Skip to main content

Advertisement

SpringerLink
Log in

Outcomes of a Phase II Study of Intraperitoneal Paclitaxel plus Systemic Capecitabine and Oxaliplatin (XELOX) for Gastric Cancer with Peritoneal Metastases

  • Peritoneal Surface Malignancy
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Adding intraperitoneal paclitaxel (IP-PTX) to paclitaxel/5-fluoropyrimidine has shown promising results in patients with gastric cancer peritoneal metastases (GCPM) but has not been studied with standard-of-care platinum/fluoropyrimidine combinations. Our goal to was evaluate IP-PTX with capecitabine/oxaliplatin (XELOX) in GCPM.

Methods

Forty-four patients with GCPM received IP PTX (40 mg/m2, Days 1, 8), oral capecitabine (1000 mg/m2 twice daily, Days 1–14) and intravenous oxaliplatin (100 mg/m2, Day 1) in 21-day cycles. Patients with synchronous GCPM underwent conversion surgery if they had good response after chemotherapy, conversion to negative cytology, no extraperitoneal metastasis, and no peritoneal disease during surgery. The primary endpoint was overall survival and secondary endpoints were progression-free survival and safety. Outcomes from the trial were compared against a matched cohort of 39 GCPM patients who received systemic chemotherapy (SC) comprising platinum/fluoropyrimidine.

Results

The median OS for the IP and SC groups was 14.6 and 10.6 months (hazard ratio [HR] 0.44; 95% confidence interval [CI], 0.26–0.74; p = 0.002). The median PFS for the IP and SC group was 9.5 and 4.4 months respectively (HR 0.39; 95% CI 0.25–0.66; p < 0.001). Patients in the SC group were younger (IP vs. SC, 61 vs. 56 years, p = 0.021) and had better performance status (ECOG 0, IP vs. SC, 47.7% vs. 76.9%, p = 0.007) compared with the IP cohort. In IP group, conversion surgery was performed in 36.1% (13/36) of patients, with a median OS of 24.2 (95% CI 13.1–35.3) months and 1-year OS of 84.6%.

Conclusions

IP PTX with XELOX is a promising treatment option for GCPM patients. In patients with good response, conversion surgery was feasible with favourable outcomes.

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

Similar content being viewed by others

References

  1. Chu DZ, Lang NP, Thompson C, et al. Peritoneal carcinomatosis in nongynecologic malignancy. A prospective study of prognostic factors. Cancer. 1989;63(2):364–7. https://doi.org/10.1002/1097-0142(19890115)63:2%3c364::aid-cncr2820630228%3e3.0.co;2-v.

    Article  CAS  PubMed  Google Scholar 

  2. Sadeghi B, Arvieux C, Glehen O, et al. Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer. 2000;88(2):358–63. https://doi.org/10.1002/(sici)1097-0142(20000115)88:2%3c358::aid-cncr16%3e3.0.co;2-o.

    Article  CAS  PubMed  Google Scholar 

  3. Muro K, Van Cutsem E, Narita Y, et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic gastric cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS. Ann Oncol. 2019;30(1):19–33. https://doi.org/10.1093/annonc/mdy502.

    Article  CAS  PubMed  Google Scholar 

  4. Dedrick RL, Myers CE, Bungay PM, et al. Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treat Rep. 1978;62(1):1–11.

    CAS  PubMed  Google Scholar 

  5. de Bree E, Michelakis D, Stamatiou D, et al. Pharmacological principles of intraperitoneal and bidirectional chemotherapy. Pleura Peritoneum. 2017;2(2):47–62. https://doi.org/10.1515/pp-2017-0010.

    Article  PubMed  Google Scholar 

  6. Chia DKA, So JBY. Recent advances in intra-peritoneal chemotherapy for gastric cancer. J Gastric Cancer. 2020;20(2):115–26. https://doi.org/10.5230/jgc.2020.20.e15.

    Article  PubMed  Google Scholar 

  7. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34–43. https://doi.org/10.1056/NEJMoa052985.

