今日の臨床サポート

癌性腹膜炎

著者: 伊澤直樹 聖マリアンナ医科大学 臨床腫瘍学

監修: 高野利実 がん研有明病院 乳腺内科

著者校正/監修レビュー済:2022/02/16
参考ガイドライン:
  1. 日本腹膜播種研究会:腹膜播種診療ガイドライン2021年版 
  1. 公益社団法人 日本産科婦人科学会:卵巣がん・胆管癌・腹膜癌治療ガイドライン2020年版
  1. 日本胃癌学会:胃癌治療ガイドライン 医師用第6版
患者向け説明資料

概要・推奨   

  1. 癌性腹膜炎は消化管癌(特に胃癌)や卵巣癌など原疾患を有する場合が多く、全身の画像検査を実施する。癌性腹膜炎は組織学的な検査によって確定診断されることが好ましいが、画像検査での診断のみとなることもある。治療は化学療法や緩和的な治療が主である。
  1. 化学療法治療は原疾患に沿って選択される。緩和的な治療方法として、腹腔-静脈シャント(デンバーシャント)や改良型腹水濾過濃縮再静注法(KM-CART)、利尿剤・麻薬など薬物療法が行われる。デンバーシャントを検討した観察研究では82.7%の症例で症状の改善を認めている(推奨度3)。ただし、合併症も多いため、適応患者を限定する必要がある。
  1. KM-CARTは、肝硬変による腹水と異なり、多数の播種を有する胃癌では腹水穿刺が不要な状態を維持できることは少ないため、KM-CARTを実施している施設は少ない(推奨度3)
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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。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※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、実際の保険適応の査定において保険適応及び保険適応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応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:
伊澤直樹 : 特に申告事項無し[2022年]
監修:高野利実 : 講演料(第一三共,日本イーライリリー,中外製薬)[2022年]

改訂のポイント:
  1. 定期レビューを行い、最新のエビデンスに基づいて症状・症候治療について加筆修正を行った。
  1. 腹膜播種診療ガイドライン 、卵巣がん・胆管癌・腹膜癌治療ガイドライン、胃癌治療ガイドラインに基づき、卵巣癌による癌性腹膜炎、胃癌による癌性腹水の治療について改訂を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 手術時の肉眼所見にて腹膜結節を確認するか、腹⽔の病理学的検査で癌を確認できれば確定診断となる。
  1. ただし、CT検査や超音波検査において水腎症や腹膜結節、腸間膜肥厚、腹水、消化管造影検査による腸管狭窄などの臨床所見のみで診断する場合も多い。
  1. すべての癌種で合併する可能性があるが、卵巣癌、胃癌で合併率が高い。
  1. 癌性腹膜炎は尿管閉塞による腎機能障害や腸閉塞による経口摂取困難など、さまざまな病態を引き起こすため、抗癌薬の選択には注意を要する。
  1. 原疾患に対する化学療法が治療の中心となるため、予後は原疾患により異なる。一般的に腹膜播種を有する場合は予後不良である。
問診・診察のポイント  
  1. 腹水を認める患者では、良性腹水を起こし得る疾患の既往歴を聴取し、腹囲を測定する。

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文献 

Shunsuke Sugawara, Miyuki Sone, Yasuaki Arai, Noriaki Sakamoto, Takeshi Aramaki, Yozo Sato, Yoshitaka Inaba, Yoshito Takeuchi, Teruko Ueno, Kiyoshi Matsueda, Michihisa Moriguchi, Takahiro Tsushima
Radiological insertion of Denver peritoneovenous shunts for malignant refractory ascites: a retrospective multicenter study (JIVROSG-0809).
Cardiovasc Intervent Radiol. 2011 Oct;34(5):980-8. doi: 10.1007/s00270-010-0057-y. Epub 2010 Dec 30.
Abstract/Text PURPOSE: Peritoneal venous shunts (PVSs) are widely used for palliating symptoms of refractory malignant ascites and are recognized as one of the practical methods. However, reliable clinical data are insufficient because most previous reports have been small studies from single centers. We conducted a retrospective, multicenter study to evaluate the safety and efficacy of radiologically placed PVSs in patients with malignant refractory ascites.
METHODS: A total of 133 patients with malignant ascites refractory to medical therapies were evaluated for patient characteristics, technical success, efficacy, survival times, adverse events, and changes in laboratory data.
RESULTS: PVSs were successfully placed in all patients and were effective (i.e., improvement of ascites symptoms lasting 7 days or more) in 110 (82.7%). The median duration of symptom palliation was 26 days and median survival time was 41 days. The most frequent adverse event was PVS dysfunction, which occurred in 60 (45.1%) patients, among whom function was recovered with an additional minimally invasive procedure in 9. Abnormalities in coagulation (subclinical disseminated intravascular coagulation) occurred in 37 (27.8%) patients, although only 7 (5.3%) developed clinical disseminated intravascular coagulation. Other major adverse events were gastrointestinal bleeding (9.8%), sepsis (3.8%), and acute heart failure (3.0%). PVS was least effective in patients with elevated serum creatinine, bloody ascites, or gynecologic tumor.
CONCLUSIONS: Radiological PVS is a technically feasible and effective method for palliating the symptoms from refractory malignant ascites, but preoperative evaluation and monitoring the postprocedural complications are mandatory to preclude severe adverse events after PVS.

