Geographic differences in approach to advanced gastric cancer: Is there a standard approach?

Critical Reviews in Oncology/Hematology 88 (2013) 416–426

Geographic differences in approach to advanced gastric cancer: Is there a standard approach? Richard Kim a,∗ , Ann Tan b , Minsig Choi c , Bassel F. El-Rayes d a

Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive FOB-2, Tampa, FL 33612, USA b Department of Solid Tumor Oncology, BC Cancer Agency, 32900 Marshall Road, Abbotsford, BC, Canada V2S 0C2 c Department of Oncology, Karmanos Cancer Institute, 4100 John R, Detroit, MI 48201, USA d Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA Accepted 15 May 2013

Contents 1. 2. 3.

4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Difference in outcomes: Asia vs West . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . First line chemotherapy for advanced gastric cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Treatment pattern in Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Treatment pattern in Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Treatment pattern in the United States (US) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Discussion on regional differences in first line treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Second line chemotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Discussion on regional differences in second line therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion on biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Biomarkers associated with targeted agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

417 417 418 418 418 419 420 421 421 422 423 423 424 424 424 424 426

Abstract Gastric cancer is one of the leading causes of cancer related deaths worldwide. Regional differences in gastric cancer are evident between Asian and Western societies with respect to etiology, prevalence, clinicopathologic features as well as treatment pattern of the disease. For patients with advanced gastric cancer (AGC), chemotherapy has been found to improve survival and quality of life compared to best supportive care alone. But contrast to other tumors such as colon or pancreatic cancer, there are regional differences in outcome in gastric cancer. Various geographic/ethnic, biology and treatment strategies may contribute to these differences. In the first line setting, cisplatin and fluoropyrimidine based therapies remain the backbone of treatment for advanced gastric cancer in Asian and Western patients, although there is preference for S1 in Asia and 5FU in the West. A third agent may be added in patients with good performance status. Recent trials from Asia and Europe demonstrate an advantage for second line chemotherapy. Irinotecan and taxanes are the most commonly used agents. The introduction of

∗

Corresponding author. Tel.: +1 813 745 1277; fax: +1 813 745 7229. E-mail address: [email protected] (R. Kim).

1040-8428/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2013.05.007

R. Kim et al. / Critical Reviews in Oncology/Hematology 88 (2013) 416–426

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trastuzumab into the frontline therapy of AGC has ushered the age of targeted therapy and personalized medicine in this disease. In this article, we will review the various first and second line chemotherapy regimens in AGC, taking into account regional differences including potential biomarkers. © 2013 Elsevier Ireland Ltd. All rights reserved. Keywords: Advanced gastric cancer; Chemotherapy; Regional differences; Biomarkers

1. Introduction Gastric cancer remains the second leading cause of cancer death worldwide [1]. Approximately 1 million new cases are diagnosed with 800,000 deaths attributed to this disease annually [1]. Except for Korea and Japan, where surveillance programs are widely practiced, approximately two thirds of gastric cancer patients will present at an advanced stage. Even after curative intent surgical resection, loco-regional and distant relapse is a common problem. In the advanced setting, palliative chemotherapy remains the mainstay of treatment. Patients receiving chemotherapy live longer than those on best supportive care (BSC) alone with an increase in median survival of approximately 6 months based on a meta-analysis [2]. There is no consensus on the approach and management of advanced gastric cancer (AGC) as it varies from region to region. Survival outcome differs between Asian and Western populations in gastric cancer; this may be due to several factors including differences in biology, stage migration, and treatment pattern. Various combinations of platinum and fluoropyrimidines are commonly used for first line treatment of AGC. In many Asian countries, chemotherapy doublets are frequently used, while in Western countries, triplet regimens are more widely adopted. Nonetheless, median survival time even with contemporary regimens is typically less than one year [3–5]. Second line therapy for AGC is more commonly practiced in East Asia than in Western countries. Until recently, there was no standard of care chemotherapy in patients who progressed on platinum and 5FU based therapies. Emerging data from Korea shows that single agent chemotherapy (irinotecan or docetaxel) improved overall survival compared to BSC [6]. In this article, we will attempt to review and explore the different regional approaches to AGC, discussing first and second line chemotherapy regimens incorporating predictive biomarkers. Discussion of molecular targeted agents is beyond the scope of this paper.