    Article  CAS  PubMed  Google Scholar 

  8. Kobayashi D, Kodera Y. Intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis. Gastric Cancer Off J Int Gastric Cancer Assoc Jpn Gastric Cancer Assoc. 2017;20(Suppl 1):111–21.

    CAS  Google Scholar 

  9. Ishigami H, Kitayama J, Kaisaki S, et al. Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis. Ann Oncol Off J Eur Soc Med Oncol. 2010;21(1):67–70.

    Article  CAS  Google Scholar 

  10. Fujiwara Y, Takiguchi S, Nakajima K, et al. Intraperitoneal docetaxel combined with S-1 for advanced gastric cancer with peritoneal dissemination. J Surg Oncol. 2012;105(1):38–42.

    Article  CAS  PubMed  Google Scholar 

  11. Imano M, Peng Y-F, Itoh T, et al. A preliminary study of single intraperitoneal administration of paclitaxel followed by sequential systemic chemotherapy with S-1 plus paclitaxel for advanced gastric cancer with peritoneal metastasis. Anticancer Res. 2012;32(9):4071–5.

    CAS  PubMed  Google Scholar 

  12. Yamaguchi H, Kitayama J, Ishigami H, et al. A phase 2 trial of intravenous and intraperitoneal paclitaxel combined with S-1 for treatment of gastric cancer with macroscopic peritoneal metastasis. Cancer. 2013;119(18):3354–8.

    Article  CAS  PubMed  Google Scholar 

  13. Fushida S, Kinoshita J, Kaji M, et al. Phase I/II study of intraperitoneal docetaxel plus S-1 for the gastric cancer patients with peritoneal carcinomatosis. Cancer Chemother Pharmacol. 2013;71(5):1265–72.

    Article  CAS  PubMed  Google Scholar 

  14. Ishigami H, Yamaguchi H, Yamashita H, et al. Surgery after intraperitoneal and systemic chemotherapy for gastric cancer with peritoneal metastasis or positive peritoneal cytology findings. Gastric Cancer Off J Int Gastric Cancer Assoc Jpn Gastric Cancer Assoc. 2017;20(Suppl 1):128–34.

    Google Scholar 

  15. 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 Off J Am Soc Clin Oncol. 2018;36(19):1922–9.

    Article  CAS  Google Scholar 

  16. Yarema R, Ohorchak M, Hyrya P, et al. Gastric cancer with peritoneal metastases: efficiency of standard treatment methods. World J Gastrointest Oncol. 2020;12(5):569–81. https://doi.org/10.4251/wjgo.v12.i5.569.

    Article  PubMed  Google Scholar 

  17. Japanese Gastric Cancer Association. Japanese Classification of Gastric Carcinoma—2nd English Edition. Gastric Cancer. 1998;1(1):10-24.

  18. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2):205–13. https://doi.org/10.1097/01.sla.0000133083.54934.ae.

    Article  PubMed  Google Scholar 

  19. Laura HT, Jordan B, Philip B, et al. Protocol for the examination of specimens from patients with carcinoma of the stomach. In: Cancer protocol. College of American Pathologists; 2014.

  20. Li Z, Xue K, Ying X, Ji J. PHOENIX-GC Trial: underpowered for significant results? J Clin Oncol. 2019;37(2):167. https://doi.org/10.1200/JCO.18.00364.

    Article  PubMed  Google Scholar 

  21. Maeda H, Kobayashi M, Sakamoto J. Evaluation and treatment of malignant ascites secondary to gastric cancer. World J Gastroenterol. 2015;21(39):10936–47. https://doi.org/10.3748/wjg.v21.i39.10936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ishigami H. Reply to Z. Li et al. J Clin Oncol. 2019;37(2):167–8. https://doi.org/10.1200/JCO.18.01003.

