HER2 exhibits tyrosine kinase activity and functions as a growth factor receptor . HER2 overexpression due to gene amplification in gastric cancer has led to aggressive clinical course and poor prognosis . Trastuzumab, a monoclonal antibody against HER2, causes cell cycle arrest at G1 and exhibits antitumor activity in HER2 overexpressed gastric cancer cells [9, 10]. Additionally, trastuzumab can enhance cytotoxic effects of chemotherapy in gastric cancer xenograft overexpressing HER2, when combined with capecitabine, cisplatin, or taxane . Phase II studies incorporating trastuzumab with cisplatin-based regimen in patients with advanced gastric cancer overexpressing HER2 have demonstrated promising activities [12, 13].
The ToGA study presented at 2009 annual meeting of American Society of Clinical Oncology has screened about 3,800 patients with advanced gastric cancer from 24 countries . HER2 overexpression was detected in 22%, and the concordance rate between IHC and FISH was high at all levels of HER2 positivity . There was a specific pattern of disease which correlated with HER2 overexpression. Higher rates occurred in intestinal and proximal or gastroesophageal junction cancers than in diffuse or distal gastric cancers.
Five hundred and eighty four patients tested positive for HER2 overexpression (IHC 3+ and/or FISH positive) were enrolled into ToGA study, a phase III trial comparing fluoropyrimidine (5-fluorouracil [5-FU] or capecitabine) and cisplatin chemotherapy with or without trastuzumab. Patients who received trastuzumab plus chemotherapy achieved longer overall survival (13.8 months vs. 11.1 months, P = 0.0046), longer progression-free survival (6.7 months vs. 5.5 months, P = 0.0002), and higher response rates (47% vs. 35%, P = 0.0017) than those who received chemotherapy alone. Complete response was noted in 5.4% of patients receiving trastuzumab plus chemotherapy vs. 2.4% in chemotherapy alone. There were no significant differences in the toxicities between these two groups. This study has established a new paradigm using trastuzumab in combination with chemotherapy in patients with advanced gastric cancer overexpressing HER2.
MAGIC trial for investigation of perioperative chemotherapy was conducted in patients with resectable adenocarcinoma of stomach, gastroesophageal junction or distal esophagus . Five hundred and three patients were randomly assigned to either perioperative chemotherapy with epirubicin, cisplatin and infusional 5-FU (ECF) and surgery or surgery alone. Despite of only 43% of patients completing the planned 6 cycles of chemotherapy (3 cycles before surgery and 3 cycles afterwards), there was statistically significant improvement in overall survival in patients receiving chemotherapy and surgery (5-year survival: 36% for chemotherapy plus surgery vs. 23% for surgery). At the time of surgery, the patients receiving preoperative chemotherapy had significantly smaller tumor size and lower stage. However, there was no pathological complete response in patients receiving preoperative ECF in this study.
The infusional 5-FU in the ECF regimen is given continuously through a venous access device, and is associated with inconvenience and higher incidence of thrombosis and infection. Furthermore, cisplatin can cause nephrotoxicity, ototoxicity, and severe emesis. REAL-2, a randomized study in patients with advanced gastroesophageal cancer using two-by-two design, has shown 5-FU can be replaced by capecitabine, and cisplatin by oxaliplatin in the regimen of ECF without affecting the efficacy .
Docetaxel has demonstrated encouraging activity in the treatment of advanced gastric cancer . Phase II/III trial V325 has shown adding docetaxel to cisplatin and 5-FU (DCF) significantly improved time to tumor progression, survival, and response rate in advanced gastric cancer patients receiving first-line treatment . Based on results of this study, Food and Drug Administration of U.S.A. approved DCF for the treatment of advanced gastric cancer in 2006. Various modifications of DCF with the intent to improve tolerability have been developed. Replacing cisplatin by oxaliplatin and 5-FU by capecitabine, the combination of docetaxel, oxaliplatin and capecitabine have demonstrated encouraging activity and good tolerability in early-phase studies [19, 20].
The administration of trastuzumab can result in sub-clinical and clinical cardiac failure, and the incidence is much higher in patients receiving trastuzumab concurrently with anthracycline-containing chemotherapy regimens . Instead of using ECF, we decided to use docetaxel, oxaliplatin and capecitabine in combination with trastuzumab as perioperative chemotherapy for our patient mainly due to the concern of cardiac toxicity. We have monitored our patient's cardiac function with periodic echocardiogram evaluation, and find no evidence of cardiac failure.
Our case illustrates the first reported case of pathological complete response after neoadjuvant chemotherapy with trastuzumab-containing regimen in a patient with locally advanced gastric cancer overexpressing HER2. The use of docetaxel, oxaliplatin and capecitabine in combination with trastuzumab in this setting remains experimental, and ideally should be considered only in the context of a clinical trial. Therefore, the role of trastuzumab as a part of perioperative therapy is worth further investigation.