Gastric Cancer

, Volume 21, Issue 6, pp 1014–1023 | Cite as

A randomized phase II multicenter trial to explore efficacy of weekly intraperitoneal in comparison with intravenous paclitaxel administered immediately after gastrectomy to the patients with high risk of peritoneal recurrence: final results of the INPACT trial

  • Naoto Takahashi
  • Mitsuro Kanda
  • Takaki Yoshikawa
  • Nobuhiro Takiguchi
  • Kazumasa Fujitani
  • Katsufumi Miyamoto
  • Yuichi Ito
  • Osamu Takayama
  • Motohiro Imano
  • Norio Mitsumori
  • Junichi Sakamoto
  • Satoshi Morita
  • Yasuhiro Kodera
Original Article



Intraperitoneal administration of paclitaxel had been considered a promising option to treat peritoneal metastasis, the most frequent pattern of recurrence in gastric cancer after D2 gastrectomy, but its safety and efficacy after gastrectomy had not been fully explored.


A phase II randomized comparison of postoperative intraperitoneal (IP) vs. intravenous (IV) paclitaxel was conducted. Patients with resectable gastric linitis plastica, cancer with minimal amount of peritoneal deposits (P1), or cancer positive for the peritoneal washing cytology (CY1) were eligible. After intraoperative confirmation of the above disease status and of resectability, patients were randomized to be treated either by the IP therapy (paclitaxel 60 mg/m2 delivered intraperitoneally on days 0, 14, 21, 28, 42, 49, and 56) or the IV therapy (80 mg/m2 administered intravenously using the identical schedule) before receiving further treatments with evidence-based systemic chemotherapy. The primary endpoint was 2-year survival rate.


Of the 86 patients who were randomized intraoperatively, 83 who actually started the protocol treatment were eligible for analysis (n = 39, IP group; n = 44, IV group). The 2-year survival rate of the IP and IV groups was 64.1% (95% CI 47.9–76.9) and 72.3% (95% CI 56.3–83.2%), respectively (p = 0.5731). The IP treatment did not confer significant overall or progression-free survival benefits, and was associated with particularly poor performance in patients with residual disease, including the CY1 P0 population.


We were unable to prove superiority of the IP paclitaxel over IV paclitaxel delivered after surgery to control advanced gastric cancer with high risk of peritoneal recurrence.


Gastric cancer Intraperitoneal administration Paclitaxel Peritoneal metastasis 



Paclitaxel was provided by Bristol-Myers K. K. for intraperitoneal administration in the study arm and testing of drug hypersensitivity. This study was supported, in part, by the nonprofit Epidemiological and Clinical Research Information Network (ECRIN).

Compliance with ethical standards

All procedures followed were in accordance with the ethical standards of the responsible institutional committee on human experimentation and with the Helsinki Declaration of 1964 and later versions. Informed consent to be included in the study, or the equivalent, was obtained from all patients.

Conflict of interest disclosure statement

Dr. Yoshikawa reports grants from Japanese Foundation for Multidisciplinary Treatment of Cancer during the conduct of the study; grants and personal fees from Chugai Pharmaceutical, Taiho Pharmaceutical, and Novartis Pharmaceuticals Japan; personal fees from Abbott Japan, Ono Pharmaceutical, Eli Lilly Japan, Kaken Pharmaceutical, Yakult Honsha, Nippon Kayaku, Johnson and Johnsons, Covidien Japan, Takeda Pharmaceutical, and Olympus outside the submitted work. Dr. Sakamoto received a consulting fee from Takeda Pharmaceutical and personal fees from Tsumura and Chugai Pharmaceutical Co. Ltd outside the submitted work. Dr. Morita received personal fees from Daiichi-Sankyo and Chugai Pharmaceutical outside the submitted work. Dr. Kodera reports grants and personal fees from Taiho Pharmaceutical, Chugai Phamaceutical, Sanofi, Merck Serono, Yakult Honsha, Daiichi Sankyo, Otsuka Pharmaceutical Factory, Takeda Pharmaceutical, Kaken Pharmaceutical, Ono Pharmaceutical, Johnson & Johnson, and Eli Lilly Japan; and grants from Pfizer Japan, EA Pharma, Covidien Japan, Shionogi, Bristol Myers Squib, Japan Blood Products Organization, AbbVie GK, Eizai, Abbott Japan, CSL Behring, Tsumura, Nippon Kayaku, Novartis Pharmaceuticals Japan, KCI, Toyama Chemical, and Maruho; and personal fees from MSD, Olympus, and Asahi Kasei Pharma outside the submitted work.


