Haruhiko Fukuda, Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group (JCOG)
雑誌名: Int J Radiat Oncol Biol Phys. 2011 Nov 1;81(3):684-90. doi: 10.1016/j.ijrobp.2010.06.033. Epub 2010 Oct 6.
Abstract/Text PURPOSE: In this Phase II study, we evaluated the efficacy and toxicity of chemoradiotherapy (CRT) with cisplatin (CDDP) and 5-fluorouracil (5-FU) for Stage II-III esophageal squamous cell carcinoma (ESCC).
PATIENTS AND METHODS: Patients with clinical Stage II-III (T1N1M0 or T2-3N0-1M0) thoracic ESCC were enrolled between April 2000 and March 2002. Chemotherapy comprised two courses of protracted infusion of 5-FU (400 mg/m(2)/day) on Days 1-5 and 8-12, and 2-h infusion of CDDP (40 mg/m(2)) on Days 1 and 8; this regimen was repeated every 5 weeks. Concurrent radiotherapy involved 60-Gy irradiation (30 fractions) for 8 weeks with a 2-week break. Responders received two courses of 5-FU (800 mg/m(2)/day) on Days 1-5 and CDDP (80 mg/m(2)) on Day 1. Final analysis was conducted in March 2007. Survival and late toxicities were monitored for 5 years.
RESULTS: The characteristics of the 76 patients enrolled were as follows: median age, 61 years; male/female, 68/8; performance status 0/1, 59/17 patients; Stage IIA/IIB/III, 26/12/38 patients. Of the 74 eligible patients, 46 (62.2%) achieved complete response. Median survival time was 29 months, with 3- and 5-year survival rates of 44.7% and 36.8%, respectively. Acute toxicities included Grade 3/4 esophagitis (17%), nausea (17%), hyponatremia (16%), and infection without neutropenia (12%). Late toxicities comprised Grade 3/4 esophagitis (13%), pericardial (16%) and pleural (9%) effusion, and radiation pneumonitis (4%), causing 4 deaths.
CONCLUSIONS: CRT is effective for Stage II-III ESCC with manageable acute toxicities and can provide a nonsurgical treatment option. However, further improvement is required for reduction in late toxicity.

Copyright © 2011 Elsevier Inc. All rights reserved.
PMID 20932658  Int J Radiat Oncol Biol Phys. 2011 Nov 1;81(3):684-90. ・・・
著者: Satoshi Ishikura, Keiji Nihei, Atsushi Ohtsu, Narikazu Boku, Shuichi Hironaka, Kiyomi Mera, Manabu Muto, Takashi Ogino, Shigeaki Yoshida
雑誌名: J Clin Oncol. 2003 Jul 15;21(14):2697-702. doi: 10.1200/JCO.2003.03.055.
Abstract/Text PURPOSE: To assess the long-term toxicity after definitive chemoradiotherapy (CRT) for squamous cell carcinoma (SCC) of the esophagus.
PATIENTS AND METHODS: Patients newly diagnosed with SCC of the esophagus and treated with definitive CRT between 1992 and 1999 in our institution were recruited from our database on the basis of the following criteria: age RESULTS: A total of 139 patients were recruited, and their characteristics were as follows: median age, 62 years (range, 38 to 75 years); 121 males and 18 females; 96 patients PS 0, 42 patients PS 1, and one patient PS 2; 15 patients T1, 11 patients T2, 60 patients T3, and 53 patients T4; and 101 patients M0, 38 patients M1a. With a median follow-up of 53 months, the median survival time and 5-year survival rate were 21 months and 29%, respectively. Of 78 patients with complete remission, two patients died as a result of acute myocardial infarction. Grade 2, 3, and 4 late toxicities occurred with the following incidences: pericarditis in eight patients, seven patients, and one patient, respectively; heart failure in zero, zero, and two patients; pleural effusion in seven, eight, and zero patients; and radiation pneumonitis in one patient, three patients, and zero patients, respectively.
CONCLUSION: Definitive CRT for SCC of the esophagus is effective with substantial toxicities. Additional investigation to minimize the normal tissue toxicities is warranted.