2. Difference in outcomes: Asia vs West Various discrepancies exist in the outcomes of early gastric cancer between Asian and Western countries. These may be attributed to differences in the location of the primary tumor (distal vs proximal), histology (intestinal vs diffuse), diet and early diagnosis as well as the management of the disease [7].

In early stage gastric cancer, the outcome of surgery alone has been superior in Asia, especially in Japan, compared to Western countries [8,9]. Western patients have higher incidences of diffuse histology and more proximal tumors which is associated with a worse prognosis [10–12]. On the other hand, treatment of early stage gastric cancer in Japan has focused on extended lymph node dissection (D2 resection) in comparison to Western countries where less extensive lymph node dissection is performed. Whether the improved outcome is due to more extensive D2 resection or a difference in biology or simply stage migration associated with more lymph node sampling is a controversial question [13]. Earlier randomized Dutch trial did not show improve outcome in western population who underwent D2 resection [14]. However 15-year follow-up showed that D2 lymphadenectomy was associated with lower loco regional recurrence and gastric-cancer-related death rates than D1 surgery [15]. Group from Memorial Sloan Kettering Cancer Center (MSKCC) attempted to compare surgical outcomes of gastric cancer patients at MSKCC to those in Japan and Korea with two retrospective reviews. This is a reasonable comparison as D2 resection is routinely performed at MSKCC, similarly to Japan and Korea. The first study, published 10 years ago, showed that favorable outcomes for gastric carcinoma patients in Japan were primarily explained by differences in tumor location, a greater frequency of early stage disease, and more accurate staging. However, the study showed similar 5-year survival rates when stratified by tumor location and T-stage [10]. However the second study comparing gastric cancer patients from MSKCC to those in Korea came to different conclusion. In this study, Korean patients demonstrated better outcomes compared to MSKCC patients even when matched by T stage and location [12]. As was the case for Japanese patients, there were more patients with lower node positivity and early stage disease in the Korean population. When multivariate analysis with a validated gastric cancer nomogram was used, disease specific survival (DSS) for Korean gastric cancer patients was significantly more favorable than that of MSKCC patients by 20–30%, suggesting inherent biological differences. In this study, patients who received neo-adjuvant treatment were excluded to decrease the influence of treatment on outcome of US patients. Another potential explanation may have to do with lymph node dissection. About 73% of Korean patients had more than 30 lymph nodes removed compared to 29% of MSKCC patients suggesting an impact of the pattern of practice. Other factors

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Table 1 Summary of selected S1 based trials in AGC. No. of patients Boku et al. [16]

704

Study arms

Response rates (%)

Median response duration (months)

Median overall survival (months)

A: Infusional 5FU vs B: Irinotecan + Cisplatin vs C: S-1

A: 9 vs B: 38 vs C: 28

PFS: A: 2.9 vs B: 4.8 vs C: 4.2

A: 10.8 vs B: 12.3 vs C: 11.4 B vs A: (HR 0.85 [95% CI: 0.70–1.04]; p = 0.0552) C vs A: (HR: 0.83 [95% CI: 0.68–1.01]; p = 0.0005 for non-inferiority)

Koizumi et al. [17]

305

A: S-1 + Cisplatin vs B: S-1

A: 54 vs B: 31 (p = 0.002)

PFS: A: 6.0 vs B: 4.0 (p < 0.0001)

A: 13.0 vs B: 11.0 (HR for death: 0.77; 95% CI: 0.61–0.98; p = 0.04)

Fujii et al. [65]

639

A: S-1 + Docetaxel vs B: S-1

A: 30 vs B: 18 (p = 0.0004)

TTP: A: 161 days vs B: 126 days (p < 0.0004, HR: 0.74)

