Skip to main content

Advertisement

SpringerLink
Log in

Treatment efficacy of ramucirumab-containing chemotherapy in patients with alpha-fetoprotein producing gastric cancer

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Alpha-Fetoprotein Producing Gastric Cancer (AFPGC) is an aggressive subgroup of gastric cancer. Recently ramucirumab has shown survival benefits in hepatocellular carcinoma, but only in those with higher Alpha-Fetoprotein (AFP) levels. However, the efficacy of ramucirumab-containing chemotherapy in AFPGC remains unclear.

Methods

We retrospectively assessed 352 patients who received ramucirumab-containing chemotherapy between June 2015 and December 2019. AFPGC was defined when serum AFP levels were elevated at diagnosis and correlated with the disease state during treatment. Non-AFPGC was defined when serum AFP levels were normal at diagnosis.

Results

Among the 352 patients, 28 patients were defined as AFPGC and 246 patients were defined as non-AFPGC. AFPGC was characterized by high frequency of liver metastasis and low frequency of peritoneal metastasis compared to non-AFPGC. Ramucirumab containing chemotherapy showed higher response rates in AFPGC (39.1% vs 24.8%, p = 0.198) and disease control rates (86.9% vs 61.5%, p = 0.028) than those of non-AFPGC, respectively. Median progression-free survival (PFS) was 5.5 months (95%CI 3.9–7.1) in AFPGC and 4.0 months (95%CI 3.6–4.6) in non-AFPGC (HR: 0.91, 95% CI 0.61–1.36, p = 0.66), and median overall survival (OS) was 10.7 months (95% CI 7.4–20.8) in AFPGC and 9.2 months (95% CI 8.1–10.4) in non-AFPGC (HR: 0.72, 95% CI 0.48–1.08, p = 0.11), respectively. In multivariate analysis, AFPGC was not a negative prognostic factor both for PFS and OS.

Conclusion

Ramucirumab containing chemotherapy showed higher response and comparable survival in AFPGC compared to those of non-AFPGC. Considering the generally poor prognosis of AFPGC, ramucirumab-containing chemotherapy might be a promising treatment option in AFPGC.

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
Fig. 4

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

References

  1. Bergstrand CG, Czar B (1956) Demonstration of a new protein fraction in serum from the human fetus. Scand J Clin Lab Invest 8:174–179

    Article  CAS  Google Scholar 

  2. Smith CJ, Ajdukiewicz A, Kelleher PC (1983) Concanavalin-a-affinity molecular heterogeneity of human hepatoma AFP and cord-serum AFP. Ann N Y Acad Sci 417:69–74

    Article  CAS  Google Scholar 

  3. Norgaard-Pedersen B, Albrechtsen R, Teilum G (1975) Serum alphafoetoprotein as a marker for endodermal sinus tumour (yolk sac tumour) or a vitelline component of “teratocarcinoma.” Acta Pathologica et Microbiologica Scand Sec A Pathol 83(6):573–589

    CAS  Google Scholar 

  4. European Association for the Study of the Liver (2019) EASL clinical practice guidelines management of hepatocellular carcinoma. J Hepatol 69(1):182–236

    Google Scholar 

  5. Metzgeroth G, Strobel P, Baumbusch T et al (2010) Hepatoid adenocarcinoma review of the literature illustrated by a rare case originating in the peritoneal cavity. Onkologie 33:263–269

    Article  Google Scholar 

  6. Kinjo T, Taniguchi H, Kushima R et al (2012) Histologic and immunohistochemical analyses of α-fetoprotein-producing cancer of the stomach. Am J Surg Pathol 36:56–65

    Article  Google Scholar 

  7. Yamagata T, Yamagata Y, Nakanishi M et al (2004) A case of primary lung cancer producing alpha-fetoprotein. Can Respir J 11:504–506

    Article  Google Scholar 

  8. Matsueda K, Yamamoto H, Yoshida Y et al (2006) Hepatoid carcinoma of the pancreas producing protein induced by vitamin K absence or antagonist II (PIVKA-II) and alpha-fetoprotein (AFP). J Gastroenterol 41:1011–1019

    Article  Google Scholar 

  9. Devi NR, Sathyalakshmi R, Devi J et al (2015) Hepatoid adenocarcinoma of the gall bladder-a rare variant. J Clin Diagn Res JCDR. https://doi.org/10.7860/JCDR/2015/10799.6324

    Article  Google Scholar 

  10. Cappetta A, Bergamo F, Mescoli C et al (2012) Hepatoid adenocarcinoma of the colon: what should we target? Pathol Oncol Res 18:93–96

    Article  Google Scholar 

  11. Bourreille J, Metayer P, Sauger F et al (1970) Existence of alpha feto protein during gastric-origin secondary cancer of the liver. Presse Med 78:1277–1278

    CAS  Google Scholar 

  12. McIntire KR, Waldmann TA, Moertel CG et al (1975) Serum alphafetoprotein in patients with neoplasms of the gastrointestinal tract. Cancer Res 35(4):991–996

