Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 3, pp 789–797 | Cite as

A phase II study of neoadjuvant combination chemotherapy with docetaxel, cisplatin, and S-1 for locally advanced resectable gastric cancer: nucleotide excision repair (NER) as potential chemoresistance marker

  • Masahiro Hirakawa
  • Yasushi Sato
  • Hiroyuki Ohnuma
  • Tetsuji Takayama
  • Tamotsu Sagawa
  • Takayuki Nobuoka
  • Keisuke Harada
  • Hiroshi Miyamoto
  • Yasuhiro Sato
  • Yasuo Takahashi
  • Shinich Katsuki
  • Michiaki Hirayama
  • Minoru Takahashi
  • Michihiro Ono
  • Masahiro Maeda
  • Kohichi Takada
  • Tsuyoshi Hayashi
  • Tsutomu Sato
  • Koji Miyanishi
  • Rishu Takimoto
  • Masayoshi Kobune
  • Koichi Hirata
  • Junji Kato
Original Article

Abstract

Purpose

The combination of docetaxel, cisplatin, and S-1 (DCS) chemotherapy is expected to be a promising regimen for advanced gastric cancer. This study was performed to evaluate the efficacy and safety of neoadjuvant DCS chemotherapy for locally advanced resectable gastric cancer.

Methods

Patients with locally advanced gastric cancer received 2 courses of preoperative chemotherapy with S-1 (40 mg/m2 b.i.d.) on days 1–14 and docetaxel (60 mg/m2) plus cisplatin (60 mg/m2) on day 8 every 3 weeks, followed by standard curative surgery within 4–8 weeks. The primary endpoint was R0 resectability. Expression of damage DNA binding protein complex subunit 2 (DDB2)/excision repair cross-complementing 1 (ERCC1) in the pretreated tumor tissues was examined by immunohistochemistry.

Results

A total of 43 patients received neoadjuvant chemotherapy. The response rate was 74.4 %, and disease control ratio was 100 %. Grade 4 neutropenia developed in 53.5 % of patients and febrile neutropenia in 16.3 %. Non-hematological grade 3/4 adverse events were anorexia (23.3 %), nausea (14.0 %), and diarrhea (23.3 %), but these were generally transient and manageable. The proportion of R0 resections in the 43 eligible patients was 90.7 %, and a pathological response was found in 65.9 % of patients. There were no treatment-related deaths and no major surgical complications. The accuracy of the combination of DDB2 and ERCC1 expression for predicting chemoresistance was 82.5 %.

Conclusions

Preoperative treatment with DCS combination for locally advanced gastric cancer demonstrated a sufficient R0 resection rate and a good pathological response with manageable toxicities. The DDB2/ERCC1-high phenotype, as determined by immunohistochemistry, may be useful predictor of resistance to DCS chemotherapy.

Keywords

Neoadjuvant chemotherapy Advanced resectable gastric cancer DSC Nucleotide excision repair 

Notes

Conflict of interest

The authors have no conflict of interest.

