A phase II prospective study of the trastuzumab combined with 5-weekly S-1 and CDDP therapy for HER2-positive advanced gastric cancer

Kataoka, Hiromi; Mori, Yoshinori; Shimura, Takaya; Nishie, Hirotada; Natsume, Makoto; Mochizuki, Hisato; Hirata, Yoshikazu; Sobue, Satoshi; Mizushima, Takashi; Sano, Hitoshi; Mizuno, Yusuke; Nakamura, Makoto; Hirano, Atsuyuki; Tsuchida, Kenji; Adachi, Kazunori; Seno, Kyoji; Kitagawa, Mika; Kawai, Takashi; Joh, Takashi

doi:10.1007/s00280-016-3013-y

Cited by 22 publications

(17 citation statements)

References 19 publications

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“…Trastuzumab, a monoclonal antibody against human HER2, in combination with capecitabine and cisplatin, has been used as the standard ﬁrst-line therapy for patients with HER2-positive advanced gastric cancer [13]. Moreover, in several phase II studies, trastuzumab, in combination with S-1 and cisplatin, has been reported to be a feasible treatment option in the first-line treatment of HER2-positive advanced gastric cancer [14,15,16,17]. In patients with HER2-positive gastric cancer, a combination therapy consisting of S-1, LV, and oxaliplatin may, in the future, be considered as the first-line therapy in combination with trastuzumab, or as a second-line therapy if the trastuzumab-containing first-line therapy fails.…”

Section: Discussionmentioning

confidence: 99%

Antitumor Efficacy of Combination Therapy Consisting of S-1, Leucovorin, and Oxaliplatin against Human Gastric Cancer Xenografts

Nagase

Nakagawa

Uchida³

2018

Chemotherapy

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Background/Aim: A phase 3 trial of S-1, leucovorin (LV), and oxaliplatin for treating gastric cancer is now underway. However, the antitumor efficacy of the combination has not yet been examined in an in vivo preclinical study. This study examined the antitumor efficacy of combination therapy consisting of S-1, LV, and oxaliplatin against 4 human gastric cancer xenografts: NUGC-4, St-40, SC-2, and SC-4. Methods: The antitumor efficacy was evaluated using human gastric cancer xenograft-bearing nude mice. S-1 and LV were administered orally once daily on days 1-7 at doses of 6.9 and 10 mg/kg, respectively. Oxaliplatin was administered intravenously at a dose of 8.3 mg/kg on day 1. The tumor volume was measured on day 15, and the relative tumor volume (RTV) was calculated. Results: In all 4 xenograft models, S-1 alone and oxaliplatin alone, but not LV alone, had significant antitumor activities (p < 0.001). Combination therapy consisting of S-1 and LV resulted in a significantly smaller RTV than S-1 alone (p < 0.001). Combination therapy consisting of S-1 and oxaliplatin also resulted in a significantly smaller RTV than either S-1 alone (p < 0.001) or oxaliplatin alone (p < 0.001). Furthermore, combination therapy consisting of S-1, LV, and oxaliplatin resulted in the highest antitumor activity in these models (p < 0.001 vs. S-1 + LV; p < 0.001 or p = 0.003 vs. S-1 + oxaliplatin). Conclusion: Combination therapy consisting of S-1, LV, and oxaliplatin administered according to a 1-week-on/1-week-off schedule may be useful for the treatment of patients with gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Antitumor Efficacy of Combination Therapy Consisting of S-1, Leucovorin, and Oxaliplatin against Human Gastric Cancer Xenografts

Nagase

Nakagawa

Uchida³

2018

Chemotherapy

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“…Japanese phase III trials showed that S-1 was non-inferior to 5-FU and that 5-weekly S-1 plus cisplatin regimen was superior to S-1 alone in AGC patients (16,37). S-1 plus cisplatin with trastuzumab has also been reported with reasonable results in non-randomized studies (38)(39)(40). S-1 in combination is a standard first-line treatment of AGC in Japan and it is also approved by the EMA but it is investigational in the USA.…”

Section: Current Therapeutic Landscape For Advanced Gastroesophageal mentioning

confidence: 99%

Current therapeutic landscape for advanced gastroesophageal cancers

et al. 2018

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Treatment of advanced gastroesophageal cancers remains challenging for clinicians, patients, and caregivers alike. Despite considerable research, the therapeutic armamentarium is restricted and hardly personalized. In the first-line setting, trastuzumab with a fluoropyrimidine and platinum agent is the standard-of-care in patients with HER2-positive tumor. For the others, a platinum-based doublet (preferably with oxaliplatin) is recommended. Three-drug cytotoxic regimens should be reserved for exceptional cases where patients have good performance status. Triple combinations produce higher toxicity and provide marginal advantage. In the second line setting, the combination of paclitaxel and ramucirumab is preferred over all others. Currently, nothing is approved in the 3 rd or later line. Nivolumab has resulted in an improved benefit in an Asian trial. Early trials of TAS-102, STAT3 inhibitors, anti-claudin 18.2 and other immune checkpoint inhibitors (alone or in combination) are ongoing. However, development of reproducible biomarkers for patient enrichment is critical for future progress.