  1. 1.
    Chang JS, Kim KH, Yoon HI, Hyung WJ, Rha SY, et al. Locoregional relapse after gastrectomy with D2 lymphadenectomy for gastric cancer. Br J Surg. 2017;104:877–84.CrossRefGoogle Scholar
  2. 2.
    Burbidge S, Mahady K, Naik K. The role of CT and staging laparoscopy in the staging of gastric cancer. Clin Radiol. 2013;68:251–5.CrossRefGoogle Scholar
  3. 3.
    Kobayashi M, Sakamoto J, Namikawa T, Okamoto K, Okabayashi T, Ichikawa K, et al. Pharmacokinetic study of paclitaxel in malignant ascites from advanced gastric cancer patients. World J Gastroenterol. 2006;12:1412–5.CrossRefGoogle Scholar
  4. 4.
    Kodera Y. Gastric cancer with minimal peritoneal metastasis: is this a sign to give up or to treat more aggressively? Nagoya J Med Sci. 2013;75:3–10.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14:101–12.CrossRefGoogle Scholar
  6. 6.
    Ohashi N, Kodera Y, Nakanishi H, Yokoyama H, Fujiwara M, Koike M, et al. Efficacy of intraperitonreal chemotherapy with paclitaxel targeting peritoneal micrometastasis as revealed by GFP-tagged human gastric cancer cell lines in nude mice. Int J Oncol. 2005;27:637–44.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, et al. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combinatino chemotherapy using fluoropyrimidine plus platinum: WJSO4007 trial. J Clin Oncol. 2013;31:4438–44.CrossRefGoogle Scholar
  8. 8.
    Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224–35.CrossRefGoogle Scholar
  9. 9.
    Kodera Y, Ito Y, Ito S, Ohashi N, Mochizuki Y, Yamamura Y, et al. Intraperitoneal paclitaxel: a possible impact of regional delivery for prevention of peritoneal carcinomatosis in patients with gastric carcinoma. Hepatogastroenterology. 2007;54:960–3.Google Scholar
  10. 10.
    Markman M, Brady MF, Spirtos NM, Hanjani P, Rubin SC. Phase II trial of intraperitoneal paclitaxel in carcinoma of the ovary, tube, and peritoneum: a Gynecologic Oncology Group Study. J Clin Oncol. 1998;16:2620–4.CrossRefGoogle Scholar
  11. 11.
    Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34–43.CrossRefGoogle Scholar
  12. 12.
    Kodera Y, Imano M, Yoshikawa T, Takahashi N, Tsuburaya A, Miyashita Y, et al. A randomized phase II trial to test the efficacy of intra-peritoneal paclitaxel for gastric cancer with high risk for the peritoneal metastasis (INPACT trial). Jpn J Clin Oncol. 2011;41:283–6.CrossRefGoogle Scholar
  13. 13.
    Kodera Y, Takahashi N, Yoshikawa T, Takiguchi N, Fujitani K, Ito Y, et al. Feasibility of weekly intraperitoneal versus intravenous paclitaxel therapy delivered from the day of radical surgery for gastric cancer: a preliminary safety analysis of the INPACT study, a randomized controlled trial. Gastric Cancer. 2017;20:190–9.CrossRefGoogle Scholar
  14. 14.
    Markman M, Walker JL. Intraperitoneal chemotherapy of ovarian cancer: a review, with a focus on practical aspects of treatment. J Clin Oncol. 2006;24:988–94.CrossRefGoogle Scholar
  15. 15.
    Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, et al. Adjuvant chemotherapy for gastric cancer with S-1, and oral fluoropyrimidine. N Engl J Med. 2007;357:1810–20.CrossRefGoogle Scholar
  16. 16.
    Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, et al. 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;9:215–21.CrossRefGoogle Scholar
  17. 17.
    Kobayashi M, Tsuburaya A, Nagata N, Miyashita Y, Oba K, Sakamoto J. A feasibility study of sequential paclitaxel and S-1 (PTX/S-1) chemotherapy as postoperative adjuvant chemotherapy for advanced gastric cancer. Gastric Cancer. 2006;9:114–9.CrossRefGoogle Scholar
  18. 18.
    Tsuburaya A, Yoshida K, Kobayashi M, Yoshino S, Takahashi M, Takiguchi N, et al. Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. Lancet Oncol. 2014;15:886–93.CrossRefGoogle Scholar
  19. 19.
    Association Japanese Gastric Cancer. Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer. 2017;20:1–19.CrossRefGoogle Scholar
  20. 20.
    Kodera Y, Ito S, Mochizuki Y, Kondo K, Koshikawa K, Suzuki N, et al. A phase II study of radical surgery followed by postoperative chemotherapy with S-1 for gastric carcinoma with free cancer cells in the peritoneal cavity (CCOG0301 study). Eur J Surg Oncol. 2009;35:1158–63.CrossRefGoogle Scholar
  21. 21.
    Yang K, Liu K, Zhang WH, Lu ZH, Chen XZ, Chen XL, et al. The value of palliative gastrectomy for gastric cancer patients with intraoperativel proven peritoneal seeding. Medicine. 2015;94:e1051.CrossRefGoogle Scholar
  22. 22.
    Ishigami H, Kitayama J, Kaisaki S, Hidemura A, Kato M, Otani K, et al. Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis. Ann Oncol. 2010;21:67–70.CrossRefGoogle Scholar
  23. 23.
    Kono K, Yong WP, Okayama H, Shabbir A, Momma T, Ohki S, et al. Intraperitoneal chemotherapy for gastric cancer with peritoneal disease: experience from Singapore and Japan. Gastric Cancer. 2017;20:122–7.CrossRefGoogle Scholar
  24. 24.
    Kitayama J, Ishigami H, Yamaguchi H, Yamashita H, Emoto S, Kaisaki S, et al. Salvage gastrectomy after intravenous and intraperitoneal paclitaxel (PTX) administration with oral S-1 for peritoneal dissemination of advanced gastric cancer with malignant ascites. Ann Surg Oncol. 2014;21:539–46.CrossRefGoogle Scholar

Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2018

Authors and Affiliations

  • Naoto Takahashi
    • 1
  • Mitsuro Kanda
    • 2
  • Takaki Yoshikawa
    • 3
  • Nobuhiro Takiguchi
    • 4
  • Kazumasa Fujitani
    • 5
  • Katsufumi Miyamoto
    • 6
  • Yuichi Ito
    • 7
  • Osamu Takayama
    • 8
  • Motohiro Imano
    • 9
  • Norio Mitsumori
    • 10
  • Junichi Sakamoto
    • 11
  • Satoshi Morita
    • 12
  • Yasuhiro Kodera
    • 2
  1. 1.Department of Surgery, Jikei University School of MedicineKashiwa HospitalChibaJapan
  2. 2.Department of Gastroenterological Surgery (Surgery II)Nagoya University Graduate School of MedicineNagoyaJapan
  3. 3.Department of Gastrointestinal SurgeryKanagawa Cancer CenterYokohamaJapan
  4. 4.Division of Gastroenterological SurgeryChiba Cancer CenterChibaJapan
  5. 5.Department of SurgeryOsaka Prefectural General Medical CenterOsakaJapan
  6. 6.Department of SurgeryHyogo Prefectural Awaji Medical CenterSumotoJapan
  7. 7.Department of Gastroenterological SurgeryAichi Cancer Center HospitalNagoyaJapan
  8. 8.Department of SurgeryItami City HospitalItamiJapan
  9. 9.Department of Surgery, Faculty of MedicineKinki UniversityHigashiosakaJapan
  10. 10.Department of SurgeryJikei University School of MedicineTokyoJapan
  11. 11.Tokai Central HospitalKakamigaharaJapan
  12. 12.Department of Biomedical Statistics and BioinformaticsKyoto University Graduate School of MedicineKyotoJapan

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