Skip to main content

Advertisement

SpringerLink
Log in

Phase II Study of Intraperitoneal Administration of Paclitaxel Combined with S-1 and Cisplatin for Gastric Cancer with Peritoneal Metastasis

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Intraperitoneal chemotherapy is promising for gastric cancer with peritoneal metastasis. Although a phase III study failed to show a statistically significant superiority of intraperitoneal paclitaxel combined with S-1 and intravenous paclitaxel, the sensitivity analysis suggested clinical efficacy. Thus, attempts to combine intraperitoneal paclitaxel with other systemic therapies with higher efficacy have been warranted. We sought to explore the efficacy of intraperitoneal paclitaxel with S-1 and cisplatin.

Patients and Methods

Gastric cancer patients with peritoneal metastasis were enrolled in the phase II trial. In addition to the established S-1 and cisplatin regimen every 5 weeks, intraperitoneal paclitaxel was administered on days 1, 8, and 22 at a dose of 20 mg/m2. The primary endpoint was overall survival rate at 1 year after treatment initiation. Secondary endpoints were progression-free survival and toxicity.

Results

Fifty-three patients were enrolled and fully evaluated for efficacy and toxicity. The 1-year overall survival rate was 73.6% (95% confidence interval 59.5–83.4%), and the primary endpoint was met. The median survival time was 19.4 months (95% confidence interval, 16.1–24.6 months). The 1-year progression-free survival rate was 49.6% (95% confidence interval, 34.6–62.9%). The incidences of grade 3/4 hematological and non-hematological toxicities were 43% and 47%, respectively. The frequent grade 3/4 toxicities included neutropenia (25%), anemia (30%), diarrhea (13%), and anorexia (17%). Intraperitoneal catheter and implanted port-related complications were observed in four patients. There was one treatment-related death.

Conclusions

Intraperitoneal paclitaxel combined with S-1 and cisplatin is well tolerated and active in gastric cancer patients with peritoneal metastasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Koizumi W, Narahara H, Hara T, 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.

    Article  CAS  PubMed  Google Scholar 

  2. Bang YJ, Van Cutsem E, Feyereislova A, et al; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomized controlled trial. Lancet. 2010; 376: 687-697.

  3. Wilke H, Muro K, Van Cutsem E, et al; RAINBOW Study Group. 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: 1224-1235.

  4. Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390:2461–71.

    Article  CAS  PubMed  Google Scholar 

  5. Shitara K, Bang YJ, Iwasa S, et al; DESTINY-Gastric01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med. 2020; 382: 2419-2430.

  6. Nakajima TE, Yamaguchi K, Boku N, et al. 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;23:677–88.

    Article  CAS  PubMed  Google Scholar 

  7. Jacquet P, Sugarbaker PH. Peritoneal-plasma barrier. Cancer Treat Res. 1996;82:53–63.

    Article  CAS  PubMed  Google Scholar 

  8. Ishigami H, Kitayama J, Otani K, et al. Phase I pharmacokinetic study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer. Oncology. 2009;76:311–4.

    Article  CAS  PubMed  Google Scholar 

  9. Kodera Y, Ito Y, Ito S, 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.

    CAS  PubMed  Google Scholar 

  10. Kobayashi D, Kodera Y. Intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis. Gastric Cancer. 2017;20:111–1121.

    Article  CAS  PubMed  Google Scholar 

  11. Takahashi N, Kanda M, Yoshikawa T, et al. 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. Gastric Cancer. 2018;21:1014–23.

    Article  CAS  PubMed  Google Scholar 

  12. Ito S, Imano M, Uenosono Y, et al. A phase II study of perioperative intraperitoneal paclitaxel plus S-1/paclitaxel for curatively resectable gastric cancer with serosal invasion: The GAPS study. J Clin Oncol. 2018;36:4033.

    Article  Google Scholar 

  13. Ishigami H, Fujiwara Y, Fukushima R, et al. Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC Trial. J Clin Oncol. 2018;36:1922–9.

    Article  CAS  PubMed  Google Scholar 

  14. Smyth EC, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D; ESMO Guidelines Committee. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016; 27: 538-549.

  15. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2021 (6th edition). Gastric Cancer. 202326: 1-25.

  16. Kang YK, Chen LT, Ryu MH, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022;23:234–47.

    Article  CAS  PubMed  Google Scholar 

  17. Kobayashi D, Ishigami H, Kanda M, et al. Phase I study of intraperitoneal administration of paclitaxel combined with S-1 plus cisplatin for gastric cancer with peritoneal metastasis. Oncology. 2020;98:48–52.