A: 390 days vs B: 334 days (p = 0.1416, HR: 0.88)

1053

A: S-1 + Cisplatin vs B: 5FU + Cisplatin

A: 29.1 vs B: 31.9 (p = 0.40)

PFS: A: 4.8 vs B: 5.5 (HR, 0.99; 95% CI: 0.86–1.14, p = 0.92)

A: 8.6 vs B: 7.9 (HR: 0.92; 95% CI: 0.80–1.05; p = 0.20)

Ajani et al. [29] a

a First

phase III study on S1 conducted outside of Japan. PFS: Progression free survival, TTP: Time to progression.

that may have contributed to the difference include differences in body habitus and surgical skills. However all of these suggestions are only hypothesis generating and further prospective studies need to be done to validate these findings.

3. First line chemotherapy for advanced gastric cancer 3.1. Treatment pattern in Asia The platinum–fluoropyrimidine doublet is the major backbone of most regimens in Western countries and in East Asia. In recent years, chemotherapy trials have explored the utility of oral fluoropyrimidines. S1 is an oral fluoropyrimidine combining tegafur; a prodrug of 5FU, 5 chloro-2,4-dihydroxyphridine (CDHP); a reversible inhibitor of dihyropyrimidine dehydrogenase (DPD), and potassium oxonate; an antidiarrheal agent protective against 5FU gastrointestinal toxicity in a molar ratio of 1:0.4:1. Most of the S1 based studies have been conducted in Japan. In the landmark Japanese Clinical Oncology Group (JCOG) 9912 study, S1 was found to be non-inferior to 5FU alone and irinotecan/cisplatin [16]. Given the ease of oral dosing, without compromise in efficacy or excessive toxicity, S1 was adopted as the standard treatment for metastatic gastric cancer in Japan. The subsequent development of new chemotherapeutic regimens for AGC in Japan centered on S1 as the backbone chemotherapy (Table 1). Subsequently, the SPIRITS (S-1 Plus cisplatin vs S-1 In RCT In the Treatment for Stomach cancer) trial showed that S1/cisplatin resulted in a significantly longer median

survival and progression free survival (PFS) compared to S1 alone [17] (Table 1). Both regimens were well tolerated although patients assigned to combination treatment experienced increased grade 3/4 events including neutropenia (40% vs 11%), anemia (26% vs 4%), nausea (11% vs 1%) and anorexia (30% vs 6%). Another phase III trial (START trial) comparing S1 and docetaxel vs S1 alone revealed longer PFS and response rate (RR) with combination treatment but failed to meet the overall survival (OS) endpoint (390 days vs 334 days, p = 0.14) [18]. The use of second and third-line therapies may have obscured the benefit on OS in first-line therapy. The combination of S1, cisplatin and docetaxel or oxaliplatin has also been studied (Table 1). [19,20]. The combination of S1 and oxaliplatin seems to be promising with median OS of 16.5 months [20]. These combinations will need to be explored further in randomized phase III trials. Based on the SPIRITS trial, the S1-cisplatin doublet remains the standard chemotherapy regimen for AGC in Japan, replacing 5FU-cisplatin. S1 is also available in Korea, Singapore, Taiwan, Philippines and China for this indication, but is not approved in North America. 3.2. Treatment pattern in Europe Unlike in Asia, where doublet regimens are more commonly used, in other parts of the world triplet regimens are preferred in patients with good performance status. Metaanalysis provides further evidence to support the role of adding an anthracycline to a platinum–fluoropyrimidine doublet [21]. Based on a randomized trial by Webb et al., epirubicin, cisplatin and 5FU (ECF) has been considered by many to be the

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419

Table 2 Summary of selected oxaliplatin based regimens in AGC. No. of patient Cunningham et al. [3]

1002

Study arms

Response rates (%)

Median response duration (months)

Median overall survival (months)