  23. Lu Z, Zhang X, Liu W, et al. A multicenter, randomized trial comparing efficacy and safety of paclitaxel/capecitabine and cisplatin/capecitabine in advanced gastric cancer. Gastric Cancer. 2018;21(5):782–91. https://doi.org/10.1007/s10120-018-0809-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jeung HC, Rha SY, Im CK, et al. A randomized phase 2 study of docetaxel and S-1 versus docetaxel and cisplatin in advanced gastric cancer with an evaluation of SPARC expression for personalized therapy. Cancer. 2011;117(10):2050–7. https://doi.org/10.1002/cncr.25729.

    Article  CAS  PubMed  Google Scholar 

  25. Smyth EC, Verheij M, Allum W, et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(suppl 5):v38-49. https://doi.org/10.1093/annonc/mdw350.

    Article  CAS  PubMed  Google Scholar 

  26. Kuo YC, Liu HT, Lin YL, et al. Modified biweekly oxaliplatin and capecitabine for advanced gastric cancer: a retrospective analysis from a medical center. Biomed J. 2014;37(3):141–6. https://doi.org/10.4103/2319-4170.117887.

    Article  PubMed  Google Scholar 

  27. Chao Y, Hsieh JS, Yeh HT, et al. A multicenter phase II study of biweekly capecitabine in combination with oxaliplatin as first-line chemotherapy in patients with locally advanced or metastatic gastric cancer. Cancer Chemother Pharmacol. 2014;73(4):799–806. https://doi.org/10.1007/s00280-014-2407-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Heger U, Bader F, Lordick F, et al. Interim endoscopy results during neoadjuvant therapy for gastric cancer correlate with histopathological response and prognosis. Gastric Cancer. 2014;17(3):478–88. https://doi.org/10.1007/s10120-013-0296-0.

    Article  CAS  PubMed  Google Scholar 

  29. Giganti F, Tang L, Baba H. Gastric cancer and imaging biomarkers: part 1—a critical review of DW-MRI and CE-MDCT findings. Eur Radiol. 2019;29(4):1743–53. https://doi.org/10.1007/s00330-018-5732-4.

    Article  PubMed  Google Scholar 

  30. Tang L, Wang XJ, Baba H, Giganti F. Gastric cancer and image-derived quantitative parameters: part 2—a critical review of DCE-MRI and 18F-FDG PET/CT findings. Eur Radiol. 2020;30(1):247–60. https://doi.org/10.1007/s00330-019-06370-x.

    Article  PubMed  Google Scholar 

  31. Emoto S, Ishigami H, Hidemura A, et al. Complications and management of an implanted intraperitoneal access port system for intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis. Jpn J Clin Oncol. 2012;42(11):1013–9. https://doi.org/10.1093/jjco/hys129.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the patients and their families who participated in this study, as well as colleagues from the Department of Surgery (National University Hospital and Ng Teng Fong General Hospital, Singapore), National University Cancer Institute, Singapore and Department of Pathology (National University Hospital, Singapore). This study received funding from the National Medical Research Council (NMRC) Translational and Clinical Flagship Programme (NMRC/TCR/009-NUHS/2013) and NMRC Centre Grants (NMRC/CG/012/2013 and NMRC/CG/M005/2017_NCIS). Dr. Raghav Sundar also is supported by a NMRC Fellowship (NMRC/Fellowship/0059/2018).

Funding

The National Medical Research Council (NMRC) oversees the development and advancement of medical research in Singapore. Trial registry: NCT01739894.

Author information

Authors and Affiliations

  1. Department of Surgery, University Surgical Cluster, National University Health System, Singapore, Singapore

    Daryl K. A. Chia FRCS, Guowei Kim FRCS, Jia Jun Ang MRCS, Asim Shabbir FRCS & Jimmy B. Y. So FRCS

  2. Department of Haematology-Oncology, National University Cancer Institute National University Health System, Singapore, Singapore

    Raghav Sundar MRCP, Cheng Ean Chee MRCP, Hon Lyn Tan MRCP, Jingshan Ho MRCP, Natalie Y. L. Ngoi MRCP, Matilda X. W. Lee MRCP, Vaishnavi Muthu MRCP, Gloria H. J. Chan MRCP, Angela S. L. Pang MRCP, Yvonne L. E. Ang MRCP, Joan R. E. Choo MRCP, Joline S. J. Lim MRCP & Wei Peng Yong MRCP

