Recent Progress in Drug Treatment for Advanced Gastric Cancer: from Chemotherapy to Molecular Targeted Therapy

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1 Japan - Taiwan Joint Symposium on Medical Oncology Session 5 journal homepage: Gastrointestinal cancers Recent Progress in Drug Treatment for Advanced Gastric Cancer: from Chemotherapy to Molecular Targeted Therapy Kun-Huei Yeh Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine National Clinical Trial and Research Center and Department of Oncology, National Taiwan University Hospital Abstract. Metastatic or recurrent gastric cancer is regarded as an incurable condition, and chemotherapy is usually used as standard palliation. Four major lines have been developed from chemotherapy to molecular targeted therapy for advanced gastric cancer (AGC) in Taiwan. First, the unique weekly 24-hour infusion of high-dose 5-fluorouracil (5-FU) and leucovorin regimen (acronym, HDFL) has satisfactory single-agent activity, minimal myelosuppression, and mild toxicity. A variety of HDFL-based doublet combinations (such as cisplatin-hdfl, paclitaxel-hdfl, oxaliplatin-hdfl) have become the cornerstone regimens with high efficacy and manageable toxicity. Second, novel active drugs hold promise for improved palliation and survival extension in AGC. Among them, oxaliplatin, taxanes (docetaxel, paclitaxel), irinotecan, and oral fluoropyrimidines (S-1, capecitabine) appear to be very relevant candidates. Third, the first-line sequential non-cross-resistant chemotherapy strategy is useful to prolong overall survival in patients with AGC. Fourth, through the applications of molecular targeted therapy (such as cetuximab, everolimus, bevacizumab, etc.), and studies of pharmacogenomics in the post-genomic era, personalized drug therapy will further improve the efficacy and decrease the toxicity. Keywords : Advanced gastric cancer, chemotherapy, molecular targeted therapy Metastatic gastric cancer is to be regarded as an incurable condition, and chemotherapy is usually used as standard palliation. For patients with recurrent or locally advanced, unresectable disease, chemotherapy is also considered mainstay treatment. Compared with best supportive care [1,2], systemic treatment can actually improve overall survival and quality of life. The prognosis for this group of patients of advanced or *Corresponding author: Kun-Huei Yeh M.D., Ph.D. Tel: ext Fax: khyeh@ntu.edu.tw metastatic gastric cancer is grave, and the median survival is in the range of approximately 6 to 10 months using conventional chemotherapy. Development of a more effective systemic chemotherapy for advanced gastric cancer is mandatory to further improve the median survival. Several chemotherapeutic agents provide active palliative roles in advanced gastric cancer (AGC), including fluoropyrimidines (5-fluorouracil, 5-FU), platinum compounds (cisplatin, oxaliplatin), taxanes (docetaxel, paclitaxel), topoisomerase I inhibitors (irinotecan), oral fluoropyrimidines (S-1, capecitabine), topoisomerase II inhibitors (etoposide), and anthracyclines (doxorubicin, epirubicin), etc.

