Cancer Res Treat.  2017 Jul;49(3):706-716. 10.4143/crt.2016.216.

A Multicenter Randomized Phase II Study of Docetaxel vs. Docetaxel Plus Cisplatin vs. Docetaxel Plus S-1 as Second-Line Chemotherapy in Metastatic Gastric Cancer Patients Who Had Progressed after Cisplatin Plus Either S-1 or Capecitabine

• Lee KW
• Kim BJ
• Kim MJ
• Han HS
• Kim JW
• Park YI
• Park SR

• KMID: 2388316
• DOI: http://doi.org/10.4143/crt.2016.216

Abstract

PURPOSE
This study evaluated the re-challenge of S-1 or cisplatin in combination with docetaxel in metastatic gastric cancer (MGC) that had progressed on a cisplatin plus either S-1 or capecitabine regimen.
MATERIALS AND METHODS
Patients with progressive disease after first-line cisplatin plus S-1 or capecitabine were randomized to receive 3-week cycles of docetaxel 75 mg/m² intravenously (IV) on D1 (D), docetaxel 60 mg/m² IV plus cisplatin 60 mg/m² IV on D1 (DC), or docetaxel 60 mg/m2 IV D1 plus oral S-1 30 mg/m² twice a day on D1-14 (DS).
RESULTS
Seventy-two patients were randomized to the D (n=23), DC (n=24), or DS (n=25) group. The confirmed response rate was 4.3% (95% confidence interval [CI], 0% to 12.6%), 4.3% (95% CI, 0% to 12.6%), and 8.7% (95% CI, 0% to 20.2%) for the D, DC, and DS groups, respectively. Compared to the D arm, the DS arm had a better progression-free survival (2.7 months vs. 1.3 months, p=0.034) without any deterioration in safety or quality of life, whereas the DC arm had a similar progression-free survival (1.8 months vs. 1.3 months, p=0.804) and poorer overall survival (5.6 months vs. 10.0 months, p=0.035).
CONCLUSION
A re-challenge with S-1, but not cisplatin, in combination with docetaxel has potential anticancer benefits over docetaxel alone in MGC with progression after prior cisplatin plus S-1 or capecitabine.

Keyword

Stomach neoplasms; Antineoplastic agents; Docetaxel; Tegafur-gimeracil-oteracil; Cisplatin

MeSH Terms

Antineoplastic Agents
Arm
Capecitabine*
Cisplatin*
Disease-Free Survival
Drug Therapy*
Humans
Quality of Life
Stomach Neoplasms*
Antineoplastic Agents
Capecitabine
Cisplatin

Figure

• 

  Fig. 1. CONSORT diagram. D, docetaxel; DC, docetaxel plus cisplatin; DS, docetaxel plus S-1; 5-FU, 5-fluorouracil. a)One ineligible patient who had received capecitabine plus oxaliplatin as first-line therapy was given the allocated study treatment (DC) and was included in the safety analysis.

• 

  Fig. 2. Kaplan-Meier curves of progression-free survival (A) and overall survival (B). CI, confidence interval; DS, docetaxel plus S-1; DC, docetaxel plus cisplatin; D, docetaxel.

• 

  Fig. 3. Mean quality of life scores by the treatment arms. Global quality of life (A), physical functioning (B), role functioning (C), emotional functioning (D), nausea and vomiting (E), fatigue (F), appetite loss (G), and reflux symptoms (H). For the global quality of life, physical, role, or emotional functioning, higher scores indicate better quality of life or functioning. For nausea and vomiting, fatigue, appetite loss, and reflux symptoms, higher scores indicate a higher level of symptoms. D, docetaxel; DC, docetaxel plus cisplatin; DS, docetaxel plus S-1. *p < 0.05.

Reference

References

1. Jung KW, Won YJ, Kong HJ, Oh CM, Cho H, Lee DH, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2012. Cancer Res Treat. 2015; 47:127–41.

2. Glimelius B, Ekstrom K, Hoffman K, Graf W, Sjoden PO, Haglund U, et al. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol. 1997; 8:163–8.

3. Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as firstline therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009; 20:666–73.

4. Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008; 358:36–46.

5. Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, et al. 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. 2010; 28:1547–53.

6. 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.

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

8. Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer: a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011; 47:2306–14.

9. Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014; 15:78–86.

10. Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012; 30:1513–8.