PMID 21191592
Koji Tomiyama, Mina Takahashi, Tetsuya Fujii, Hironori Kunisue, Yoshiaki Kanaya, Shuitirou Maruyama, Nobuji Yokoyama, Atsunori Nakao, Mitsuhiro Soda, Nobuyoshi Shimizu
Improved quality of life for malignant ascites patients by Denver peritoneovenous shunts.
Anticancer Res. 2006 May-Jun;26(3B):2393-5.
Abstract/Text BACKGROUND: Intractable ascites secondary to malignant disease deteriorates the patients' quality of life.
PATIENTS AND METHODS: Thirty-three patients, who had undergone Denver peritoneovenous shunt for the treatment of ascites associated with malignant tumor from May 1998 to February 2004, were retrospectively analyzed.
RESULTS: Post-operative complications had occurred in twelve patients, including disseminated intravascular coagulation in eight, pulmonary edema in three and wound hematoma in one. The patients' post-operative mean survival was 54.5 days with occlusion occurring in four (12.1%). Comparison of pre- and postoperative values showed a significant decrease of body weight and abdominal girth. Thirteen patients needed no post-operative therapy for ascites, whereas 17 patients could tentatively remain at home or be discharged.
CONCLUSION: The Denver shunt for malignant ascites is useful in improving quality of life, if indications are selected properly. Further experience and discussion are necessary to establish the patient selection criteria.

PMID 16821622
Hooman Yarmohammadi, George I Getrajdman
Symptomatic Fluid Drainage: Peritoneovenous Shunt Placement.
Semin Intervent Radiol. 2017 Dec;34(4):343-348. doi: 10.1055/s-0037-1608705. Epub 2017 Dec 14.
Abstract/Text Ascites causes significant discomfort and has negative impact on patient's quality of life. Medical therapies including dietary restriction and diuretics are successful in only 40 to 44% of patients with malignant ascites and repeated paracentesis only provides temporary symptomatic relief. Therefore, a more permanent solution is necessary. Indwelling catheters or peritoneovenous shunt placement can provide more permanent symptomatic relief and improve patients' quality of life. Unlike indwelling catheters, peritoneovenous shunts do not limit patients' life style and therefore should be offered as first option in patients who are good candidates. Denver shunt (CareFusion-BD Worldwide) is the current available peritoneovenous shunt. In this article, the indications, contraindications, technical aspects of shunt placement, and techniques to prevent postprocedure complications will be discussed.

PMID 29249858
Taeko Ueda, Miyako Maehara, Yoko Takahashi, Naomi Nakayama, Haruhiko Kondo, Kyoko Shirota, Toshiyuki Yoshizato, Shingo Miyamoto
Clinical significance of cell-free and concentrated ascites re-infusion therapy for advanced and recurrent gynecological cancer.
Anticancer Res. 2012 Jun;32(6):2353-7.
Abstract/Text BACKGROUND: The management of malignant ascites is critical for the treatment of patients with advanced gynecological cancer. The purpose of this study was to assess the clinical significance of cell-free and concentrated ascites re-infusion therapy (CART).
PATIENTS AND METHODS: Adverse events, alterations in Eastern Cooperative Oncology Group performance status, serum albumin, body weight and abdominal circumference, and overall survival were examined in 22 patients with advanced gynecological cancer which were treated with CART.
RESULTS: Most of the adverse events were grade 1 or 2 fever. CART treatment had little effect on ECOG performance status and on levels of serum albumin. There was a significant decrease in body weight and in abdominal circumference post-treatment with CART, relative to pre-treatment (p<0.01). The overall survival rate was significantly prolonged in 14 patients after CART plus chemotherapy, as compared with eight patients after CART alone (p<0.01).
CONCLUSION: CART may contribute to the improvement of quality of life and of survival in patients with advanced gynecological cancer.