2 K. H. Yeh / Proc JTJS (2007) Four major lines have been developed from chemotherapy to molecular targeted therapy for AGC in Taiwan. First, the unique HDFL regimen (weekly 24-hour infusion of high-dose 5-FU 2,000-2,600 mg/m 2 and leucovorin 300 mg/m 2 ) has satisfactory single-agent activity, minimal myelosuppression, and mild toxicity. The HDFL regimen was initially designed (using a higher dose of leucovorin, 500 mg/m 2 ) for the treatment of advanced colorectal cancer [3]. To overcome central venous portable pump blockage by calcite, a slightly lower dose of leucovorin (300 mg/m 2 ) has been used in Taiwan [4]. This regimen was found not only highly effective for colorectal cancer, but associated with a surprisingly low treatment-related toxicity [4,5]. HDFL regimen has been successfully used to treat the patients of advanced gastric cancer with a response rate of 48% (95% confidence interval: 32-72%) [6,7]. The low-myelosuppressive nature of HDFL has made it ideal for gastric cancer patients presenting with poor general condition [6], or even with acute DIC (disseminated intravascular coagulation) [7,8]. The half-life of 5-FU in serum is very short and in the range of 8-14 minutes. The steady state serum concentration (Css) of 5-FU (about 7.5 μm) by 24- hour high-dose 5-FU ( mg/m 2 ) infusion is much lower than the serum concentration (about 420 μm) of 5-FU ( mg/m 2 ) by bolus injection [9,10]. Moreover, due to a probable physiological bone-marrow barrier, the concentration of 5-FU in bone marrow is about one-third to one-fifth of that in serum during low Css achieved by infusional 5-FU [9,11]. In contrast, the physiological bone-marrow barrier does not exist during high concentration of 5-FU achieved by bolus injection, and the concentration of 5-FU in bone marrow is about the same as that in serum [9]. Evidence has been shown that prolonged exposure of gastric cancer cells to low concentration 5-FU for 24 hours enhances the inhibition of thymidylate synthase (TS), and thereby increases the cytotoxicity of 5-FU [12]. Further, HDFL regimen has repeatedly been demonstrated to cause minimal myelosuppression [5-7] and is therefore an ideal component for combination chemotherapy with other cytotoxic agents against gastric cancer. The possible mechanism responsible for the very low myelotoxicity of HDFL has been reported [13]. The low-myelosuppressive nature of HDFL has made it ideal for combining with other active chemotherapeutic agents. A variety of HDFL-based combinations have become the cornerstone regimens with high efficacy and manageable toxicity. All HDFLbased doublets ( cisplatin-hdfl, paclitaxel-hdfl, oxaliplatin-hdfl ) are well tolerated, and have a respectable objective tumor response of 52% to 61% [14-17]. The median overall survival of intent-to-treat patients is 10 to 11.4 months [14-17]. Second, novel active drugs hold promise for improved palliation and survival extension in AGC. Among them, oxaliplatin, taxanes (docetaxel, paclitaxel), irinotecan, and oral fluoropyrimidines (S-1, capecitabine) appear to be very relevant candidates. ORAL FLUOROPYRIMIDINES Both in the REAL-2 and XP/FP ML17032 trials [18,19], oral capecitabine has shown to be a non-inferior alternative to suboptimal use of 5-FU (i.e., continuous infusion of 200 mg/m 2 daily, in ECF of REAL-2 trial [18]; 800 mg/m 2, days 1 to 5, in FP of XP/FP trial [19]). S-1 monotherapy (40 mg/m 2, b.i.d., days 1-28, every 6 weeks) has been approved for use in AGC since 1999 in Japan. Grade 3/4 adverse events and early deaths have been shown during S-1 treatment in 25.0% and 2.4% patients, respectively [20,21]. Response rates of S-1 monotherapy [22], and S-1 plus cisplatin [23] have been shown in the ranges of 30-43%, and 53-66% patients, respectively. The combination treatment of S-1 and cisplatin has significant better overall survival in a randomized phase III SPI-

3 46 K. H. Yeh / Proc JTJS (2007) RITS trial [24]. S-1 is also under development and evaluation in the West [25], and in Taiwan [26] for AGC. DOCETAXEL Classical DCF regimen-in the randomized V325 trial [27], the superiority of adding docetaxel to cisplatin and 5-FU (classical DCF regimen) compared to cisplatin and 5-FU alone (CF regimen) has been shown with longer time to progression (p< 0.001), overall survival (p= 0.02), and a significantly higher response rate (p= 0.01) in AGC with a potentially troublesome toxicity profile [27]. Rates of grade 3/4 neutropenia were high in both groups (82% versus 57%), and rates of complicated neutropenia (febrile neutropenia and/or neutropenic infection) were 29% and 12%, respectively [27]. Modified DCF regimen (such as docetaxel-cisplatin-hdfl regimen)-weekly docetaxel 1-hour infusion of 40 mg/m 2, followed by weekly 24-hour infusion of cisplatin (30 mg/m 2 ), 5-FU (2,000 mg/m 2 ) and leucovorin (300 mg/m 2 ), days 1 and 8, every 3 weeks, is an active alternative with a better toxicity profile [28]. OXALIPLATIN In the REAL-2 trial, oxaliplatin has shown to be a non-inferior alternative to cisplatin in AGC, and EOX (epirubicin-oxaliplatin-capecitabine) has a superior overall survival than ECF (epirubicin-cisplatin-5-fu); 11.2 versus 9.9 months, p= 0.02 [18]. Third, a first-line sequential non-cross-resistant strategy is useful to prolong overall survival and to further improve the clinical outcome in patients with AGC. Infusional cisplatin-hdfl, followed by weekly docetaxel-irinotecan regimen to prolong overall survival and to overcome emergence of drug resistance, the first-line sequential non-cross-resistant chemotherapy strategy (infusional cisplatin-hdfl, followed by weekly docetaxel-irinotecan) was designed [14,17]. Weekly docetaxel-irinotecan consists of weekly docetaxel 30-min infusion of mg/m 2, followed by weekly irinotecan 60-min infusion of mg/m 2, days 1, 8, and 15, every 4 weeks. A promising median overall survival of the whole intent-to-treat group was 15 months [14,17]. Fourth, through the applications of molecular targeted therapy (such as cetuximab, everolimus, bevacizumab, etc.), and studies of pharmacogenomics in the post-genomic era, personalized drug therapy will further improve efficacy and decrease toxicity. EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) PATHWAY Epidermal growth factor receptor (EGFR) signaling pathways are deregulated in most cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. Cetuximab has clinically significant activity when given alone or in combination with irinotecan in irinotecan-refractory colorectal cancer (CRC) patients [29]. Expression of EGFR was detected in about 50% gastric cancer (GC) patients, and high tumor EGFR levels were associated with an unfavorable prognosis in GC patients [30]. Yeh et al have shown that growth inhibitory effects of cetuximab, and chemosensitizing effects for 5-fluorouracil, cisplatin, or irinotecan by cetuximab in human gastric cancer cells [31]. In a multi-center phase II study of cetuximab plus cisplatin-hdfl for the first-line treatment of AGC in Taiwan, preliminary data show a confirmed overall response rate of 69.2% (39%-91% of 95% C.I., 9 confirmed partial responses in initial 13 patients) with mild and easily tolerated treatment-related toxicity [32]. ANGIOGENESIS PATHWAY There are evidences that link angiogenesis and cell growth in gastric cancer (GC) [33,34]. One promising treatment approach in GC involves therapeutic agents (such as bevacizumab) that inhibit angiogenesis and cell growth. Bevacizumab is a monoclonal antibody that specifically blocks the vascular endothelial gro-