    CAS  Google Scholar 

  13. Chang YC, Nagasue N, Kohno H et al (1990) Clinicopathologic features and long-term results of alphafetoprotein-producing gastric cancer. Am J Gastroenterol 85(11):1480–1485

    CAS  Google Scholar 

  14. Adachi Y, Tsuchihashi J, Shiraishi N et al (2003) AFP-producing gastric carcinoma: multivariate analysis of prognostic factors in 270 patients. Oncology 65(2):95–101

    Article  CAS  Google Scholar 

  15. Bozkaya Y, Demirci NS, Kurtipek A et al (2017) Clinicopathological and prognostic characteristics in patients with AFP-secreting gastric carcinoma. Mol Clin Oncol 7(2):267–274

    Article  CAS  Google Scholar 

  16. Fuchs CS, Tomasek J, Yong CJ et al (2014) Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383:31–39

    Article  CAS  Google Scholar 

  17. Wilke H, Muro K, Van Cutsem E et al (2014) 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 15:1224–1235

    Article  CAS  Google Scholar 

  18. Zhu AX, Park JO, Ryoo BY et al (2015) Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 16(7):859–870

    Article  CAS  Google Scholar 

  19. Zhu AX, Kang YK, Yen CJ et al (2019) Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 20(2):282–296

    Article  CAS  Google Scholar 

  20. Inagawa S, Shimazaki J, Hori M et al (2001) Hepatoid adenocarcinoma of the stomach. Gastric Cancer 4(1):43–52

    Article  CAS  Google Scholar 

  21. Inoue M, Sano T, Kuchiba A et al (2010) Long-term results of gastrectomy for alpha-fetoprotein-producing gastric cancer. Br J Surg 97(7):1056–1061

    Article  CAS  Google Scholar 

  22. Yoshizawa J, Ishizone S, Ikeyama M et al (2017) Gastric hepatoid adenocarcinoma resulting in a spontaneous gastric perforation: a case report and review of the literature. BMC Cancer 17(1):368

    Article  Google Scholar 

  23. He R, Yang Q, Dong X et al (2017) Clinicopathologic and prognostic characteristics of alpha-fetoprotein-producing gastric cancer. Oncotarget 8(14):23817–23830

    Article  Google Scholar 

  24. Wang Y-K, Shen L, Jiao Xi et al (2018) Predictive and prognostic value of serum AFP level and its dynamic changes in advanced gastric cancer patients with elevated serum AFP. World J Gastroenterol 24(2):266–273

    Article  CAS  Google Scholar 

  25. Li N, Bai C, Zhang R et al (2021) Efficacy and safety of apatinib for the treatment of AFP-producing gastric cancer. Translat Oncolo 14(2):101004

    Article  CAS  Google Scholar 

  26. Kanda Y (2013) Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant 48:452–458

    Article  CAS  Google Scholar 

  27. Bang YJ, Van Cutsem E, Feyereislova A et al (2010) 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, randomised controlled trial. Lancet 376:687–697

    Article  CAS  Google Scholar 

  28. Kang YK, Boku N, Satoh T et al (2017) 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 390(10111):2461–2471

    Article  CAS  Google Scholar 

  29. Yoshioka M, Inoue N, Someda H et al (2011) A case of AFP-producing gastric cancer resected after efficient S-1/CDDP combination chemotherapy. Gan To Kagaku Ryoho 38(1):105

    Google Scholar 

  30. Fukuda K, Ito S, Shimizu K et al (2013) Retrospective analysis concerning AFP-producing gastric cancer. Gan Kagaku Ryoho 40(2):191

    Google Scholar 

  31. Kunoki N, Nishiyama R, Ryuzaki H et al (2008) A case of alpha-fetoprotein-producing gastric cancer with hepatic metastasis successfully treated with combination chemotherapy. Nihon Shokakibyo Gakkai Zasshi 105(10):1489

    Google Scholar 

  32. Arakawa Y, Tamura M, Aiba K et al (2017) Significant response to ramucirumab monotherapy in chemotherapy-resistant recurrent alpha-fetoprotein-producing gastric cancer: a case report. Oncol Lett 14(3):3039–3042

    Article  Google Scholar 

  33. Takada J, Araki H, Ozawa N et al (2019) Effective treatment of cytotoxic agent refractory alpha-fetoprotein-producing gastric cancer with ramucirumab: a case report and review of the literature. J Gastrointest Canc 50:556–559

    Article  CAS  Google Scholar 

  34. Iida A, Katayama K, Yamaguchi A (2013) Five-year survival of alpha-fetoprotein-producing gastric cancer with synchronous liver metastasis: a case report. J Gastric Cancer 13:58–64

    Article  Google Scholar 

  35. Fang YU, Wang L, Yang N et al (2015) Successful multimodal therapy for an α-fetoprotein-producing gastric cancer patient with simultaneous liver metastases. Oncol Lett 10:3021–3025