PMID 22641674
Keisuke Matsusaki, Kazumasa Orihashi
Feasibility, efficacy, and safety of cell-free and concentrated ascites reinfusion therapy (KM-CART) for malignant ascites.
Artif Organs. 2020 Oct;44(10):1090-1097. doi: 10.1111/aor.13691. Epub 2020 Apr 20.
Abstract/Text Efficacy for alleviating signs/symptoms of malignant ascites of a renovated CART (cell-free and concentrated ascites reinfusion therapy) system, called KM-CART, was evaluated. A total of 4781 KM-CART procedures were performed in 2109 patients. All patients were accepted unless hemodynamically unstable or consciousness impaired. The ascites were processed and drip-infused into the patient. There were no major complications or deaths. The mean drainage volume was 6.2 L (maximum: 27.7 L), patient symptoms (numerical scale system) were significantly alleviated (45.1 ± 19.0 reduced to 21.2 ± 14.2, P < .001), and patient leg circumference significantly decreased (33.3 ± 4.4 cm reduced to 30.5 ± 4.4 cm, P < .001) without exacerbation of renal function. Collected cancer cells could be utilized for immune therapy. KM-CART is capable of improving the "quality of best supportive care" and can be beneficial in conjunction with medication for alleviating malignant pain.

© 2020 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.
PMID 32242939
S A Amiel, A M Blackburn, R D Rubens
Intravenous infusion of frusemide as treatment for ascites in malignant disease.
Br Med J (Clin Res Ed). 1984 Apr 7;288(6423):1041.
Abstract/Text
PMID 6423185
B Greenway, P J Johnson, R Williams
Control of malignant ascites with spironolactone.
Br J Surg. 1982 Aug;69(8):441-2.
Abstract/Text Thirteen of 15 patients with malignant ascites achieved an excellent response to spironolactone, with an increase in urinary sodium excretion rates from less than 35 mEq/d before treatment to between 50 and 245 mEq/d after treatment. Plasma renin activity was raised in all of 5 patients in whom it was measured, whereas aldosterone was raised in only 3; these results are similar to those found in ascites due to cirrhosis.

PMID 7049306
Michael A Bookman, Mark F Brady, William P McGuire, Peter G Harper, David S Alberts, Michael Friedlander, Nicoletta Colombo, Jeffrey M Fowler, Peter A Argenta, Koen De Geest, David G Mutch, Robert A Burger, Ann Marie Swart, Edward L Trimble, Chrisann Accario-Winslow, Lawrence M Roth
Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a Phase III Trial of the Gynecologic Cancer Intergroup.
J Clin Oncol. 2009 Mar 20;27(9):1419-25. doi: 10.1200/JCO.2008.19.1684. Epub 2009 Feb 17.
Abstract/Text PURPOSE: To determine if incorporation of an additional cytotoxic agent improves overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma who receive carboplatin and paclitaxel.
PATIENTS AND METHODS: Women with stages III to IV disease were stratified by coordinating center, maximal diameter of residual tumor, and intent for interval cytoreduction and were then randomly assigned among five arms that incorporated gemcitabine, methoxypolyethylene glycosylated liposomal doxorubicin, or topotecan compared with carboplatin and paclitaxel. The primary end point was OS and was determined by pairwise comparison to the reference arm, with a 90% chance of detecting a true hazard ratio of 1.33 that limited type I error to 5% (two-tail) for the four comparisons.
RESULTS: Accrual exceeded 1,200 patients per year. An event-triggered interim analysis occurred after 272 events on the reference arm, and the study closed with 4,312 women enrolled. Arms were well balanced for demographic and prognostic factors, and 79% of patients completed eight cycles of therapy. There were no improvements in either PFS or OS associated with any experimental regimen. Survival analyses of groups defined by size of residual disease also failed to show experimental benefit in any subgroup.
CONCLUSION: Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent provided no benefit in PFS or OS after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.

