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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)

Abstract

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.

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References

  1. 1.

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

  2. 2.

    Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, ToGA Trial Investigators, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-esophageal junction cancer (ToGA): a phase 3, open-label, randomized controlled trial. Lancet. 2010;376:687–97.

  3. 3.

    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.

  4. 4.

    Yamada Y, Higuchi K, Nishikawa K, Gotoh M, Fuse N, Sugimoto N, 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.

  5. 5.

    Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, RAINFALL Study Group, et al. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomized, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20:420–35.

  6. 6.

    Sasako M, Sano T, Yamamoto S, Kurokawa Y, Nashimoto A, Kurita A, Japan Clinical Oncology Group, et al. D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. N Engl J Med. 2008;359:453–62.

  7. 7.

    Koizumi W, Kim YH, Fujii M, Kim HK, Imamura H, Lee KH, JACCRO, and KCSG Study Group, et al. Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START). J Cancer Res Clin Oncol. 2014;140:319–28.

  8. 8.

    Iwasa S, Nakajima TE, Nakamura K, Takashima A, Kato K, Hamaguchi T, et al. Systemic chemotherapy for peritoneal disseminated gastric cancer with inadequate oral intake: a retrospective study. Int J Clin Oncol. 2011;16:57–62.

  9. 9.

    Iwasa S, Nakajima TE, Nakamura K, Takashima A, Kato K, Hamaguchi T, et al. First-line fluorouracil-based chemotherapy for patients with severe peritoneal disseminated gastric cancer. Gastric Cancer. 2012;15:21–6.

  10. 10.

    Hara H, Kadowaki S, Asayama M, Ooki A, Yamada T, Yoshii T, et al. First-line bolus 5-fluorouracil plus leucovorin for peritoneally disseminated gastric cancer with massive ascites or inadequate oral intake. Int J Clin Oncol. 2018;23:275–80.

  11. 11.

    Shirao K, Boku N, Yamada Y, Yamaguchi K, Doi T, Goto M, et al. Randomized Phase III study of 5-Fluorouracil continuous infusion vs. sequential methotrexate and 5-fluorouracil therapy in far advanced gastric cancer with peritoneal metastasis (JCOG0106). Jpn J Clin Oncol. 2013;43:972–80.

  12. 12.

    Sawaki A, Yamaguchi K, Nabeya Y, Sakai Y, Osanai H, Denda T, et al. 5-FU/l-LV (RPMI) versus S-1 as first-line therapy in patients with advanced gastric cancer: a randomized phase III non-inferiority trial (ISO-5FU10 Study Group trial). Eur J Cancer Suppl. 2009;7:364.

  13. 13.

    Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group, et al. Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomized phase 3 study. Lancet Oncol. 2009;10:1063–9.

  14. 14.

    Nishina T, Boku N, Gotoh M, Shimada Y, Hamamoto Y, Yasui H, Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group, et al. Randomized phase II study of second-line chemotherapy with the best available 5-fluorouracil regimen versus weekly administration of paclitaxel in far advanced gastric cancer with severe peritoneal metastases refractory to 5-fluorouracil-containing regimens (JCOG0407). Gastric Cancer. 2016;19:902–10.

  15. 15.

    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 K Gastroenterol. 2006;12:1412–5.

  16. 16.

    Kano Y, Akutsu M, Tsunoda S, Ando J, Matsui J, Suzuki K, et al. Schedule-dependent interaction between paclitaxel and 5-fluorouracil in human carcinoma cell lines in vitro. Br J Cancer. 1996;74:704–10.

  17. 17.

    Matsubara J, Shimada Y, Kato K, Nagai Y, Iwasa S, Nakajima TE, et al. Phase II study of bolus 5-fluorouracil and leucovorin combined with weekly paclitaxel as first-line therapy for advanced gastric cancer. Oncology. 2011;81:291–7.

  18. 18.

    Iwasa S, Goto M, Yasui H, Nishina T, Takahari D, Nakayama N, et al. Multicenter feasibility study of combination therapy with fluorouracil, leucovorin and paclitaxel (FLTAX) for peritoneal disseminated gastric cancer with massive ascites or inadequate oral intake. Jpn J Clin Oncol. 2012;42:787–93.

  19. 19.

    Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics. 1975;31:103–15.

  20. 20.

    The Economics Network. EQ-5D index calculator. [Cited 2019 May 2]. https://www.economicsnetwork.ac.uk/health/EQ_5D_index_calculator.xls

  21. 21.

    Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 1983;70:659–63.