11. Takahashi I, Emi Y, Kakeji Y, Uchida J, Fukushima M, Maehara Y. Increased antitumor activity in combined treatment TS-1 and docetaxel: a preclinical study using gastric cancer xenografts. Oncology. 2005; 68:130–7.

12. Wada Y, Yoshida K, Suzuki T, Mizuiri H, Konishi K, Ukon K, et al. Synergistic effects of docetaxel and S-1 by modulating the expression of metabolic enzymes of 5-fluorouracil in human gastric cancer cell lines. Int J Cancer. 2006; 119:783–91.

13. Maeda S, Sugiura T, Saikawa Y, Kubota T, Otani Y, Kumai K, et al. Docetaxel enhances the cytotoxicity of cisplatin to gastric cancer cells by modification of intracellular platinum metabolism. Cancer Sci. 2004; 95:679–84.

14. Takiuchi H, Kawabe S, Gotoh M, Katsu K. Thymidylate synthase gene expression in primary tumors predicts activity of s-1-based chemotherapy for advanced gastric cancer. Gastrointest Cancer Res. 2007; 1:171–6.

15. Endo K, Maehara Y, Kusumoto T, Ichiyoshi Y, Kuwano M, Sugimachi K. Expression of multidrug-resistance-associated protein (MRP) and chemosensitivity in human gastric cancer. Int J Cancer. 1996; 68:372–7.

16. Lee JL, Ryu MH, Chang HM, Kim TW, Yook JH, Oh ST, et al. A phase II study of docetaxel as salvage chemotherapy in advanced gastric cancer after failure of fluoropyrimidine and platinum combination chemotherapy. Cancer Chemother Pharmacol. 2008; 61:631–7.

17. Kunisaki C, Imada T, Yamada R, Hatori S, Ono H, Otsuka Y, et al. Phase II study of docetaxel plus cisplatin as a second-line combined therapy in patients with advanced gastric carcinoma. Anticancer Res. 2005; 25:2973–7.

18. Polyzos A, Tsavaris N, Kosmas C, Polyzos K, Giannopoulos A, Felekouras E, et al. Subsets of patients with advanced gastric cancer responding to second-line chemotherapy with docetaxel-cisplatin. Anticancer Res. 2006; 26:3749–53.

19. Park SH, Kang WK, Lee HR, Park J, Lee KE, Lee SH, et al. Docetaxel plus cisplatin as second-line therapy in metastatic or recurrent advanced gastric cancer progressing on 5-fluorouracil-based regimen. Am J Clin Oncol. 2004; 27:477–80.

20. Kim H, Park JH, Bang SJ, Kim DH, Cho HR, Kim GY, et al. A phase II study of docetaxel and cisplatin in patients with gastric cancer recurring after or progressing during 5-FU/platinum treatment. Jpn J Clin Oncol. 2005; 35:727–32.

21. Yoshida K, Ninomiya M, Takakura N, Hirabayashi N, Takiyama W, Sato Y, et al. Phase II study of docetaxel and S-1 combination therapy for advanced or recurrent gastric cancer. Clin Cancer Res. 2006; 12(11 Pt 1):3402–7.

22. Koizumi W, Kim YH, Fujii M, Kim HK, Imamura H, Lee KH, 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.

23. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000; 92:205–16.

24. Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, et al. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013; 31:4438–44.

25. Higuchi K, Tanabe S, Shimada K, Hosaka H, Sasaki E, Nakayama N, et al. Biweekly irinotecan plus cisplatin versus irinotecan alone as second-line treatment for advanced gastric cancer: a randomised phase III trial (TCOG GI-0801/BIRIP trial). Eur J Cancer. 2014; 50:1437–45.

26. Nishikawa K, Fujitani K, Inagaki H, Akamaru Y, Tokunaga S, Takagi M, et al. Randomised phase III trial of second-line irinotecan plus cisplatin versus irinotecan alone in patients with advanced gastric cancer refractory to S-1 monotherapy: TRICS trial. Eur J Cancer. 2015; 51:808–16.

27. Tanabe K, Fujii M, Nishikawa K, Kunisaki C, Tsuji A, Matsuhashi N, et al. Phase II/III study of second-line chemotherapy comparing irinotecan-alone with S-1 plus irinotecan in advanced gastric cancer refractory to first-line treatment with S-1 (JACCRO GC-05). Ann Oncol. 2015; 26:1916–22.

28. Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol. 2003; 21:2059–69.

29. Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007; 370:143–52.

30. Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004; 22:229–37.