4 K. H. Yeh / Proc JTJS (2007) wth factor (VEGF). The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant improvement in survival among patients with metastatic colorectal cancer (CRC) [35]. Expression of VEGF was detected in 55-70% gastric cancer (GC) patients, and high tumor VEGF levels were associated with an unfavorable prognosis in GC patients [33,34]. In a multi-center phase II study of bevacizumab plus cisplatin and irinotecan has been shown to have an overall response rate of 66.7% (51%-83%, 95% C.I.) for the first-line treatment of gastric and gastroesophageal junctional (GEJ) adenocarcinomas [36]. A double-blind, randomized, multicenter, phase III study of bevacizumab versus placebo in combination with cisplatin and capecitabine as the first-line therapy in patients with AGC has been started since PHOSPHOINOSITIDE-3-KINASE (PI3K) / AKT / mtor PATHWAY Phosphoinositide-3-kinase (PI3K) / AKT / mtor pathway is actively participating in cell proliferation and survival of human gastric cancers. The PI3K/AKT pathway is negatively regulated by a tumor suppressor gene, the phosphatase and tensin homologue gene (PTEN). Loss of heterozygosity of PTEN and activation of PI3K/AKT/mTOR pathway are significantly more (>60%) in poorly differentiated advanced gastric cancers [37,38]. RAD001 (Everolimus) is a rapamycin derivative that specifically inhibits the mammalian target of rapamycin (mtor) [39], which is a potential targeted agent in the treatment of gastric cancers. Yeh et al have shown that chemosensitizing effects and sustained G1-S cell cycle arrest by low-dose RAD001 (everolimus) for cisplatin and 5-fluorouracil (5-FU) in human gastric cancer cells [40]. A multi-center phase II study of everolimus (RAD001) plus cisplatin-hdfl for the first-line treatment of AGC has also been started in Taiwan. REFERENCES 1. Pyrhonen S, Kuitunen T, Nyandoto P, et al. Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 71(3): , Glimelius B, Ekstrom K, Hoffman K, et al. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 8(2): 163-8, Ardalan B, Chua L, Tian EM, et al. A phase II study of weekly 24-hour infusion with high-dose fluorouracil with leucovorin in colorectal carcinoma. J Clin Oncol 9(4): , Yeh KH, Cheng AL. An alternative method to overcome central venous portable external infusion pump blockage in patients receiving weekly 24-hour high-dose fluorouracil and leucovorin. J Clin Oncol 12(4): 875-6, Yeh KH, Cheng AL, Lin MT, et al. A phase II study of weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin (HDFL) in the treatment of recurrent or metastatic colorectal cancers. Anticancer Res 17(5B): , Hsu CH, Yeh KH, Chen LT, et al. Weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin in the treatment of advanced gastric cancers. An effective and low-toxic regimen for patients with poor general condition. Oncology 54(4): , Yeh KH, Cheng AL. Gastric cancer associated with acute disseminated intravascular coagulation: successful initial treatment with weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin. Br J Haematol 100(4): , Huang TC, Yeh KH, Cheng AL, et al. Weekly 24- hour infusional 5-fluorouracil as initial treatment for advanced gastric cancer with acute disseminated intravascular coagulation. Anticancer Res

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