  22. 22.

    Yuan SQ, Nie RC, Chen YM, Qiu HB, Li XP, Chen XJ, et al. Glasgow Prognostic Score is superior to ECOG PS as a prognostic factor in patients with gastric cancer with peritoneal seeding. Oncol Lett. 2018;15 4193–4200.

  23. 23.

    Abdel-Rahman O. Prognostic impact of baseline quality of life status among patients with advanced gastric cancer; results from two randomized studies. Expert Rev Pharmacoecon Outcomes Res. 2019;22:1–5.

  24. 24.

    Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, V325 Study Group, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 study group. J Clin Oncol. 2006;24:4991–7.

  25. 25.

    Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14:490–9.

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Acknowledgments

We thank the patients and their families, our collaborators who contributed to the study and recruited patients, the members of the JCOG/WJOG Data Center and JCOG/WJOG Operations Office for their support, and ASCA Corporation for editing a draft of this manuscript.

Funding

The study was supported in part by the National Cancer Research and Development Fund (26-A-4, 29-A-3), a Grant-in-Aid for Clinical Cancer Research (H26-144) from the Ministry of Health, Labour and Welfare of Japan, and by the Japan Agency for Medical Research and Development (AMED) (Grant Numbers JP16ck0106139 and JP18ck0106351). 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.

Author information

All authors contributed to the study conception, design, and conduct. Material preparation, data collection, and analysis were performed by Junki Mizusawa, Hiroshi Katayama, and Shinichiro Nakamura. The first draft of the manuscript was written by Takako Eguchi Nakajima, and all authors commented on the previous versions of the manuscript. All authors read and approved the final manuscript.

Correspondence to Takako Eguchi Nakajima.

