Skip to main content

Advertisement

SpringerLink
Log in

Suggestion of added value by bevacizumab to chemotherapy in patients with unresectable or recurrent small bowel cancer

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Standard therapy for advanced small bowel adenocarcinoma (SBA) has not yet been established. The present study assessed the efficacy and safety of chemotherapy (CT) in association with molecular targeting approaches for SBA.

Methods

The histories of 33 advanced SBA patients from six different institutions in Japan, who received CT from 2008 to 2016, were retrospectively examined for background, clinical course and outcome.

Results

Median patient age was 65 years (range 39–83). Primary tumor was located in the duodenum in 21 patients (67%), the ampulla of Vater in three patients (9%), the jejunum in seven patients (21%) and the ileum in one patient (3%). Histologically, well-to-moderately and poorly differentiated adenocarcinoma were identified in 20 (61%) and nine (27%) patients, respectively. Thirteen patients received a single CT regimen, seven patients received two types of CT regimen, and 13 patients received three or more CT regimens. As first-line CT, modified FOLFOX6, capecitabine plus oxaliplatin, and S-1 plus cisplatin were employed in 13, 1, and 4 patients, respectively. The response rate (RR) and median progression-free survival (PFS) were 25% and 6.0 months, respectively. Median overall survival (OS) was 13.0 months. Nine out of the 33 patients received bevacizumab-containing CT and three received cetuximab-containing CT. Median OS of bevacizumab-containing CT patients was 21.9 months. No unexpected serious adverse events were observed.

Conclusions

The analysis indicates that combination CT for advanced SBA is associated with modest efficacy and safety, and bevacizumab-containing CT may contribute to favorable outcome in these patients.

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

Similar content being viewed by others

References

  1. Radhav K, Overman MJ (2013) Small bowel adenocarcinoma-existing evidence and evolving paradigm. Nat Rev Clin Oncol 10:534–544

    Article  Google Scholar 

  2. Bilimoria KY, Bentrem DJ, Wayne JD, Ko CY, Bennett CL, Talamonti MS (2009) Small bowel cancer in the United States: changes in epidemiology, treatment, and survival over the last 20 years. Ann Surg 249:63–71. doi:10.1097/SLA.0b013e31818e4641

    Article  PubMed  Google Scholar 

  3. Dabaja BS, Suki D, Pro B, Bonnen M, Ajani J (2004) Adenocarcinoma of the small bowel: presentation, prognostic factors, and outcome of 217 patients. Cancer 101:518–526

    Article  PubMed  Google Scholar 

  4. Talamonti MS, Goetz LH, Rao S, Joehl RJ (2002) Primary cancers of the small bowel: analysis of prognostic factors and results of surgical management. Arch Surg 137:564–570

    Article  PubMed  Google Scholar 

  5. Howe JR, Karnell LH, Menck HR, Scott-Conner C (1999) The American College of Surgeons Commission on Cancer and the American Cancer Society. Adenocarcinoma of the small bowel: review of the National Cancer Data Base, 1985–1995. Caner 86:2693–2706

    Article  CAS  Google Scholar 

  6. Overman MJ, Varadhachary GR, Kopetz S, Adinin R, Lin E, Morris JS, Eng C, Abbruzzese JL, Wolff RA (2009) Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater. J Clin Oncol 27:2598–2603. doi:10.1200/JCO.2008.19.7145

    Article  CAS  PubMed  Google Scholar 

  7. Xiang XJ, Liu YW, Zhang L, Qiu F, Yu F, Zhan ZY, Feng M, Yan J, Zhao JG, Xiong JP (2012) A phase II study of modified FOLFOX as first-line chemotherapy in advanced small bowel adenocarcinoma. Anticancer Drugs 23:561–566. doi:10.1097/CAD.0b013e328350dd0d

    Article  CAS  PubMed  Google Scholar 

  8. Zaanan A, Gauthier M, Malka D, Locher C, Gornet JM, Thirot-Bidault A, Tougeron D, Taïeb J, Bonnetain F, Aparicio T (2011) Second-line chemotherapy with fluorouracil, leucovorin, and irinotecan (FOLFIRI regimen) in patients with advanced small bowel adenocarcinoma after failure of first-line platinum-based chemotherapy: a multicentre AGEO study. Cancer 117:1422–1428. doi:10.1002/cncr.25614

    Article  CAS  PubMed  Google Scholar 

  9. Tsushima T, Taguri M, Honma Y et al (2012) Multicenter retrospective study of 132 patients with unresectable small bowel adenocarcinoma treated with chemotherapy. Oncologist 17:1163–1170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zaanan A, Costes L, Gauthier M et al (2010) Chemotherapy of advanced small-bowel adenocarcinoma: a multicenter AGEO study. Ann Oncol 21:1786–1793. doi:10.1093/annonc/mdq038