PMID 19224846
Noriyuki Katsumata, Makoto Yasuda, Fumiaki Takahashi, Seiji Isonishi, Toshiko Jobo, Daisuke Aoki, Hiroshi Tsuda, Toru Sugiyama, Shoji Kodama, Eizo Kimura, Kazunori Ochiai, Kiichiro Noda, Japanese Gynecologic Oncology Group
Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial.
Lancet. 2009 Oct 17;374(9698):1331-8. doi: 10.1016/S0140-6736(09)61157-0. Epub 2009 Sep 18.
Abstract/Text BACKGROUND: Paclitaxel and carboplatin given every 3 weeks is standard treatment for advanced ovarian carcinoma. Attempts to improve patient survival by including other drugs have yielded disappointing results. We compared a conventional regimen of paclitaxel and carboplatin with a dose-dense weekly regimen in women with advanced ovarian cancer.
METHODS: Patients with stage II to IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer were eligible for enrolment in this phase 3, open-label, randomised controlled trial at 85 centres in Japan. Patients were randomly assigned by computer-generated randomisation sequence to receive six cycles of either paclitaxel (180 mg/m(2); 3-h intravenous infusion) plus carboplatin (area under the curve [AUC] 6 mg/mL per min), given on day 1 of a 21-day cycle (conventional regimen; n=320), or dose-dense paclitaxel (80 mg/m(2); 1-h intravenous infusion) given on days 1, 8, and 15 plus carboplatin given on day 1 of a 21-day cycle (dose-dense regimen; n=317). The primary endpoint was progression-free survival. Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00226915.
FINDINGS: 631 of the 637 enrolled patients were eligible for treatment and were included in the ITT population (dose-dense regimen, n=312; conventional regimen, n=319). Median progression-free survival was longer in the dose-dense treatment group (28.0 months, 95% CI 22.3-35.4) than in the conventional treatment group (17.2 months, 15.7-21.1; hazard ratio [HR] 0.71; 95% CI 0.58-0.88; p=0.0015). Overall survival at 3 years was higher in the dose-dense regimen group (72.1%) than in the conventional treatment group (65.1%; HR 0.75, 0.57-0.98; p=0.03). 165 patients assigned to the dose-dense regimen and 117 assigned to the conventional regimen discontinued treatment early. Reasons for participant dropout were balanced between the groups, apart from withdrawal because of toxicity, which was higher in the dose-dense regimen group than in the conventional regimen group (n=113 vs n=69). The most common adverse event was neutropenia (dose-dense regimen, 286 [92%] of 312; conventional regimen, 276 [88%] of 314). The frequency of grade 3 and 4 anaemia was higher in the dose-dense treatment group (214 [69%]) than in the conventional treatment group (137 [44%]; p<0.0001). The frequencies of other toxic effects were similar between groups.
INTERPRETATION: Dose-dense weekly paclitaxel plus carboplatin improved survival compared with the conventional regimen and represents a new treatment option in women with advanced epithelial ovarian cancer.
FUNDING: Bristol-Myers Squibb.

