Trastuzumab in combination with docetaxel/cisplatin/S-1 (DCS) for patients with HER2-positive metastatic gastric cancer: feasibility and preliminary efficacy

Mitsui, Yasuhiro; Sato, Yasushi; Miyamoto, Hiroshi; Fujino, Yuichi; Takaoka, T; Miyoshi, Jinsei; Kagawa, Masaaki; Ohnuma, Hiroyuki; Hirakawa, Masahiro; Kubo, Tomohiro; Osuga, Takahiro; Sagawa, Tamotsu; Sato, Yasuhiro; Takahashi, Yasuo; Katsuki, Shinich; Okuda, Toshinori; Takimoto, Rishu; Kobune, Masayoshi; Nobuoka, Takayuki; Hirata, Koichi; Kato, Junji; Takayama, Tetsuji

doi:10.1007/s00280-015-2807-7

Cited by 30 publications

(21 citation statements)

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“…In addition, no cases of cardiac failure or mortality due to cardiac toxicity were observed. Similarly, previous reports have shown that adding trastuzumab to chemotherapy does not increase the toxic effects associated with standard fluoropyrimidine and platinum chemotherapy (4,(16)(17)(18)(19). The toxicity profile of trastuzumab plus chemotherapy has been shown to be comparable to that for chemotherapy alone in phase II and III trials (4,20,21).…”

Section: No Patients -----------------------------------------------mentioning

confidence: 84%

“…High efficacy of trastuzumab has been confirmed prior to and following chemotherapy in patients with HER2-positive breast cancer, and expanded indications in gastric cancer are anticipated (14,15). Previous studies that have assessed chemotherapy plus trastuzumab treatment regimens for patients with HER2-positive gastric cancer have revealed good tolerance and high efficacy with cytotoxic chemotherapy including S-1 plus cisplatin, capecitabine plus oxaliplatin (or docetaxel), and cisplatin plus S-1, however, not capecitabine plus cisplatin (16)(17)(18)(19)(20)(21). Therefore, trastuzumab with cytotoxic chemotherapy is considered a standard treatment regimen for patients with HER2-positive gastric cancer.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of a trastuzumab-containing treatment regimen for patients with unresectable advanced or recurrent gastric cancer

Namikawa

Munekage

et al. 2016

Molecular and Clinical Oncology

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Abstract. The present study aimed to evaluate the efficacy and safety of trastuzumab plus chemotherapy for patients with unresectable advanced or recurrent gastric cancer. A retrospective analysis of 213 patients with unresectable advanced or recurrent gastric cancer who received systemic chemotherapy, including 15 patients who were also administered trastuzumab, at Kochi Medical School between 2007 and 2013 was performed. The overall survival was compared between patients who received trastuzumab plus chemotherapy and patients who received chemotherapy alone, and the safety and efficacy of the trastuzumab-containing regimen was evaluated. Human epidermal growth factor receptor (HER)2 status was examined in 86 patients, of whom 15 (17.4%) exhibited strong positive HER2 expression. The rate of strong positive HER2 expression was significantly higher for intestinal type tumors compared with diffuse type tumors [23.6 (13/55) vs. 6.5% (2/31); P=0.044]. The median overall survival of the patients treated with trastuzumab was significantly longer compared with that for patients who were not treated with trastuzumab (22.9 vs. 11.6 months; P= 0.014). The objective response rate and disease control rate for trastuzumab plus chemotherapy were 46.7 and 86.7%, respectively. Frequently encountered grade 3-4 toxicities included neutropenia (26.7%; 4/15), anemia (13.3%; 2/15) and fatigue (13.3%; 2/15). Trastuzumab plus chemotherapy is effective for patients with HER2-positive advanced or recurrent gastric cancer, and the frequencies of hematological and non-hematological toxicities experienced by patients in the present study indicated that it can be safely administered clinically. IntroductionGastric cancer is the third most commonly diagnosed cancer type worldwide and one of the leading causes of cancer-associated mortality (1). In patients with recurrent, metastatic, or advanced gastric cancer, chemotherapy can prolong survival and improve quality of life compared with the best supportive care.Human epidermal growth factor receptor (HER)2 is a member of a family of receptors that is associated with tumor cell proliferation, apoptosis, adhesion, migration and differentiation. It is overexpressed in 15-20% of patients with primary gastric and gastroesophageal junction cancers (2,3). Trastuzumab, a monoclonal antibody that targets HER2, induces antibody-dependent cellular cytotoxicity and inhibits HER2-mediated signaling by binding to the extracellular domain of HER2 (4). The trastuzumab for gastric cancer (ToGA) trial recently validated the additive effects of trastuzumab for HER2-positive, unresectable advanced or recurrent gastric cancer. This trial revealed a significant increase in the overall survival and progression-free survival when trastuzumab was used in combination with chemotherapy, thus supporting the use of trastuzumab in individualized, biomarker-based treatment (5). Additionally, it has been shown that second-line and later lines of chemotherapy can significantly improve patient outcomes, and that the additive...