References

  1. 1.
    Jemal A, Center MM, DeSantis C et al (2010) Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev 19:1893–1907PubMedCrossRefGoogle Scholar
  2. 2.
    Shi Y, Zhou Y (2010) The role of surgery in the treatment of gastric cancer. J Surg Oncol 101:687–692PubMedCrossRefGoogle Scholar
  3. 3.
    Songun I, Putter H, Kranenbarg EM et al (2010) Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol 11:439–449PubMedCrossRefGoogle Scholar
  4. 4.
    Sakuramoto S, Sasako M, Yamaguchi T et al (2007) Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 357:1810–1820PubMedCrossRefGoogle Scholar
  5. 5.
    Cunningham D, Allum WH, Stenning SP et al (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11–20PubMedCrossRefGoogle Scholar
  6. 6.
    Ychou M, Boige V, Pignon JP et al (2011) Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 29:1715–1721PubMedCrossRefGoogle Scholar
  7. 7.
    Ajani JA (2005) Evolving chemotherapy for advanced gastric cancer. Oncologist 10:49–58PubMedCrossRefGoogle Scholar
  8. 8.
    Van Cutsem E, Moiseyenko VM, Tjulandin S et al (2006) 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 24:4991–4997PubMedCrossRefGoogle Scholar
  9. 9.
    Ajani JA, Rodriguez W, Bodoky G et al (2010) Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol 28:1547–1553PubMedCrossRefGoogle Scholar
  10. 10.
    Koizumi W, Narahara H, Hara T et al (2008) S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 9:215–221PubMedCrossRefGoogle Scholar
  11. 11.
    Takayama T, Sato Y, Sagawa T et al (2007) Phase I study of S-1, docetaxel and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer. Br J Cancer 97:851–856PubMedGoogle Scholar
  12. 12.
    Sato Y, Takayama T, Sagawa T et al (2010) Phase II study of S-1, docetaxel and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer. Cancer Chemother Pharmacol 66:721–728PubMedCrossRefGoogle Scholar
  13. 13.
    Koizumi W, Nakayama N, Tanabe S et al (2012) A multicenter phase II study of combined chemotherapy with docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer (KDOG 0601). Cancer Chemother Pharmacol 69(2):407–413PubMedCrossRefGoogle Scholar
  14. 14.
    Japanese Gastric Cancer Association (1998) Japanese classification of gastric carcinoma—2nd english edition. Gastric Cancer 1:10–24PubMedCrossRefGoogle Scholar
  15. 15.
    Japanese Gastric Cancer Association (2001) Japanese classification of gastric carcinoma—2nd english edition—response assessment of chemotherapy and radiotherapy for gastric carcinoma: clinical criteria. Gastric Cancer 4:1–8CrossRefGoogle Scholar
  16. 16.
    Japanese Gastric Cancer Association (2011) Japanese classification of gastric carcinoma: 3rd english edition. Gastric Cancer 14:101–112CrossRefGoogle Scholar
  17. 17.
    Kwon HC, Roh MS, Oh SY, Kim SH, Kim MC, Kim JS, Kim HJ (2007) Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/oxaliplatin chemotherapy in advanced gastric cancer. Ann Oncol 18(3):504–509PubMedCrossRefGoogle Scholar
  18. 18.
    Schuhmacher CP, Fink U, Becker K et al (2001) Neoadjuvant therapy for patients with locally advanced gastric carcinoma with etoposide, doxorubicin, and cisplatinum. Closing results after 5 years of follow-up. Cancer 91:918–927PubMedCrossRefGoogle Scholar
  19. 19.
    Yoshikawa T, Sasako M, Yamamoto S et al (2009) Phase II study of neoadjuvant chemotherapy and extended surgery for locally advanced gastric cancer. Br J Surg 96:1015–1022PubMedCrossRefGoogle Scholar
  20. 20.
    Kinoshita T, Sasako M, Sano T et al (2009) Phase II trial of S-1 for neoadjuvant chemotherapy against scirrhous gastric cancer (JCOG 0002). Gastric Cancer 12:37–42PubMedCrossRefGoogle Scholar
  21. 21.