    Article  CAS  Google Scholar 

  36. Di Bartolomeo M, Niger M, Tirino G et al (2018) Ramucirumab as second-line therapy in metastatic gastric cancer: real-world data from the ramoss study. Target Oncol 13(2):227–234

    Article  Google Scholar 

  37. Lu J, Ding Y, Chen Y et al (2021) Whole-exome sequencing of alpha-fetoprotein producing gastric carcinoma reveals genomic profile and therapeutic targets. Nat Commun 12(1):3946

    Article  CAS  Google Scholar 

  38. Liu D, Li B, Yan B et al (2020) The clinicopathological features and prognosis of serum AFP positive gastric cancer: a report of 16 cases. Int J Clin Exp Pathol 13(9):2439–2446

    Google Scholar 

  39. Yamashita T, Forgues M, Wang W et al (2008) EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res 68:1451–1461

    Article  CAS  Google Scholar 

  40. Shan YF, Huang YL, Xie YK et al (2011) Angiogenesis and clinicopathologic characteristics in different hepatocellular carcinoma subtypes defined by EpCAM and alpha-fetoprotein expression status. Med Oncol 28:1012–1016

    Article  CAS  Google Scholar 

  41. Zucman-Rossi J, Villanueva A, Nault JC et al (2015) Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 149:1226–1239

    Article  CAS  Google Scholar 

  42. Koide N, Nishio A, Igarashi J et al (1999) Alpha-fetoprotein-producing gastric cancer: Histochemical analysis of cell proliferation, apoptosis, and angiogenesis. Am J Gastroenterol 94:1658–1663

    Article  CAS  Google Scholar 

  43. Kamei S, Kono K, Amemiya H et al (2003) Evaluation of VEGF and VEGF-C expression in gastric cancer cells producing alpha-fetoprotein. J Gastroenterol 38:540–547

    Article  CAS  Google Scholar 

  44. Wang Y, Sun L, Li Z et al (2019) Hepatoid adenocarcinoma of the stomach: a unique subgroup with distinct clinicopathological and molecular features. Gastric Cancer 22:1183–1192

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank all staff who managed the study patients at the ambulatory treatment center and on the wards.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Gastrointestinal Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake Koto-ku, Tokyo, 135-8550, Japan

    Daisaku Kamiimabeppu, Takeru Wakatsuki, Daisuke Takahari, Naoki Fukuda, Keitaro Shimozaki, Hiroki Osumi, Izuma Nakayama, Mariko Ogura, Akira Ooki, Eiji Shinozaki, Keisho Chin & Kensei Yamaguchi

Authors
  1. Daisaku Kamiimabeppu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takeru Wakatsuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daisuke Takahari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Naoki Fukuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Keitaro Shimozaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroki Osumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Izuma Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mariko Ogura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Akira Ooki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Eiji Shinozaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Keisho Chin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kensei Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takeru Wakatsuki.

Ethics declarations

Conflict of interests

Daisuke Takahari reports receiving honoraria from Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co. and Eli Lilly. Kensei Yamaguchi reports receiving honoraria from Eli Lilly, receiving research funding from Eli Lilly. The other authors declare that they have no conflict of interest.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Table.1 Summary of 28 AFPPGC patients in this study (XLSX 14 KB)

Supplementary Fig.1 CONSORT flow diagram of patients with AFPGC in this study (PPTX 45 KB)

10147_2022_2263_MOESM3_ESM.pptx

Supplementary Fig.2 Correlations between the baseline AFP levels at the stating of 2nd-line treatment, PFS (a) and OS (b), respectively (PPTX 69 KB)

10147_2022_2263_MOESM4_ESM.pptx

Supplementary Fig.3 Comparison of PFS (a) and OS (b) according to the baseline AFP levels with the cutoff value of 1,200 ng/ml (PPTX 70 KB)

10147_2022_2263_MOESM5_ESM.pptx

Supplementary Fig.4 Comparison of ORR (a) and DCC (b) according to the baseline AFP levels with the cutoff value of 1,200 ng/ml (PPTX 67 KB)

10147_2022_2263_MOESM6_ESM.pptx

Supplementary Fig.5 Changes in AFP levels during 2nd-line treatment (a). Comparison of ORR (b) and DCR (c) according to changes in AFP levels during 2nd-line treatment (PPTX 73 KB)

10147_2022_2263_MOESM7_ESM.pptx

Supplementary Fig.6 Comparison of PFS (a) and OS (b) according to changes in AFP levels during 2nd-line treatment  (PPTX 69 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kamiimabeppu, D., Wakatsuki, T., Takahari, D. et al. Treatment efficacy of ramucirumab-containing chemotherapy in patients with alpha-fetoprotein producing gastric cancer. Int J Clin Oncol 28, 121–129 (2023). https://doi.org/10.1007/s10147-022-02263-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-022-02263-0

Keywords

Search

Navigation