PMID 12860946  J Clin Oncol. 2003 Jul 15;21(14):2697-702. doi: 10.1200・・・
著者: Sadamoto Zenda, Shuichi Hironaka, Keisei Taku, Hiroshi Sato, Takayuki Hashimoto, Noriaki Hasuike, Narikazu Boku, Yasuhiro Tsubosa, Hiroyuki Ono, Tetsuo Nishimura
雑誌名: Dig Endosc. 2009 Oct;21(4):245-51. doi: 10.1111/j.1443-1661.2009.00900.x.
Abstract/Text BACKGROUND: Although use of gastrointestinal endoscopy for response evaluation in patients with esophageal cancer undergoing chemoradiotherapy or radiotherapy (CRT/RT) treatment is widely accepted, optimal timing for evaluation has not been sufficiently investigated. Here, we investigated optimal timing of primary site response evaluation in esophageal cancer patients treated with CRT/RT.
PATIENTS AND METHODS: This study examined esophageal cancer patients who underwent CRT/RT between September 2002 and December 2004. Time to complete response (CR) at the primary site was assessed in patients designated as CR at the primary site, while progression-free survival at the primary site (PFSp) was assessed in patients designated as incomplete response at the primary site.
RESULTS: Eighty-three patients were enrolled in this study. Median total RT dose was 60 Gy (range, 50-60 Gy), and median RT duration was 53 days (range, 35-74 days). Mean time to CR at the primary site was 97 days (range, 52-201 days). In four patients, although initial examination of biopsy specimens found evidence of viable cancer cells within 75 days of treatment initiation, subsequent examination found no such evidence, and the patients were thus designated as CR. Median PFSp was 149 days (range, 67-399 days), and PFSp rate at 90 days was 97%. Median interval between the previous examination and initial primary progressive disease was 37 days.
CONCLUSION: Recommended time of first response evaluation for esophageal cancer following initiation of CRT/RT was found to be between 75 and 90 days. Subsequent evaluation should be carried out approximately one month following non-CR/non-progressive disease declassification.

PMID 19961523  Dig Endosc. 2009 Oct;21(4):245-51. doi: 10.1111/j.1443-・・・
著者: T Yano, M Muto, S Hattori, K Minashi, M Onozawa, K Nihei, S Ishikura, A Ohtsu, S Yoshida
雑誌名: Endoscopy. 2008 Sep;40(9):717-21. doi: 10.1055/s-2008-1077480. Epub 2008 Sep 4.
Abstract/Text BACKGROUND AND STUDY AIMS: Local failure after definitive chemoradiotherapy (CRT) in patients with esophageal cancer remains one of the major problems in finding a cure. Endoscopic mucosal resection (EMR) is one treatment option when failure lesions are superficial. However, there are no relevant long-term survival data. The aim of this study was to clarify the long-term survival of salvage EMR.
PATIENTS AND METHODS: Between January 1998 and March 2004, 289 patients with esophageal squamous cell carcinoma were treated with definitive CRT at the National Cancer Center Hospital East, Japan. Of these 289 patients, 21 patients with local failure without lymph-node or distant metastases were treated with salvage EMR. The technique of salvage EMR involved a strip biopsy method. We retrospectively analyzed the long-term survival data for the patients who underwent salvage EMR.
RESULTS: At a median follow-up period of 54 months (range, 16-108 months), eight of 21 patients (38%) were alive with no recurrence and two patients had died from another disease but with no recurrence of esophageal cancer. Local recurrence after EMR was detected in four patients, with local and lymph-node recurrence in two patients, and lymph-node and/or distant metastases in five patients. The 5-year survival rate from the initiation of salvage EMR was 49.1%. There were no severe complications associated with EMR.
CONCLUSION: EMR is one of the curative salvage treatment options for local failure after definitive CRT, if the failure lesion is superficial and there are no lymph-node or distant metastases.