Ethics declarations

Conflict of interest

Dr. Nakajima reports grants from AMED, during the conduct of the study; grants and personal fees from Taiho Pharmaceutical Co., Ltd., grants and personal fees from Merck Serono Co., Ltd., grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants and personal fees from Takeda Pharmaceutical Co., Ltd., grants and personal fees from Sanofi K.K., grants from Daiichi Sankyo Co., Ltd., grants and personal fees from Eli Lilly Japan K.K., grants and personal fees from Nippon Kayaku Co., Ltd., grants and personal fees from Ono Pharmaceutical Co., Ltd., grants from Astellas Pharma Inc., grants and personal fees from Sumitomo Dainippon Pharma Co., Ltd., grants from Eisai Co., grants and personal fees from MSD K.K., grants from Solasia Pharma K.K., grants from AstraZeneca K.K., personal fees from Sawai Pharmaceutical Co., personal fees from Bayer Yakuhin, Ltd., personal fees from Bristol-Myers Squibb, personal fees from Mochida Pharmaceutical Co., Ltd., personal fees from Kyowa Kirin Co., Ltd., personal fees from Maruho Co., Ltd., personal fees from Teijin Pharma Limited, and grants from AMED unrelated to the present study. Dr. Yamaguchi reports grants from AMED, during the conduct of the study; grants and personal fees from Taiho Pharmaceutical Co., Ltd., grants and personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from Merck Serono Co., Ltd., personal fees from Takeda Pharmaceutical Co., Ltd., grants and personal fees from Daiichi Sankyo Co., Ltd., grants and personal fees from Ono Pharmaceutical Co., Ltd., personal fees from Elli Lilly Japan K.K., personal fees from Bristol-Myers Squibb, grants from Sumitomo Dainippon Pharma Co., Ltd., grants from Boehringer Ingelheim, grants from Gilead Sciences, Inc., grants from MSD K.K., and grants from Yakult Honsha Co. unrelated to the present study. Dr. Boku reports grants and personal fees from Ono Pharmaceutical Co., Ltd., grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Taiho Pharmaceutical Co., Ltd., personal fees from Chugai Pharmaceutical Co., Ltd., and personal fees from Eli-Lilly Japan K.K. unrelated to the present study. Dr. Hyodo reports grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants and personal fees from Taiho Pharmaceutical Co., Ltd., grants and personal fees from Eli Lilly Japan K.K., grants and personal fees from Daiichi Sankyo Co., Ltd., and grants and personal fees from Ono Pharmaceutical Co., Ltd., unrelated to the present study. Dr. Mizusawa reports grants from Ministry of Health, Labour and Welfare, Japan, grants from AMED, during the conduct of the study; personal fees from Chugai Pharmaceutical Co., Ltd., unrelated to the present study. Dr. Hara reports grants from AMED, during the conduct of the study; grants from Astra Zeneca K.K., grants and personal fees from Daiichi Sankyo Co., Ltd., grants from Sumitomo Dainippon Pharma Co., Ltd., personal fees from Eli Lilly Japan K.K., grants from Merck Serono Co., Ltd., grants and personal fees from MSD K.K., grants and personal fees from Taiho Pharmaceutical Co., Ltd., grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants from Eisai Co., grants from LSK BioPharma, grants from Incyte, grants from Pfizer Inc., grants from Boehringer Ingelheim, grants from BeiGene, grants and personal fees from Ono Pharmaceutical Co., Ltd., grants and personal fees from Bristol-Myers Squibb, personal fees from Yakult Honsha Co., personal fees from Sanofi K.K., and personal fees from Takeda Pharmaceutical Co., Ltd., unrelated to the present study. Dr. Nishina reports grants and personal fees from Taiho Pharmaceutical Co., Ltd., grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants from Daiichi Sankyo Co., Ltd., grants from MSD K.K., grants and personal fees from Ono Pharmaceutical Co., Ltd., grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Eli Lilly Japan K.K., and grants from Sumitomo Dainippon Pharma Co., Ltd., unrelated to the present study. Dr. Sakamoto has nothing to disclose. Dr. Shitara reports grants and personal fees from Astellas Pharma Inc., grants and personal fees from Eli Lilly Japan K.K., personal fees from Bristol-Myers Squibb, personal fees from Takeda Pharmaceutical Co., Ltd., personal fees from Pfizer Inc., grants and personal fees from Ono Pharmaceutical Co., Ltd., personal fees from Novartis, personal fees from AbbVie, personal fees from Yakult Honsha, grants from Sumitomo Dainippon Pharma Co., Ltd., grants from Daiichi Sankyo Co., Ltd., grants from Taiho Pharmaceutical Co., Ltd., grants from Chugai Pharmaceutical Co., Ltd., grants and personal fees from MSD K.K., and grants from Medi-Science, Inc. unrelated to the present work. Dr. Shinozaki reports personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from Takeda Pharmaceutical Co., Ltd., personal fees from Mochida Pharmaceutical Co., Ltd., personal fees from Merck Serono Co., Ltd., personal fees from Taiho Pharmaceutical Co., Ltd., personal fees from Yakult Honsha Co., personal fees from Ono Pharmaceutical Co., Ltd., personal fees from Eisai Co., personal fees from Shionogi & Co., personal fees from Eli Lilly Japan K.K., personal fees from Sanofi K.K., personal fees from Daiichi Sankyo Co., Ltd., personal fees from Bayer Yakuhin, Ltd., and personal fees from Pfizer Inc. unrelated to the present study. Dr. Katayama reports grants and nonfinancial support from the Ministry of Health, Labour and Welfare, Japan, grants and nonfinancial support from AMED, during the conduct of the study, and personal fees from Johnson & Johnson K.K. unrelated to the present study. Dr. Nakamura has nothing to disclose. Dr. Muro reports grants from Gilead Sciences, Inc., grants from Daiichi Sankyo Co., Ltd., grants from Shionogi & Co., grants from MSD K.K., grants from Sanofi K.K., grants from Kyowa Kirin Co., Ltd., grants from Merck Serono Co., Ltd., grants from Pfizer Inc., personal fees from Eli Lilly Japan K.K., personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from Takeda Pharmaceutical Co., Ltd., personal fees from Taiho Pharmaceutical Co., Ltd., personal fees from Sanofi K.K., personal fees from Bayer Yakuhin, Ltd., and personal fees from Bristol-Myers Squibb unrelated to the present study. Dr. Terashima reports personal fees from Taiho Pharmaceutical Co., Ltd., personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from Ono Pharmaceutical Co., Ltd., personal fees from Bristol-Myers Squibb, personal fees from Yakult Honsha, personal fees from Takeda Pharmaceutical Co., Ltd., personal fees from Eli Lilly Japan K.K., personal fees from Pfizer Inc., and personal fees from Daiichi Sankyo Co., Ltd., unrelated to the present study.

Ethical approval

The review committees of the JCOG and WJOG and the institutional review boards of all participating institutions approved the study protocol, which was conducted according to the Declaration of Helsinki and Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects.

Informed consent

Informed consent to be included in the study was obtained from all patients.

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Nakajima, T.E., 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). https://doi.org/10.1007/s10120-020-01043-x

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