    Article  CAS  PubMed  Google Scholar 

  11. Douillard JY, Siena S, Cassidy J et al (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28:4697–4705. doi:10.1200/JCO.2009.27.4860

    Article  CAS  PubMed  Google Scholar 

  12. Saltz LB, Clarke S, Díaz-Rubio E et al (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26:2013–2019. doi:10.1200/JCO.2007.14.9930

    Article  CAS  PubMed  Google Scholar 

  13. Bang YJ, Van Cutsem E, Feyereislova A, ToGA Trial Investigators 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, randomized controlled trial. Lancet 376:687–697. doi:10.1016/S0140-6736(10)61121-X

    Article  CAS  PubMed  Google Scholar 

  14. Wilke H, Muro K, Van Cutsem E, RAINBOW Study Group 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. doi:10.1016/S1470-2045(14)70420-6

    Article  CAS  PubMed  Google Scholar 

  15. Aparicio T, Svrcek M, Zaanan A et al (2013) Small bowel adenocarcinoma phenotyping, a clinicobiological prognostic study. Br J Cancer 109:3057–3061. doi:10.1038/bjc.2013.677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gulhati P, Raghav K, Shroff RT et al (2017) Bevacizumab combined with capecitabine and oxaliplatin in patients with advanced adenocarcinoma of the small bowel or ampulla of Vater: a single-center, open-label, phase 2 study. Cancer 123:1011–1017

    Article  CAS  PubMed  Google Scholar 

  17. Aydin D, Sendur MA, Kefeli U et al (2016) Evaluation of bevacizumab in advanced small bowel adenocarcinoma. Clin Corolectal Cancer. doi:10.1016/j.clcc.2016.04.013

    Google Scholar 

  18. Santini D, Fratto ME, Spoto C, Russo A, Galluzzo S, Zoccoli A, Vincenzi B, Tonini G (2010) Cetuximab in small bowel adenocarcinoma: a new friend? Br J Cancer 103:1305. doi:10.1038/sj.bjc.6605898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247. doi:10.1016/j.ejca.2008.10.026

    Article  CAS  PubMed  Google Scholar 

  20. National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed 10 Feb 2017

  21. Cassidy J, Clarke S, Díaz-Rubio E et al (2008) Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 26:2006–2012

    Article  CAS  PubMed  Google Scholar 

  22. Halfdanarson TR, McWilliams RR, Donohue JH, Quevedo JF (2010) A single-institution experience with 491 cases of small bowel adenocarcinoma. Am J Surg 199:797–803. doi:10.1016/j.amjsurg.2009.05.037

    Article  PubMed  Google Scholar 

  23. Nicholl MB, Ahuja V, Conway WC, Vu VD, Sim MS, Singh G (2010) Small bowel adenocarcinoma: understaged and undertreated? Ann Surg Oncol 17:2728–2732. doi:10.1245/s10434-010-1109-x

    Article  PubMed  Google Scholar 

  24. Overman MJ, Hu CY, Wolff RA, Chang GJ (2010) Prognostic value of lymph node evaluation in small bowel adenocarcinoma: analysis of the surveillance, epidemiology, and end results database. Cancer 116:5374–5382. doi:10.1002/cncr.25324

    Article  PubMed  Google Scholar 

  25. Kim IJ, Park JH, Kang HC, Shin Y, Park HW, Park HR, Ku JL, Lim SB, Park JG (2003) Mutational analysis of BRAF and K-ras in gastric cancers: absence of BRAF mutations in gastric cancers. Hum Genet 114:118–120

    Article  CAS  PubMed  Google Scholar 

  26. Moehler M, Mueller A, Trarbach T, Lordick F, Seufferlein T, Kubicka S, Geissler M, Schwarz S, Galle PR (2011) Cetuximab with irinotecan folinic acid and 5-fluorouracil as first-line treatment in advanced gastroesophageal cancer: a prospective multi-center biomarker-oriented phase II study. Ann Oncol 22:1358–1366. doi:10.1093/annonc/mdq591

    Article  CAS  PubMed  Google Scholar 

  27. Lordick F, Luber B, Lorenzen S et al (2010) Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Br J Cancer 102:500–505. doi:10.1038/sj.bjc.6605521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Koornstra JJ, Kleibeuker JH, Vasen HF (2008) Small-bowel cancer in Lynch syndrome: is it time for surveillance? Lancet Oncol 9:901–905. doi:10.1016/S1470-2045(08)70232-8

    Article  PubMed  Google Scholar 

  29. Watson P, Vasen HF, Mecklin JP, Bernstein I, Aarnio M, Järvinen HJ, Myrhøj T, Sunde L, Wijnen JT, Lynch HT (2008) The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer 123:444–449. doi:10.1002/ijc.23508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vasen HF, Watson P, Mecklin JP, Lynch HT (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 116:1453–1456