PMID 18773340  Endoscopy. 2008 Sep;40(9):717-21. doi: 10.1055/s-2008-1・・・
著者: Yuji Tachimori, Norio Kanamori, Norihisa Uemura, Norikazu Hokamura, Hiroyasu Igaki, Hoichi Kato
雑誌名: J Thorac Cardiovasc Surg. 2009 Jan;137(1):49-54. doi: 10.1016/j.jtcvs.2008.05.016.
Abstract/Text OBJECTIVE: Chemoradiotherapy is a popular definitive therapy for esophageal carcinoma among many patients and oncologists. Although the complete response rates are high and short-term survival is favorable after chemoradiotherapy, persistent or recurrent locoregional disease is frequent. Salvage surgery is the sole curative intent treatment option for this course of the disease. The present study evaluates the safety and value of salvage esophagectomy for locoregional failure after high-dose definitive chemoradiotherapy for esophageal squamous cell carcinoma.
METHODS: We reviewed 59 consecutive patients with thoracic esophageal squamous cell carcinoma who underwent salvage esophagectomy after definitive chemoradiotherapy. All patients received more than 60 Gy of radiation plus concurrent chemotherapy for curative intent. The data were compared with those of patients who received esophagectomy without preoperative therapy.
RESULTS: Postoperative morbidity and mortality rates were increased among patients who underwent salvage esophagectomy compared with those who underwent esophagectomy without preoperative therapy (mean hospital stay, 38 vs 33 days; anastomotic leak rates, 31% vs 25%; respiratory complication rates, 31% vs 20%; reintubation within 1 week, 2% vs 2%; hospital mortality rates, 8% vs 2%). Tracheobronchial necrosis and gastric conduit necrosis were highly lethal complications after salvage esophagectomy; 3-year postoperative survivals were 38% and 58%, respectively.
CONCLUSION: Patients who underwent salvage esophagectomy after definitive high-dose chemoradiotherapy had increased morbidity and mortality. Nevertheless, this is acceptable in view of the potential long-term survival after salvage esophagectomy. Such treatment should be considered for carefully selected patients at specialized centers.

PMID 19154902  J Thorac Cardiovasc Surg. 2009 Jan;137(1):49-54. doi: 1・・・
著者: Ken Kato, Byoung Chul Cho, Masanobu Takahashi, Morihito Okada, Chen-Yuan Lin, Keisho Chin, Shigenori Kadowaki, Myung-Ju Ahn, Yasuo Hamamoto, Yuichiro Doki, Chueh-Chuan Yen, Yutaro Kubota, Sung-Bae Kim, Chih-Hung Hsu, Eva Holtved, Ioannis Xynos, Mamoru Kodani, Yuko Kitagawa
雑誌名: Lancet Oncol. 2019 Nov;20(11):1506-1517. doi: 10.1016/S1470-2045(19)30626-6. Epub 2019 Sep 30.
Abstract/Text BACKGROUND: Chemotherapy for patients with advanced oesophageal squamous cell carcinoma offers poor long-term survival prospects. We report the final analysis from our study of the immune checkpoint PD-1 inhibitor nivolumab versus chemotherapy in patients with previously treated advanced oesophageal squamous cell carcinoma.
METHODS: We did a multicentre, randomised, open-label, phase 3 trial (ATTRACTION-3) at 90 hospitals and cancer centres in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the UK, and the USA. We enrolled patients aged 20 years and older with unresectable advanced or recurrent oesophageal squamous cell carcinoma (regardless of PD-L1 expression), at least one measurable or non-measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a baseline Eastern Cooperative Oncology Group performance status of 0-1, and who were refractory or intolerant to one previous fluoropyrimidine-based and platinum-based chemotherapy and had a life expectancy of at least 3 months. Patients were randomly assigned (1:1) to either nivolumab (240 mg for 30 min every 2 weeks) or investigator's choice of chemotherapy (paclitaxel 100 mg/m2 for at least 60 min once per week for 6 weeks then 1 week off; or docetaxel 75 mg/m2 for at least 60 min every 3 weeks), all given intravenously. Treatment continued until disease progression assessed by the investigator per RECIST version 1.1 or unacceptable toxicity. Randomisation was done using an interactive web response system with a block size of four and stratified according to geographical region (Japan vs rest of the world), number of organs with metastases, and PD-L1 expression. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival, defined as the time from randomisation until death from any cause, in the intention-to-treat population that included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT02569242, and follow-up for long-term outcomes is ongoing.