PMID 19767092
D M Provencher, C J Gallagher, W R Parulekar, J A Ledermann, D K Armstrong, M Brundage, C Gourley, I Romero, A Gonzalez-Martin, M Feeney, P Bessette, M Hall, J I Weberpals, G Hall, S K Lau, P Gauthier, M Fung-Kee-Fung, E A Eisenhauer, C Winch, D Tu, H J MacKay
OV21/PETROC: a randomized Gynecologic Cancer Intergroup phase II study of intraperitoneal versus intravenous chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer.
Ann Oncol. 2018 Feb 1;29(2):431-438. doi: 10.1093/annonc/mdx754.
Abstract/Text Background: The purpose of this multistage, adaptively, designed randomized phase II study was to evaluate the role of intraperitoneal (i.p.) chemotherapy following neoadjuvant chemotherapy (NACT) and optimal debulking surgery in women with epithelial ovarian cancer (EOC).
Patients and methods: We carried out a multicenter, two-stage, phase II trial. Eligible patients with stage IIB-IVA EOC treated with platinum-based intravenous (i.v.) NACT followed by optimal (<1 cm) debulking surgery were randomized to one of the three treatment arms: (i) i.v. carboplatin/paclitaxel, (ii) i.p. cisplatin plus i.v./i.p. paclitaxel, or (iii) i.p. carboplatin plus i.v./i.p. paclitaxel. The primary end point was 9-month progressive disease rate (PD9). Secondary end points included progression-free survival (PFS), overall survival (OS), toxicity, and quality of life (QOL).
Results: Between 2009 and 2015, 275 patients were randomized; i.p. cisplatin containing arm did not progress beyond the first stage of the study after failing to meet the pre-set superiority rule. The final analysis compared i.v. carboplatin/paclitaxel (n = 101) with i.p. carboplatin, i.v./i.p. paclitaxel (n = 102). The intention to treat PD9 was lower in the i.p. carboplatin arm compared with the i.v. carboplatin arm: 24.5% (95% CI 16.2% to 32.9%) versus 38.6% (95% CI 29.1% to 48.1%) P = 0.065. The study was underpowered to detect differences in PFS: HR PFS 0.82 (95% CI 0.57-1.17); P = 0.27 and OS HR 0.80 (95% CI 0.47-1.35) P = 0.40. The i.p. carboplatin-based regimen was well tolerated with no reduction in QOL or increase in toxicity compared with i.v. administration alone.
Conclusion: In women with stage IIIC or IVA EOC treated with NACT and optimal debulking surgery, i.p. carboplatin-based chemotherapy is well tolerated and associated with an improved PD9 compared with i.v. carboplatin-based chemotherapy.
Clinical trial number: clinicaltrials.gov, NCT01622543.

© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
PMID 29186319
Joan L Walker, Mark F Brady, Lari Wenzel, Gini F Fleming, Helen Q Huang, Paul A DiSilvestro, Keiichi Fujiwara, David S Alberts, Wenxin Zheng, Krishnansu S Tewari, David E Cohn, Matthew A Powell, Linda Van Le, Susan A Davidson, Heidi J Gray, Peter G Rose, Carol Aghajanian, Tashanna Myers, Angeles Alvarez Secord, Stephen C Rubin, Robert S Mannel
Randomized Trial of Intravenous Versus Intraperitoneal Chemotherapy Plus Bevacizumab in Advanced Ovarian Carcinoma: An NRG Oncology/Gynecologic Oncology Group Study.
J Clin Oncol. 2019 Jun 1;37(16):1380-1390. doi: 10.1200/JCO.18.01568. Epub 2019 Apr 19.
Abstract/Text PURPOSE: To evaluate the impact of two different intraperitoneal (IP) chemotherapy regimens on progression-free survival (PFS) among women with newly diagnosed advanced ovarian carcinoma.
METHODS: Eligible patients were randomly assigned to six cycles of IV paclitaxel 80 mg/m2 once per week with intravenous (IV) carboplatin area under the curve 6 (IV carboplatin) versus IV paclitaxel 80 mg/m2 once per week with IP carboplatin area under the curve 6 (IP carboplatin) versus once every 3 weeks IV paclitaxel 135 mg/m2 over 3 hours day 1, IP cisplatin 75 mg/m2 day 2, and IP paclitaxel 60 mg/m2 day 8 (IP cisplatin). All participants received bevacizumab 15 mg/kg IV every 3 weeks in cycles 2 to 22.
RESULTS: A total of 1,560 participants were enrolled and had 84.8 months of follow-up. The median PFS duration was 24.9 months in the IV carboplatin arm, 27.4 months in the IP carboplatin arm, and 26.2 months in the IP cisplatin arm. For the subgroup of 1,380 patients with stage II/III and residual disease of 1 cm or less, median PFS was 26.9 (IV-carboplatin), 28.7 (IP-carboplatin), and 27.8 months (IP cisplatin), respectively. Median PFS for patients with stage II/III and no residual disease was 35.9, 38.8, and 35.5 months, respectively. Median overall survival for all enrolled was 75.5, 78.9, and 72.9 months, respectively, and median overall survival for stage II/III with no gross residual disease was 98.8 months, 104.8 months, and not reached. Mean patient-reported Functional Assessment of Cancer Therapy neurotoxicity scores (Gynecologic Oncology Group) were similar for all arms, but the mean Trial Outcome Index of the Functional Assessment of Cancer Therapy-Ovary scores during chemotherapy were statistically worse in the IP cisplatin arm.
CONCLUSION: Compared with the IV carboplatin reference arm, the duration of PFS was not significantly increased with either IP regimen when combined with bevacizumab and was better tolerated than IP cisplatin.