    Article  CAS  PubMed  Google Scholar 

  18. Jacquet P, Sugarbaker PH. Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis. Cancer Treat Res. 1996;82:359–74.

    Article  CAS  PubMed  Google Scholar 

  19. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.

    Article  CAS  PubMed  Google Scholar 

  20. http://www.swogstat.org/statoolsout.html Biometrics 38, 29-41, 1982

  21. Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29:3968–76.

    Article  CAS  PubMed  Google Scholar 

  22. Cunningham D, Starling N, Rao S, et al; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008; 358: 36-46.

  23. Yamada Y, Higuchi K, Nishikawa K, et al. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer. Ann Oncol. 2015;26:141–8.

    Article  CAS  PubMed  Google Scholar 

  24. Janjigian Y, Shitara K, Moehler M, et al. Nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/oesophageal adenocarcinoma (CheckMate 649): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2021;398:27–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kang YK, Chen LT, Ryu MH, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet. 2022;23:234–47.

    Article  CAS  Google Scholar 

  26. Saito S, Yamaguchi H, Ohzawa H, et al. Intraperitoneal administration of paclitaxel combined with S-1 plus oxaliplatin as induction therapy for patients with advanced gastric cancer with peritoneal metastases. Ann Surg Oncol. 2021;28:3863–70.

    Article  PubMed  Google Scholar 

  27. Shi M, Yang Z, Lu S, et al. Oxaliplatin plus S-1 with intraperitoneal paclitaxel for the treatment of Chinese advanced gastric cancer with peritoneal metastases. BMC Cancer. 2021;21:1344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chia DKA, Sundar R, Kim G, et al. Outcomes of a phase II study of intraperitoneal paclitaxel plus systemic capecitabine and oxaliplatin (XELOX) for gastric cancer with peritoneal metastases. Ann Surg Oncol. 2022;29:8597–605.

    Article  PubMed  Google Scholar 

  29. Kang SH, Min SH, Kim JW, et al. Safety and efficacy of intraperitoneal paclitaxel plus intravenous fluorouracil, leucovorin, and oxaliplatin (FOLFOX) for gastric cancer with peritoneal metastasis. Ann Surg Oncol. 2022;29:5084–91.

    Article  PubMed  Google Scholar 

  30. Tu L, Zhang W, Ni L, et al. Study of SOX combined with intraperitoneal high-dose paclitaxel in gastric cancer with synchronous peritoneal metastasis: a phase II single-arm clinical trial. Cancer Med. 2023;12:4161–9.

    Article  CAS  PubMed  Google Scholar 

  31. Yamada Y, Boku N, Mizusawa J, et al. Docetaxel plus cisplatin and S-1 versus cisplatin and S-1 in patients with advanced gastric cancer (JCOG1013): an open-label, phase 3, randomised controlled trial. Lancet Gastroenterol Hepatol. 2019;4:501–10.

    Article  PubMed  Google Scholar 

  32. Ryu MH, Baba E, Lee KH, et al. SOS study investigators. Comparison of two different S-1 plus cisplatin dosing schedules as first-line chemotherapy for metastatic and/or recurrent gastric cancer: a multicenter, randomized phase III trial (SOS). Ann Oncol. 2015; 26: 2097-2101.

Download references

Acknowledgement

We sincerely thank all the participating patients and their families; investigators; support staff; members of the data and safety monitoring board. This study was supported in part by funding from Clinical Trials of Cancer Research Grant Program conducted by the Japan Society of Clinical Oncology and the Japan Agency for Medical Research and Development.

Author information

Authors and Affiliations

  1. Department of Gastroenterological Surgery, Komaki City Hospital, Komaki, Japan

    Daisuke Kobayashi MD, PhD

  2. Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Daisuke Kobayashi MD, PhD, Yasuhiro Kodera MD, PhD, Koki Nakanishi MD, PhD & Dai Shimizu MD, PhD

  3. Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan

    Ryoji Fukushima MD, PhD

  4. Department of Gastroenterological Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan

    Masaru Morita MD, PhD

  5. Department of Gastrointestinal Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan

    Sachio Fushida MD, PhD

  6. Department of Surgery, Tsuboi Hospital, Koriyama, Japan

    Naoyuki Yamashita MD, PhD

  7. Department of Digestive and Transplant Surgery, Tokushima University Hospital, Tokushima, Japan

    Kozo Yoshikawa MD, PhD

  8. Department of Gastroenterological Surgery and Oncology, Medical Research Institute Kitano Hospital, Osaka, Japan

    Shugo Ueda MD, PhD

  9. Department of Gastroenterological Surgery, Niigata Cancer Center Hospital, Niigata, Japan

    Hiroshi Yabusaki MD, PhD

  10. Department of Gastroenterological Surgery, Clinical Research Institute Cancer Research Division, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan

    Tetsuya Kusumoto MD, PhD

  11. Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    Takaaki Arigami MD, PhD

  12. Department of Surgery, Kanto Rosai Hospital, Kawasaki, Japan

    Akio Hidemura MD, PhD

  13. Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan

    Takeshi Omori MD, PhD

  14. Department of Clinical Oncology, Jichi Medical University, Shimotsuke, Japan

    Hironori Yamaguchi MD, PhD

  15. Cancer Care Promotion Center, University of Fukui Hospital, Fukui, Japan

    Yasuo Hirono MD, PhD

  16. Department of Medical Oncology, Tonan Hospital, Sapporo, Japan

    Yasushi Tsuji MD, PhD

  17. Department of Surgery, Osaka Police Hospital, Osaka, Japan

    Jeong Ho Moon MD, PhD

  18. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo Medical University, Nishinomiya, Japan

    Toshihiko Tomita MD, PhD

  19. Department of Surgery, Toyonaka Municipal Hospital, Toyonaka, Japan

    Hiroshi Imamura MD, PhD

  20. Department of Clinical Biostatistics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

    Akihiro Hirakawa PhD

  21. Department of Chemotherapy, The University of Tokyo, Tokyo, Japan

    Hironori Ishigami MD, PhD

  22. Center for Clinical Research, Jichi Medical University Hospital, Shimotsuke, Japan

    Joji Kitayama MD, PhD

Authors
  1. Daisuke Kobayashi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yasuhiro Kodera MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ryoji Fukushima MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masaru Morita MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sachio Fushida MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naoyuki Yamashita MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kozo Yoshikawa MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shugo Ueda MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hiroshi Yabusaki MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tetsuya Kusumoto MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takaaki Arigami MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Akio Hidemura MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Takeshi Omori MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hironori Yamaguchi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yasuo Hirono MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yasushi Tsuji MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Jeong Ho Moon MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Toshihiko Tomita MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Hiroshi Imamura MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Koki Nakanishi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Dai Shimizu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Akihiro Hirakawa PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Hironori Ishigami MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Joji Kitayama MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daisuke Kobayashi MD, PhD.

Ethics declarations

Disclosure

This study was supported in part by funding from Clinical Trials of Cancer Research Grant Program conducted by Japan Society of Clinical Oncology and the Japan Agency for Medical Research and Development. D. Kobayashi received honoraria from Taiho Pharmaceutical Co., Ltd., and Bristol-Myers Squibb Co., Ltd. Y. Kodera received research funding from Taiho Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., and Pfizer Co., Ltd., and honoraria from Taiho Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., and Bristol-Myers Squibb Co., Ltd. S. Ueda received honoraria from Pfizer Co., Ltd. T. Arigami received honoraria from Bristol-Myers Squibb Co., Ltd. A. Hidemura received honoraria from Taiho Pharmaceutical Co., Ltd. T. Omori received research funding from Taiho Pharmaceutical Co., Ltd., and honoraria from Taiho Pharmaceutical Co., Ltd., and Bristol-Myers Squibb Co., Ltd. H. Yamaguchi received research funding from Taiho Pharmaceutical Co., Ltd., and Nippon Kayaku Co., Ltd., and honoraria from Taiho Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., and Bristol-Myers Squibb Co., Ltd. H. Y. Hirono received research funding from Taiho Pharmaceutical Co., Ltd., and honoraria from Taiho Pharmaceutical Co., Ltd. Y. Tsuji received honoraria from Taiho Pharmaceutical Co., Ltd. T. Tomita received honoraria from Taiho Pharmaceutical Co., Ltd., and Bristol-Myers Squibb Co., Ltd. K. Nakanishi received honoraria from Taiho Pharmaceutical Co., Ltd. A. Hirakawa received consulting fees from Taiho Pharmaceutical Co., Ltd. H. Ishigami received research funding from Taiho Pharmaceutical Co., Ltd., and drugs from Nippon Kayaku Co., Ltd.

Ethical Approval

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) 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.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kobayashi, D., Kodera, Y., Fukushima, R. et al. Phase II Study of Intraperitoneal Administration of Paclitaxel Combined with S-1 and Cisplatin for Gastric Cancer with Peritoneal Metastasis. Ann Surg Oncol 31, 735–743 (2024). https://doi.org/10.1245/s10434-023-14240-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-023-14240-6

Search

Navigation