FINDINGS: Between Jan 7, 2016, and May 25, 2017, we assigned 419 patients to treatment: 210 to nivolumab and 209 to chemotherapy. At the time of data cutoff on Nov 12, 2018, median follow-up for overall survival was 10·5 months (IQR 4·5-19·0) in the nivolumab group and 8·0 months (4·6-15·2) in the chemotherapy group. At a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17·6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (median 10·9 months, 95% CI 9·2-13·3 vs 8·4 months, 7·2-9·9; hazard ratio for death 0·77, 95% CI 0·62-0·96; p=0·019). 38 (18%) of 209 patients in the nivolumab group had grade 3 or 4 treatment-related adverse events compared with 131 (63%) of 208 patients in the chemotherapy group. The most frequent grade 3 or 4 treatment-related adverse events were anaemia (four [2%]) in the nivolumab group and decreased neutrophil count (59 [28%]) in the chemotherapy group. Five deaths were deemed treatment-related: two in the nivolumab group (one each of interstitial lung disease and pneumonitis) and three in the chemotherapy group (one each of pneumonia, spinal cord abscess, and interstitial lung disease).
INTERPRETATION: Nivolumab was associated with a significant improvement in overall survivaland a favourable safety profile compared with chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma, and might represent a new standard second-line treatment option for these patients.
FUNDING: ONO Pharmaceutical Company and Bristol-Myers Squibb.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 31582355  Lancet Oncol. 2019 Nov;20(11):1506-1517. doi: 10.1016/S・・・
著者: Hiroya Takeuchi, Yoshiro Saikawa, Takashi Oyama, Soji Ozawa, Koichi Suda, Norihito Wada, Tsunehiro Takahashi, Rieko Nakamura, Naoyuki Shigematsu, Nobutoshi Ando, Masaki Kitajima, Yuko Kitagawa
雑誌名: World J Surg. 2010 Feb;34(2):277-84. doi: 10.1007/s00268-009-0331-9.
Abstract/Text BACKGROUND: Salvage esophagectomy is potentially the only treatment available that can offer a chance of long-term survival when definitive chemoradiotherapy (CRT) fails to achieve local control for patients with esophageal squamous cell carcinoma (ESCC). However, salvage esophagectomy is a highly invasive procedure with various postoperative complications compared to planned esophagectomy after neoadjuvant chemoradiotherapy (CRT). We hypothesize that severe postoperative complications may affect not only surgical mortality but also tumor recurrence and long-term survival for patients with salvage esophagectomy after definitive CRT.
METHODS: For the present study we reviewed the surgical procedures, postoperative complications, and the prognosis of 65 consecutive patients with thoracic ESCC who underwent the esophagectomy after neoadjuvant (neoadjuvant group: n = 40) or definitive (salvage group: n = 25) CRT.
RESULTS: Most patients underwent right-transthoracic extended esophagectomy and reconstruction using gastric conduit by way of subcutaneous route with left cervical anastomosis. The incidence of postoperative pneumonia was found to be higher in the salvage group than in the neoadjuvant group. In both groups, the survival of patients with R0 resection was significantly better than those with R1/R2 resection. Moreover, in the salvage group, the postoperative survival rate of patients with pneumonia or bacteremia/sepsis was significantly lower than that for patients who did not suffer the same complications. In the neoadjuvant group, R0 resection was selected to be the only independent prognostic factor in univariate and multivariate analysis. In contrast, in the salvage group, R0 resection and bacteremia/sepsis remained significant and were independent of the other factors in multivariate analysis.
CONCLUSIONS: This study reveals that postoperative morbidity affects not only the perioperative mortality but also the long-term survival of patients with ESCC who undergo salvage esophagectomy after definitive CRT.