PMID 31002578
Narikazu Boku, Seiichiro Yamamoto, Haruhiko Fukuda, Kuniaki Shirao, Toshihiko Doi, Akira Sawaki, Wasaburo Koizumi, Hiroshi Saito, Kensei Yamaguchi, Hiroya Takiuchi, Junichiro Nasu, Atsushi Ohtsu, Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group
Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study.
Lancet Oncol. 2009 Nov;10(11):1063-9. doi: 10.1016/S1470-2045(09)70259-1. Epub 2009 Oct 7.
Abstract/Text BACKGROUND: The best chemotherapy regimen for metastatic gastric cancer is uncertain, but promising findings have been reported with irinotecan plus cisplatin and S-1 (tegafur, 5-chloro-2,4-dihydropyrimidine, and potassium oxonate). We aimed to investigate the superiority of irinotecan plus cisplatin and non-inferiority of S-1 compared with fluorouracil, with respect to overall survival, in patients with metastatic gastric cancer.
METHODS: We undertook a phase 3 open label randomised trial in 34 institutions in Japan. We enrolled patients aged 20-75 years or younger, who had histologically proven gastric adenocarcinoma, and randomly assigned them by minimisation to receive either: a continuous infusion of fluorouracil (800 mg/m(2) per day, on days 1-5) every 4 weeks (n=234); intravenous irinotecan (70 mg/m(2), on days 1 and 15) and cisplatin (80 mg/m(2), on day 1) every 4 weeks (n=236); or oral S-1 (40 mg/m(2), twice a day, on days 1-28) every 6 weeks (n=234). The primary endpoint was overall survival. Analyses were done by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00142350, and with UMIN-CTR, number C000000062.
FINDINGS: All randomised patients were included in the primary analysis. Median overall survival was 10.8 months (IQR 5.7-17.8) for individuals assigned fluorouracil, 12.3 months (8.1-19.5) for those allocated irinotecan plus cisplatin (hazard ratio 0.85 [95% CI 0.70-1.04]; p=0.0552), and 11.4 months (6.4-21.3) for those assigned S-1 (0.83 [0.68-1.01]; p=0.0005 for non-inferiority). Three treatment-related deaths occurred in the irinotecan plus cisplatin group and one was recorded in the S-1 group.
INTERPRETATION: S-1 is non-inferior to fluorouracil and, in view of the convenience of an oral administration, could replace intravenous fluorouracil for treatment of unresectable or recurrent gastric cancer, at least in Asia. Irinotecan plus cisplatin is not superior to fluorouracil in this setting.

PMID 19818685
Wasaburo Koizumi, Hiroyuki Narahara, Takuo Hara, Akinori Takagane, Toshikazu Akiya, Masakazu Takagi, Kosei Miyashita, Takashi Nishizaki, Osamu Kobayashi, Wataru Takiyama, Yasushi Toh, Takashi Nagaie, Seiichi Takagi, Yoshitaka Yamamura, Kimihiko Yanaoka, Hiroyuki Orita, Masahiro Takeuchi
S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial.
Lancet Oncol. 2008 Mar;9(3):215-21. doi: 10.1016/S1470-2045(08)70035-4. Epub 2008 Feb 20.
Abstract/Text BACKGROUND: Phase I/II clinical trials of S-1 plus cisplatin for advanced gastric cancer have yielded good responses and the treatment was well tolerated. In this S-1 Plus cisplatin versus S-1 In RCT In the Treatment for Stomach cancer (SPIRITS) trial, we aimed to verify that overall survival was better in patients with advanced gastric cancer treated with S-1 plus cisplatin than with S-1 alone.
METHODS: In this phase III trial, chemotherapy-naive patients with advanced gastric cancer were enrolled between March 26, 2002, and Nov 30, 2004, at 38 centres in Japan, and randomly assigned to S-1 plus cisplatin or S-1 alone. In patients assigned to S-1 plus cisplatin, S-1 (40-60 mg depending on patient's body surface area) was given orally, twice daily for 3 consecutive weeks, and 60 mg/m(2) cisplatin was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. Those assigned to S-1 alone received the same dose of S-1 twice daily for 4 consecutive weeks, followed by a 2-week rest period, within a 6-week cycle. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportions of responders, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00150670.
FINDINGS: 305 patients were enrolled; seven patients were ineligible or withdrew consent, therefore, 148 patients were assigned to S-1 plus cisplatin and 150 patients were assigned to S-1 alone. Median overall survival was significantly longer in patients assigned to S-1 plus cisplatin (13.0 months [IQR 7.6-21.9]) than in those assigned to S-1 alone (11.0 months [5.6-19.8]; hazard ratio for death, 0.77; 95% CI 0.61-0.98; p=0.04). Progression-free survival was significantly longer in patients assigned to S-1 plus cisplatin than in those assigned to S-1 alone (median progression-free survival 6.0 months [3.3-12.9] vs 4.0 months [2.1-6.8]; p<0.0001). Additionally, of 87 patients assigned S-1 plus cisplatin who had target tumours, one patient had a complete response and 46 patients had partial responses, ie, a total of 54% (range 43-65). Of 106 patients assigned S-1 alone who had target tumours, one patient had a complete response and 32 had partial responses, ie, a total of 31% (23-41). We recorded more grade 3 or 4 adverse events including leucopenia, neutropenia, anaemia, nausea, and anorexia, in the group assigned to S-1 plus cisplatin than in the group assigned to S-1 alone. There were no treatment-related deaths in either group.
INTERPRETATION: S-1 plus cisplatin holds promise of becoming a standard first-line treatment for patients with advanced gastric cancer.