    Fareed KR, Al-Attar A, Soomro IN, Kaye PV, Patel J, Lobo DN, Parsons SL, Madhusudan S (2010) Tumour regression and ERCC1 nuclear protein expression predict clinical outcome in patients with gastro-oesophageal cancer treated with neoadjuvant chemotherapy. Br J Cancer 102(11):1600–1607PubMedCrossRefGoogle Scholar
  22. 22.
    Matsubara J, Nishina T, Yamada Y, Moriwaki T, Shimoda T, Kajiwara T, Nakajima TE, Kato K, Hamaguchi T, Shimada Y, Okayama Y, Oka T, Shirao K (2008) Impacts of excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase, and epidermal growth factor receptor on the outcomes of patients with advanced gastric cancer. Br J Cancer 98(4):832–839PubMedCrossRefGoogle Scholar
  23. 23.
    Takimoto R, MacLachlan TK, Dicker DT, Niitsu Y, Mori T, el-Deiry WS (2002) BRCA1 transcriptionally regulates damaged DNA binding protein (DDB2) in the DNA repair response following UV-irradiation. Cancer Biol Ther 1(2):177–186PubMedGoogle Scholar
  24. 24.
    Li W, Qin J, Sun YH et al (2010) Neoadjuvant chemotherapy for advanced gastric cancer: a meta-analysis. World J Gastroenterol 16:5621–5628PubMedCrossRefGoogle Scholar
  25. 25.
    De Vita F, Giuliani F, Galizia G et al (2007) Neo-adjuvant and adjuvant chemotherapy of gastric cancer. Ann Oncol 18(Suppl 6):120–123Google Scholar
  26. 26.
    Mezhir JJ, Tang LH, Coit DG (2010) Neoadjuvant therapy of locally advanced gastric cancer. J Surg Oncol 101:305–314PubMedCrossRefGoogle Scholar
  27. 27.
    Saka M, Morita S, Fukagawa T et al (2011) Present and future status of gastric cancer surgery. Jpn J Clin Oncol 41:307–313PubMedCrossRefGoogle Scholar
  28. 28.
    Kawashima Y, Sasako M, Tsuburaya A et al (2008) Phase II study of preoperative neoadjuvant chemotherapy (CX) with S-1 plus cisplatin for gastric cancer (GC) with bulky and/or para-aortic lymph node metastases: a Japan clinical oncology group study (JCOG0405). In: ASCO gastrointestinal cancers symposium. Abstract no. 118, San FranciscoGoogle Scholar
  29. 29.
    Fujitani K, Sasako M, Iwasaki Y et al (2007) A phase II study of preoperative chemotherapy (CX) with S-1 and cisplatin followed by gastrectomy for clinically resectable type 4 and large type 3 gastric cancer. JCOG 0210 J Clin Oncol 25:18 (suppl; abstr 4609)Google Scholar
  30. 30.
    Ajani JA, Mansfield PF, Crane CH et al (2005) Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome. J Clin Oncol 23:1237–1244PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Masahiro Hirakawa
    • 1
  • Yasushi Sato
    • 1
  • Hiroyuki Ohnuma
    • 1
  • Tetsuji Takayama
    • 2
  • Tamotsu Sagawa
    • 3
  • Takayuki Nobuoka
    • 4
  • Keisuke Harada
    • 4
  • Hiroshi Miyamoto
    • 2
  • Yasuhiro Sato
    • 3
  • Yasuo Takahashi
    • 3
  • Shinich Katsuki
    • 5
  • Michiaki Hirayama
    • 6
  • Minoru Takahashi
    • 7
  • Michihiro Ono
    • 8
  • Masahiro Maeda
    • 8
  • Kohichi Takada
    • 1
  • Tsuyoshi Hayashi
    • 1
  • Tsutomu Sato
    • 1
  • Koji Miyanishi
    • 1
  • Rishu Takimoto
    • 1
  • Masayoshi Kobune
    • 1
  • Koichi Hirata
    • 4
  • Junji Kato
    • 1
  1. 1.Fourth Department of Internal MedicineSapporo Medical University School of MedicineSapporoJapan
  2. 2.Department of Gastroenterology and Oncology, Institute of Health BiosciencesThe University of Tokushima Graduate SchoolTokushimaJapan
  3. 3.Division of GastroenterologyHokkaido Cancer CenterSapporoJapan
  4. 4.First Department of SurgerySapporo Medical University School of MedicineSapporoJapan
  5. 5.Division of GastroenterologyOtaru Ekisaikai HospitalOtaruJapan
  6. 6.Division of GastroenterologyTonan HospitalSapporoJapan
  7. 7.Division of GastroenterologySapporo Kyoritsu Gorinbashi HospitalSapporoJapan
  8. 8.Division of GastroenterologySteel Memorial Muroran HospitalMuroranJapan

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