PMID 20033687  World J Surg. 2010 Feb;34(2):277-84. doi: 10.1007/s0026・・・
著者: Jonathan Shenfine, Paul McNamee, Nick Steen, John Bond, S Michael Griffin
雑誌名: Am J Gastroenterol. 2009 Jul;104(7):1674-85. doi: 10.1038/ajg.2009.155. Epub 2009 May 12.
Abstract/Text OBJECTIVES: A dramatic rise in incidence, an aging population, and expensive palliative treatments have led to an escalating burden on clinicians managing inoperable esophageal cancer with only limited evidence of effectiveness. This study compares the clinical effectiveness and cost-effectiveness of self-expanding metal stents (SEMSs) with other palliative therapies to aid clinicians in making an evidence-based treatment choice.
METHODS: We conducted a prospective, multicenter, randomized, controlled, clinical trial with 215 patients followed until death or study closure. The primary outcome measures were dysphagia, quality of life (QL) 6 weeks following treatment, and total cost of treatment. Secondary outcome measures included treatment-associated morbidity, mortality, survival, and cost-effectiveness. An intention-to-treat analysis was carried out.
RESULTS: There was a significant difference in mean dysphagia grade between treatment arms 6 weeks following treatment (P=0.046), with worse swallowing reported by rigid stent-treated patients (mean dysphagia score difference=-0.49; 95% confidence interval (CI) -0.10 to -0.89, P=0.014). Global QL scores were lower at both 1 and 6 weeks following treatment for patients treated by SEMSs (mean difference QL index week 1=-0.66; 95% CI: -0.02 to -1.30, P=0.04; mean difference QL index week 6=-1.01; 95% CI -0.30 to -1.72, P=0.006). These findings were associated with higher post-procedure pain scores in the SEMS patient group (mean difference of the European Organisation for Research and Treatment of Cancer QLQ C-30 pain symptom score at week 1=11.13; 95% CI: 2.89-19.4; P=0.01). Although mean EQ-5D QL values differed between the treatments (P<0.001), this difference dissipated following generation of quality-adjusted life year values. Total costs varied between treatment arms but these findings canceled out when SEMSs were compared with non-SEMS therapies (95% CI -845.15-1,332.62). These results were robust to sensitivity analysis. There were no differences in the in-hospital mortality or early complication rates, but late complications were more frequent after rigid stenting (risk ratio=2.47; 95% CI 1.88-3.04). There was a survival advantage for non-stent-treated patients (log-rank statistic=4.21, P=0.04).
CONCLUSIONS: The treatment choice for patients with inoperable esophageal cancer should be between a SEMS or a non-stent treatment after consideration has been given to both patient and tumor characteristics and clinician and patient preferences.

PMID 19436289  Am J Gastroenterol. 2009 Jul;104(7):1674-85. doi: 10.10・・・
著者: Massimo Conio, Alessandro Repici, Giorgio Battaglia, Giovanni De Pretis, Luigi Ghezzo, Max Bittinger, Helmut Messmann, Jean-François Demarquay, Sabrina Blanchi, Michele Togni, Rita Conigliaro, Rosangela Filiberti
雑誌名: Am J Gastroenterol. 2007 Dec;102(12):2667-77. doi: 10.1111/j.1572-0241.2007.01565.x.
Abstract/Text OBJECTIVES: Self-expanding metal stents (SEMS) provide effective palliation in patients with malignant dysphagia, although severe complications and mortality may result. We performed a prospective controlled trial to compare a new self-expanding polyester mesh stent (Polyflex) with SEMS (Ultraflex).
METHODS: One hundred one patients with unresectable esophageal carcinoma were randomized to placement of a Polyflex (N=47) or a partially covered Ultraflex (N=54) stent. Patients with esophagogastric junction (EGJ) malignancy were excluded.