    Article  CAS  PubMed  Google Scholar 

  31. Ohtsu A, Shah MA, Van Cutsem E et al (2011) 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 29:3968–3976. doi:10.1200/JCO.2011.36.2236

    Article  CAS  PubMed  Google Scholar 

  32. Sartore-Bianchi A, Trusolino L, Martino C et al (2016) Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol 17:738–746. doi:10.1016/S1470-2045(16)00150-9

    Article  CAS  PubMed  Google Scholar 

  33. Nagaraj G, Zarbalian Y, Flora K, Tan BR Jr (2014) Complete response and prolonged disease-free survival in a patient with recurrent duodenal adenocarcinoma treated with bevacizumab plus FOLFOX6. J Gastrointest Oncol 5:E1–E6. doi:10.3978/j.issn.2078-6891.2013.038

    PubMed  PubMed Central  Google Scholar 

  34. Okubo K, Yoshioka S, Asukai K et al (2010) A case report of primary adenocarcinoma of small intestine. Gan To Kagaku Ryoho 37:2792–2794

    PubMed  Google Scholar 

  35. Overman MJ, Pozadzides J, Kopetz S, Wen S, Abbruzzese JL, Wolff RA, Wang H (2010) Immunophenotype and molecular characterisation of adenocarcinoma of the small intestine. Br J Cancer 102:144–150. doi:10.1038/sj.bjc.6605449

    Article  CAS  PubMed  Google Scholar 

  36. Hapani S, Chu D, Wu S (2009) Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis. Lancet Oncol 10:559–568. doi:10.1016/S1470-2045(09)70112-3

    Article  CAS  PubMed  Google Scholar 

  37. Kozloff M, Yood MU, Berlin J, Flynn PJ, Kabbinavar FF, Purdie DM, Ashby MA, Dong W, Sugrue MM, Grothey A (2009) Investigators of the BRiTE study. Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer: the BRiTE observational cohort study. Oncologist 14:862–870. doi:10.1634/theoncologist.2009-0071

    Article  CAS  PubMed  Google Scholar 

  38. Garcia AA, Hirte H, Fleming G et al (2008) Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 26:76–82. doi:10.1200/JCO.2007.12.1939

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the patients and their families for participating in this study, and the medical staff for their respective contributions to the treatment of patients.

Author information

Authors and Affiliations

  1. Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Kotoe Takayoshi, Hitoshi Kusaba, Kyoko Inadomi, Kenji Tsuchihashi, Hiroshi Ariyama & Koichi Akashi

  2. Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, 811-1395, Japan

    Kotoe Takayoshi, Yudai Shinohara & Taito Esaki

  3. Department of Oncology, Hamanomachi Hospital, 3-3-1, Nagahama, Chuou-ku, Fukuoka, 810-8539, Japan

    Masato Uenomachi & Kenji Mitsugi

  4. Department of Hematology and Oncology, Japan Community Healthcare Organization Kyushu Hospital, 1-8-1, Kishinoura, Yahatanishi-ku, Kitakyushu, 806-8501, Japan

    Chinatsu Makiyama & Akitaka Makiyama

  5. Department of Medical Oncology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1, Jigyouhama, Chuou-ku, Fukuoka, 810-0065, Japan

    Keita Uchino

  6. Department of Oncology, Miyazaki Prefectural Miyazaki Hospital, 5-30, Kita-takamatsucho, Miyazaki, 880-8510, Japan

    Tsuyoshi Shirakawa

  7. Department of Medical Oncology, Fukuoka Wajiro Hospital, 2-2-75, Wajirooka, Higashi-ku, Fukuoka, 811-0213, Japan

    Yoshihiro Shibata

  8. Department of Comprehensive Clinical Oncology, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Shuji Arita & Eishi Baba

Authors
  1. Kotoe Takayoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hitoshi Kusaba
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masato Uenomachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenji Mitsugi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chinatsu Makiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Akitaka Makiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Keita Uchino
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tsuyoshi Shirakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yoshihiro Shibata
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yudai Shinohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kyoko Inadomi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kenji Tsuchihashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shuji Arita
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hiroshi Ariyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Taito Esaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Koichi Akashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Eishi Baba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eishi Baba.

Ethics declarations

Conflict of interest

Baba E. has received research Grants from Chugai and Merck Serono. Akashi K. has received research Grants from Chugai, Yakult and Merck Serono and an honorarium from Chugai. Esaki T. has received a research Grant from Merck Serono and honoraria from Chugai and Merck Serono.

Ethical approval

The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The study was approved by the ethics committee of each participating institution. For this type of study formal consent is not required.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Takayoshi, K., Kusaba, H., Uenomachi, M. et al. Suggestion of added value by bevacizumab to chemotherapy in patients with unresectable or recurrent small bowel cancer. Cancer Chemother Pharmacol 80, 333–342 (2017). https://doi.org/10.1007/s00280-017-3371-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-017-3371-0

Keywords

Search

Navigation