PMID 18282805
Hiroyuki Narahara, Hiroyasu Iishi, Hiroshi Imamura, Akira Tsuburaya, Keisho Chin, Haruhiko Imamoto, Taito Esaki, Hiroshi Furukawa, Chikuma Hamada, Yuh Sakata
Randomized phase III study comparing the efficacy and safety of irinotecan plus S-1 with S-1 alone as first-line treatment for advanced gastric cancer (study GC0301/TOP-002).
Gastric Cancer. 2011 Mar;14(1):72-80. doi: 10.1007/s10120-011-0009-5. Epub 2011 Feb 23.
Abstract/Text BACKGROUND: Irinotecan hydrochloride and S-1, an oral fluoropyrimidine, have shown antitumor activity against advanced gastric cancer as single agents in phase I/II studies. The combination of irinotecan and S-1 (IRI-S) is also active against advanced gastric cancer. This study was conducted to compare the efficacy and safety of IRI-S versus S-1 monotherapy in patients with advanced or recurrent gastric cancer.
METHODS: Patients were randomly assigned to oral S-1 (80 mg/m² daily for 28 days every 6 weeks) or oral S-1 (80 mg/m² daily for 21 days every 5 weeks) plus irinotecan (80 mg/m² by intravenous infusion on days 1 and 15 every 5 weeks) (IRI-S). The primary endpoint was overall survival. Secondary endpoints included the time to treatment failure, 1- and 2-year survival rates, response rate, and safety.
RESULTS: The median survival time with IRI-S versus S-1 monotherapy was 12.8 versus 10.5 months (P = 0.233), time to treatment failure was 4.5 versus 3.6 months (P = 0.157), and the 1-year survival rate was 52.0 versus 44.9%, respectively. The response rate was significantly higher for IRI-S than for S-1 monotherapy (41.5 vs. 26.9%, P = 0.035). Neutropenia and diarrhea occurred more frequently with IRI-S, but were manageable. Patients treated with IRI-S received more courses of therapy at a relative dose intensity similar to that of S-1 monotherapy.
CONCLUSIONS: Although IRI-S achieved longer median survival than S-1 monotherapy and was well tolerated, it did not show significant superiority in this study.