RESULTS: Placement was successful in 46 (98%) patients with the Polyflex and 54 (100%) patients with the Ultraflex stent. In one patient, the Polyflex stent could not be placed. After 1 wk, dysphagia was improved by at least 1 grade in 100% of the Polyflex group and in 94% of the Ultraflex group. Major complications were observed in 48% of the Polyflex group and 33% of the Ultraflex group. Intraprocedural perforation occurred in 1 Polyflex and 1 Ultraflex patient. Two Polyflex patients had postprocedural hemorrhage. Twenty (44%) patients with a Polyflex stent and 18 (33%) with an Ultraflex stent had recurrent dysphagia because of tumor overgrowth, stent migration, hyperplastic granulomatous reaction, or food bolus impaction. Multivariate analysis showed a significantly higher complication rate with Polyflex than with Ultraflex stents (odds ratio 2.3, 95% CI 1.2-4.4). However, median survival was 134 days with Polyflex and 122 days with Ultraflex stents (P=NS).
CONCLUSIONS: No difference was seen in palliation of dysphagia between the two stents. Significantly more complications, especially late stent migration, were observed in the Polyflex group.

PMID 18042102  Am J Gastroenterol. 2007 Dec;102(12):2667-77. doi: 10.1・・・
著者: Els M L Verschuur, Alessandro Repici, Ernst J Kuipers, Ewout W Steyerberg, Peter D Siersema
雑誌名: Am J Gastroenterol. 2008 Feb;103(2):304-12. doi: 10.1111/j.1572-0241.2007.01542.x. Epub 2007 Sep 25.
Abstract/Text BACKGROUND & AIM: Stents are often used for the palliation of inoperable esophageal or gastric cardia cancer. One of the drawbacks of the currently used stents is the high percentage of recurrent dysphagia due to stent migration and tissue growth. New stents have been designed to overcome this unwanted sequela of stent placement. In the present study, we investigated whether results of stent placement could be improved with newer stent designs.
METHODS: Between June 2004 and May 2006, 125 patients with dysphagia from inoperable carcinoma of the esophagus or gastric cardia were randomized to placement of an Ultraflex stent (N = 42), Polyflex stent (N = 41), or Niti-S stent (N = 42). Patients were followed by scheduled telephone calls at 14 days after treatment, and then monthly for 6 months or until death. Technical and functional outcome, complications, recurrent dysphagia, and survival were analyzed with, chi(2) tests, Kaplan-Meier curves, and log-rank tests.
RESULTS: Stent placement was technically successful in all patients with an Ultraflex stent, in 34/41 (83%) patients with a Polyflex stent, and in 40/42 (95%) patients treated with a Niti-S stent (P= 0.008). Dysphagia score improved from a median of 3 (liquids only) to 1 (ability to eat some solid food) in all patients. There were no differences in complications among the three stent types. Recurrent dysphagia, caused by tissue in- or overgrowth, migration, or food obstruction, was significantly different between patients with an Ultraflex stent and patients with a Polyflex stent or Niti-S stent (22 [52%]vs 15 [37%]vs 13 [31%], P= 0.03). Stent migration occurred more frequently with Polyflex stents, whereas tissue in- or overgrowth was more frequently seen with Ultraflex stents, and to a lesser degree, Niti-S stents. No differences were found in survival (median survival: Ultraflex stent 132 days vs Polyflex stent 102 days vs Niti-S stent 159 days) among the three stent types.
CONCLUSIONS: All three stents are safe and offer adequate palliation of dysphagia from esophageal or gastric cardia cancer. Nonetheless, Polyflex stents seem the least preferable in this patient group, as placement of this device is technically demanding and associated with a high rate of stent migrations.

PMID 17900325  Am J Gastroenterol. 2008 Feb;103(2):304-12. doi: 10.111・・・
著者: Danny Yakoub, Ramy Fahmy, Thanos Athanasiou, Afshin Alijani, Christopher Rao, Ara Darzi, George B Hanna
雑誌名: World J Surg. 2008 Sep;32(9):1996-2009. doi: 10.1007/s00268-008-9654-1.
Abstract/Text BACKGROUND: The type of stent used for the management of patients with malignant dysphagia is chosen according to subjective physician's preference. There is no recent study available to provide updated evidence on early outcomes related to the use of different types of stents.