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Section: No Patients -----------------------------------------------mentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Evaluation of a trastuzumab-containing treatment regimen for patients with unresectable advanced or recurrent gastric cancer

Namikawa

Munekage

et al. 2016

Molecular and Clinical Oncology

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“…Approximately 25% of all female breast cancers exhibit an over-expression of HER2, which is known to drive aggressive cellular behavior[3–7]. Trastuzumab (a monoclonal antibody), the first-line of treatment for HER2+ breast cancers[8–10], has been shown to be active as a single agent[11,12] as well as in combination with chemotherapy[9,10,13] for the treatment of advanced stage HER2+ breast cancer. Its use has been shown to positively affect patient outcomes such as progression-free survival (PFS) and overall survival (OS).…”

Section: Introductionmentioning

confidence: 99%

An Experimental Analysis of the Molecular Effects of Trastuzumab (Herceptin) and Fulvestrant (Falsodex), as Single Agents or in Combination, on Human HR+/HER2+ Breast Cancer Cell Lines and Mouse Tumor Xenografts

Chen

Weng

et al. 2017

PLoS ONE

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PurposeTo investigate the effects of trastuzumab (herceptin) and fulvestrant (falsodex) either in combination or alone, on downstream cell signaling pathways in lab-cultured human HR+/HER2+ breast cancer cell lines ZR-75-1 and BT-474, as well as on protein expression levels in mouse xenograft tissue.MethodsCells were cultivated in the presence of trastuzumab or fulvestrant or both. Molecular events that resulted in an inhibition of cell proliferation and cell cycle progression or in an increased rate of apoptosis were studied. The distribution and abundance of the proteins p-Akt and p-Erk expressed in these cells in response to single agents or combinatorial treatment were also investigated. In addition, the effects of trastuzumab and fulvestrant, either as single agents or in combination on tumor growth as well as on expression of the protein p-MED1 expressed in in vivo mouse xenograft models was also examined.ResultsCell proliferation was increasingly inhibited by trastuzumab or fulvestrant or both, with a CI<1 and DRI>1 in both human cell lines. The rate of apoptosis increased only in the BT-474 cell line and not in the ZR-75-1 cell line upon treatment with fulvestrant and not trastuzumab as a single agent (P<0.05). Interestingly, fulvestrant, in combination with trastuzumab, did not significantly alter the rate of apoptosis (in comparison with fulvestrant alone), in the BT-474 cell line (P>0.05). Cell accumulation in the G1 phase of cell cycle was investigated in all treatment groups (P<0.05), and the combination of trastuzumab and fulvestrant reversed the effects of fulvestrant alone on p-Akt and p-Erk protein expression levels. Using ZR-75-1 or BT-474 to generate in vivo tumor xenografts in BALB/c athymic mouse models, we showed that a combination of both drugs resulted in a stronger inhibition of tumor growth (P<0.05) and a greater decrease in the levels of activated MED1 (p-MED1) expressed in tumor issues compared with the use of either drug as a single agent.ConclusionsWe demonstrate that the administration of trastuzumab and fulvestrant in combination results in positive synergistic effects on both, ZR-75-1 and BT-474 cell lines. This combinatorial approach is likely to reduce physiological side effects of both drugs, thus providing a theoretical basis for the use of such combination treatment in order to resolve HR+/HER2+ triple positive breast cancer that has previously been shown to be resistant to endocrine treatment alone.

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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%

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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Trastuzumab in combination with docetaxel/cisplatin/S-1 (DCS) for patients with HER2-positive metastatic gastric cancer: feasibility and preliminary efficacy

Abstract: UMIN000005603.

Cited by 30 publications

References 20 publications

Evaluation of a trastuzumab-containing treatment regimen for patients with unresectable advanced or recurrent gastric cancer

Evaluation of a trastuzumab-containing treatment regimen for patients with unresectable advanced or recurrent gastric cancer

An Experimental Analysis of the Molecular Effects of Trastuzumab (Herceptin) and Fulvestrant (Falsodex), as Single Agents or in Combination, on Human HR+/HER2+ Breast Cancer Cell Lines and Mouse Tumor Xenografts

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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