  3. Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Raghav Sundar MRCP, Asim Shabbir FRCS & Jimmy B. Y. So FRCS

  4. The N.1 Institute for Health, National University of Singapore, Singapore, Singapore

    Raghav Sundar MRCP

  5. Department of Pathology, National University Hospital, National University Health System, Singapore, Singapore

    Jeffrey H. Y. Lum FRCPath, Min En Nga FRCPath, Giap Hean Goh FRCPath & Ju Ee Seet FRCPath

  6. Department of General Surgery, Ng Teng Fong General Hospital, Singapore, Singapore

    Jun Liang Teh FRCS, Aung Lwin FRCS & Yuen Soon FRCS

  7. Division of Surgical Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore

    Asim Shabbir FRCS & Jimmy B. Y. So FRCS

  8. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

    Wei Peng Yong MRCP

Authors
  1. Daryl K. A. Chia FRCS
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raghav Sundar MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guowei Kim FRCS
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jia Jun Ang MRCS
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeffrey H. Y. Lum FRCPath
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Min En Nga FRCPath
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Giap Hean Goh FRCPath
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ju Ee Seet FRCPath
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cheng Ean Chee MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hon Lyn Tan MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jingshan Ho MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Natalie Y. L. Ngoi MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Matilda X. W. Lee MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Vaishnavi Muthu MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Gloria H. J. Chan MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Angela S. L. Pang MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Yvonne L. E. Ang MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Joan R. E. Choo MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Joline S. J. Lim MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Jun Liang Teh FRCS
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Aung Lwin FRCS
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Yuen Soon FRCS
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Asim Shabbir FRCS
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Jimmy B. Y. So FRCS
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Wei Peng Yong MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors report no conflict of interests. Individual contributions to the submission are as follows: D.K.A.C. participated in data curation, formal analysis, investigation, methodology, supervision, validation, writing-original draft, writing-editing, and review of this submission. R.S. participated in formal analysis, investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. G.K. participated in conceptualizing, investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. J.J.A. participated in data curation, formal analysis, investigation, methodology, validation, writing-original draft, writing-editing, and review of this submission. J.H.Y.L. participated in formal analysis, investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. M.E.N. participated in formal analysis, investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. G.H.G. participated in formal analysis, investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. S.J.E. participated in formal analysis, investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. C.E.C. participated in conceptualizing, investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. H.L.T. participated in investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. J.H. participated in investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. N.Y.L.N. participated in investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. M.X.W.L. participated in investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. V.M. participated in investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. G.H.J.C. participated in investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. A.S.L.P. participated in investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. Y.L.E.A. participated in investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. J.R.E.C. participated in investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. J.S.J.L. participated in investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. J.L.T. participated in investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. A.L. participated in investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. Y.S. participated in investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. A.S. participated in investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. W.P.Y. participated in conceptualizing, data curation, funding acquisition, investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission. J.B.Y.S. participated in conceptualizing, data curation, funding acquisition, investigation, methodology, project administration, supervision, validation, writing-editing, and review of this submission.

Corresponding author

Correspondence to Jimmy B. Y. So FRCS.

Ethics declarations

Disclosures

Sundar Raghav—Advisory board—Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD; Honoraria for talks—MSD, Eli Lilly, BMS, Roche, Taiho, Astra Zeneca, DKSH; Travel—Roche, Astra Zeneca, Taiho, Eisai; Research funding—Paxman Coolers, MSD.

Additional information

Publisher's Note

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

Supplementary Information

Rights and permissions

Springer Nature or its licensor 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

Chia, D.K.A., 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 29, 8597–8605 (2022). https://doi.org/10.1245/s10434-022-11998-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-022-11998-z

Search

Navigation