METHODS: A literature search was performed using Embase, MEDLINE, Cochrane Library, and Google Scholar databases for comparative studies assessing different types of stents. The primary end point was stent-related mortality; secondary end points included: stent-related morbidity, successful palliation of dysphagia, and 30-day mortality. A random-effects model was used and heterogeneity was assessed.
RESULTS: Twelve studies that included 911 patients compared metallic (46.54%) and plastic stents (53.45%), and eight studies that included 564 patients compared covered (43.26%) and uncovered metal stents (56.73%). Meta-analysis of randomized, controlled trials showed that metallic stents were associated with significantly reduced stent-related mortality (1.7% vs. 11.1% for the plastic group, odds ratio (OR), 0.2; 95% confidence interval (CI), 0.06-0.74; P = 0.02), morbidity in the form of reduced esophageal perforation (1.4% vs. 9.4% for plastic stent, OR, 0.27; 95% CI, 0.08-0.89; P = 0.03), and stent migration, yet increased rate of tumor in-growth (13% vs. 1.6% for plastic stents, OR, 4.84; 95% CI, 0.99-23.76; P = 0.05). Covered metallic stents had significantly less tumor in-growth than the uncovered and an increased migration rate. There was no significant difference between metallic and plastic stents in terms of any other stent-related morbidity and 30-day mortality.
CONCLUSION: Self-expanding metallic stents are superior to plastic stents in terms of stent insertion-related mortality, morbidity, and quality of palliation. The uncovered variety is disadvantaged by high rate of tumor in-growth; adequately designed randomized, controlled trials need to examine outcomes and cost-effectiveness of covered versus uncovered metallic stents.

PMID 18594905  World J Surg. 2008 Sep;32(9):1996-2009. doi: 10.1007/s0・・・
著者: Yasumasa Nishimura, Kenji Nagata, Susumu Katano, Saeko Hirota, Katsumasa Nakamura, Fumi Higuchi, Toshinori Soejima, Heitetsu Sai, Japanese Society for Esophageal Diseases
雑誌名: Int J Radiat Oncol Biol Phys. 2003 Aug 1;56(5):1327-32.
Abstract/Text PURPOSE: A questionnaire survey was performed to evaluate the complications and prognosis of esophageal cancer treated with esophageal intubation before or during radiotherapy.
METHODS AND MATERIALS: Clinical data were accumulated on a total of 47 patients treated at 17 institutions in Japan. Five patients had Stage II, 30 Stage III, and 11 Stage IV, and the stage was unknown in 1 patient. Covered expandable metallic stents were inserted in 30 patients, uncovered expandable metallic stents in 13, plastic or silicon prosthesis in 3, and an unknown type in 1 patient. Esophageal stenting was performed before the start of RT for 23 patients and during the course of RT for 24 patients. The reasons for the stenting were severe stricture in 32 patients (Group 1) and esophageal fistula in 15 patients (Group 2).
RESULTS: The most frequent toxicity was formation or worsening of esophageal fistulas in 13 patients (28%), followed by massive hematemesis or GI bleeding in 10 patients (21%). In total, 24 patients (51%), including 10 patients with possible treatment-related deaths (Grade 5), had nonhematologic toxicities of Grade 3-5. The interval from the start of RT to the nonhematologic toxicity ranged from 16 to 312 days (median 78). The incidence of toxicities was higher for Group 1 (59%) than for Group 2 (33%), although the difference was not statistically significant. The median survival time for those with Stage II-III and Stage IV was 5 and 3.5 months, respectively.
CONCLUSIONS: Patients with esophageal intubation before or during RT have a high risk of life-threatening complications, especially for those with severe esophageal stricture. Because long survival is expected for a substantial proportion of patients with locally advanced esophageal cancer after chemoradiotherapy, palliative intubation should be delayed until radiotherapy or chemoradiotherapy appears to have failed.

PMID 12873677  Int J Radiat Oncol Biol Phys. 2003 Aug 1;56(5):1327-32.・・・

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