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“…In total, 15 studies containing 557 patients were included, investigating nine alternative backbone regimens ( Table 1). [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] The ToGA trial included 228 patients in the trastuzumab plus cisplatin and capecitabine/5-FU arm. In the doublet and triplet backbone studies, no major differences in patient population were observed compared to the ToGA population (Table 1).…”

Section: Description Of the Included Studiesmentioning

confidence: 99%

“…Triplet backbone regimens including docetaxel, cisplatin and S-1 or docetaxel, oxaliplatin and capecitabine showed more haematological toxicity compared to the ToGA regimen. Also, trastuzumab with bevacizumab plus triplet (71) 57 (27-78) 38 (75) 13 (25) 48 (94) 3 (6) 18 (35) (66) 57 (29-74) 49 (89) 6 (11) 51 (93) 4 (7) 55 (100 Retrospective multicentre cohort 27 (79) 63 (30-82) 30 (88) 4 (12) 27 (79) 7 (21) 24 (71) (78) 66 (34-75) 45 (83) 9 (17) 54 (100) 0 (0) 55 (100) Kataoka et al 21 20 Cis 60 mg/m 2 d8 1 S-1 80-120 mg d1-21, q5w…”

Section: Toxicitymentioning

confidence: 99%

Comparing cytotoxic backbones for first‐line trastuzumab‐containing regimens in human epidermal growth factor receptor 2‐positive advanced oesophagogastric cancer: A meta‐analysis

Veer

Creemers

Waal

et al. 2018

Intl Journal of Cancer

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According to the Trastuzumab for Gastric Cancer (ToGA) study, trastuzumab plus cisplatin and capecitabine/5-fluorouracil (5-FU) is standard first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive advanced oesophagogastric cancer. We examined the relative efficacy and safety of alternative trastuzumab-based cytotoxic backbone regimens compared to the standard ToGA regimen using meta-analysis. We searched Medline, EMBASE, CENTRAL and ASCO and ESMO up to March 2017 for studies investigating alternative first-line trastuzumab-based regimens for HER2-positive oesophagogastric cancer, defined as high protein expression IHC3+ or IHC2+ and gene amplification by in situ hybridisation. We compared primary outcome overall survival (OS) of alternative trastuzumab-based regimens to the ToGA regimen. Hazard ratios (HRs) and 95% confidence intervals (95%CI) were calculated by extraction of the published Kaplan-Meier curves. Incidence counts and toxicity sample-sizes were extracted for adverse events and compared using single-arm proportion meta-analysis in R. Fifteen studies (N = 557 patients) were included. OS was significantly longer with regimen trastuzumab plus doublet oxaliplatin and capecitabine/5-FU (median OS = 20.7 months) versus ToGA (16.0 months, HR = 0.75, 95% CI = 0.59-0.99) and was less toxic. Trastuzumab plus doublet cisplatin and S-1 showed no OS difference versus ToGA, but showed a different toxicity profile, including less hand-foot syndrome. Trastuzumab plus cisplatin or capecitabine as singlet backbone showed significantly worse survival and more toxicity versus ToGA regimen. Trastuzumab with triplet cytotoxic backbones or with bevacizumab and doublet cytotoxic backbone showed no survival benefit and more toxicity. In conclusion, trastuzumab plus doublet cytotoxic backbone containing oxaliplatin is preferable over the ToGA regimen with cisplatin. S-1 can substitute capecitabine or 5-FU when specific toxicities are encountered.

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A phase II prospective study of the trastuzumab combined with 5-weekly S-1 and CDDP therapy for HER2-positive advanced gastric cancer

Abstract: Five-weekly S-1 and cisplatin combined with trastuzumab showed effective with favorable safety profile in patients with HER2-positive AGC.

Cited by 22 publications

References 19 publications

Antitumor Efficacy of Combination Therapy Consisting of S-1, Leucovorin, and Oxaliplatin against Human Gastric Cancer Xenografts

Antitumor Efficacy of Combination Therapy Consisting of S-1, Leucovorin, and Oxaliplatin against Human Gastric Cancer Xenografts

Current therapeutic landscape for advanced gastroesophageal cancers

Comparing cytotoxic backbones for first‐line trastuzumab‐containing regimens in human epidermal growth factor receptor 2‐positive advanced oesophagogastric cancer: A meta‐analysis

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