PMID 21340666
Hiroki Hara, Shigenori Kadowaki, Masako Asayama, Akira Ooki, Toko Yamada, Takako Yoshii, Kensei Yamaguchi
First-line bolus 5-fluorouracil plus leucovorin for peritoneally disseminated gastric cancer with massive ascites or inadequate oral intake.
Int J Clin Oncol. 2018 Apr;23(2):275-280. doi: 10.1007/s10147-017-1198-7. Epub 2017 Oct 16.
Abstract/Text BACKGROUND: There are few chemotherapeutic options for advanced gastric cancer with severe disseminated peritoneal metastases, which are usually accompanied by ascites. Bolus 5-fluorouracil (5-FU) plus leucovorin therapy has been widely used against gastrointestinal malignancies, with resulting mild toxicities.
METHODS: We retrospectively analyzed the efficacy and safety of first-line chemotherapy with bolus 5-FU plus l-leucovorin in 30 advanced gastric cancer patients who had massive ascites and/or inadequate oral intake. This therapy consisted of 5-FU (600 mg/m2 IV bolus) plus l-leucovorin (250 mg/m2 2-h IV infusion) administered on a 6 weeks on/2 weeks off schedule.
RESULTS: Among all the patients, 26 (87%) were unable to eat and 12 (40%) had massive ascites. Major grade 3 or 4 adverse events were neutropenia (17%), nausea (7%), fatigue (7%), and diarrhea (3%); no treatment-related deaths were observed. The median progression-free survival and overall survival (OS) were 2.4 months [95% confidence interval (CI), 0.6-4.1] and 6.0 months (95% CI, 2.1-9.9), respectively. Objective improvement in oral intake was seen in 7 patients (27%). Improvement in ascites occurred in 9 (39%) of 23 patients. In multivariate analyses, the presence of both massive ascites and inadequate oral intake was significantly associated with worse OS (hazard ratio, 5.25; 95% CI, 1.61-17.1). The median OS for patients (n = 22) without this factor was 7.2 months (95% CI, 4.2-10.3).
CONCLUSION: Our study suggests that bolus 5-FU plus l-leucovorin therapy is feasible and has clinical activity as palliative therapy in patients with severe peritoneal metastases from gastric cancer.

PMID 29039072
Takako Eguchi Nakajima, Kensei Yamaguchi, Narikazu Boku, Ichinosuke Hyodo, Junki Mizusawa, Hiroki Hara, Tomohiro Nishina, Takeshi Sakamoto, Kohei Shitara, Katsunori Shinozaki, Hiroshi Katayama, Shinichiro Nakamura, Kei Muro, Masanori Terashima
Randomized phase II/III study of 5-fluorouracil/l-leucovorin versus 5-fluorouracil/l-leucovorin plus paclitaxel administered to patients with severe peritoneal metastases of gastric cancer (JCOG1108/WJOG7312G).
Gastric Cancer. 2020 Jul;23(4):677-688. doi: 10.1007/s10120-020-01043-x. Epub 2020 Feb 8.
Abstract/Text BACKGROUND: Oral fluoropyrimidine plus cisplatin is often not tolerated by patients with severe peritoneal metastases of gastric cancer. Combination of 5-fluorouracil (5-FU), l-leucovorin (l-LV), and paclitaxel (FLTAX) has promising activity for such patients. We conducted a phase II/III study comparing FLTAX with 5-FU/l-LV.
METHODS: Eligibility criteria included: unresectable or recurrent gastric adenocarcinoma; 20-75 years; performance status (PS) 0-2; peritoneal metastases + ; massive ascites and/or inadequate oral intake; no prior chemotherapy. Patients were randomly assigned to receive 5-FU/l-LV or FLTAX. The primary endpoint of phase III was overall survival: UMIN000010949.
RESULTS: We enrolled 101 patients. Early deaths occurred in patients with PS 2 having massive ascites and inadequate oral intake simultaneously; the protocol was amended to exclude such patients. Median survival times were 6.1 and 7.3 months for the 5-FU/l-LV and the FLTAX arms, respectively (HR 0.792; 80% CI 0.596-1.053; one-sided p = 0.1445). FLTAX arm had longer progression-free survival (PFS) [1.9 vs 5.4 months (HR 0.64; 95% CI, 0.43-0.96; p = 0.029)]. Grade 3/4 adverse events such as leucopenia and anorexia were more frequently observed in the 5-FU/l-LV arm. In the 5-FU/l-LV arm, two deaths were treatment-related. In the 5-FU/l-LV and FLTAX arms, 12 and 3 deaths occurred within 30 days after the last protocol treatment, respectively.
CONCLUSIONS: Chemotherapy was indicated for patients with severe peritoneal metastases excluding patients with PS 2 having massive ascites and inadequate oral intake simultaneously. FLTAX did not confer a significant survival benefit but may be preferred because of longer PFS and acceptable toxicity.

PMID 32036492

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