A: ECF vs B: EOF vs C: EOX vs D: ECX

A: 40.7 vs B: 42.4 vs C:46.4 vs D: 47.9

PFS: A: 6.2 vs B: 6.5 vs C: 6.7 vs D: 7.0

A: 9.9 vs B: 9.3 vs C: 9.9 11.2 Capecitabine vs 5FU HR: 0.86 (0.80–0.99) Oxaliplatin vs cislpatin HR: 0.92 (0.80–1.10) Prespecified upper limit of 95% CI for HR for non-inferiority < 1.23

Al Batran et al. [23]

220

A: FLO vs B:FLP

A: 41.3 vs B: 13.7 (p = 0.012)

PFS: A: 5.8 vs B: 3.9 (p = 0.077)

A: 10.7 vs B: 8.8 (p = NS)

Koizumi et al. [19]

55

Oxaliplatin + S-1

59

PFS: 6.5

16.5

PFS: progression free survival; TTP: time to progression; ECF: epirubicin, cisplatin and 5FU; EOF: epirubicin, oxaliplatin, 5FU; EOX: epirubicin, oxaliplatin capecitabine; ECX: epirubicin, cisplatin capecitabine; FLO: 5FU, leucovorin, oxaliplatin; FLP: 5FU, leucovorin, cisplatin.

reference regimen [5]. In another randomized trial, ECF was equivalent to mitomycin, cisplatin and 5FU (MCF) in RR, PFS and OS, albeit global quality of life scores were superior with ECF, leading the authors to recommend this regimen to be the reference treatment for advanced esophagogastric cancer [22]. The REAL-2 study was designed to determine whether 5FU can be replaced by capecitabine and cisplatin by oxaliplatin in the ECF regimen. Patients were randomized to receive ECF, EOF (epirubicin/oxaliplatin/5FU), ECX (epirubicin/cisplatin/capecitabine) or EOX (epirubicin/oxaliplatin/capecitabine) [3] (Table 2). The median survival times were not significantly different with no significant differences in RR and PFS. Compared to cisplatin, oxaliplatin seemed to be better tolerated except for side effects of diarrhea and neuropathy. Apart from higher incidences of hand foot syndrome, toxicities between the 5FU and capecitabine containing groups were rather similar. Similar findings were demonstrated by Al Batran et al. comparing 5FU, leucovorin and oxaliplatin (FLO) vs 5FU/cisplatin (FLP), revealing no significant differences in PFS and OS even though this study suffered from low statistical power (Table 2). The oxaliplatin regimen was again better tolerated [23]. Notably, patients over 65 years of age discontinued treatment earlier with the cisplatin compared to oxaliplatin based regimen (median treatment duration 2.1 vs 5.2 months, p = 0.0015), translating into poorer RR, PFS and OS with cisplatin in the elderly patient population. Although, this finding is limited by small patient numbers, it reflects the increased vulnerability of the elderly to cisplatin containing regimens. The ESMO (European Society for Medical Oncology) guidelines indicate that 5FU can be replaced with capecitabine and cisplatin with oxaliplatin in AGC patients [24]. The addition of taxanes as a third agent to the cisplatin/fluoropyrimidine backbone is also increasingly used in many European countries outside United Kingdom.

3.3. Treatment pattern in the United States (US) Cisplatin/fluoropyrimidine based therapies are the most commonly used backbone regimens in North America. However, instead of anthracycline as a third agent, taxanes are more frequently used. In the V325 global study, DCF (docetaxel/cisplatin/5FU) was superior to 5FU/cisplatin (FC) in RR, time to progression (TTP) and OS but was associated with significantly higher rates of grade 3/4 neutropenia (82% vs 57%) and febrile neutropenia (29% vs 12%). Non-hematologic toxicities were also more common [4]. Despite increased toxicities with DCF, quality of life (QOL) or clinical benefit did not appear to be negatively affected. This suggests that tumor control is important in QOL in advanced cancer patients [25,26]. Due to the high toxicity profile of DCF in exchange for small OS benefit (9.2 months vs 8.6 months; 95% CI: 7.2–9.5; HR: 1.29), this regimen has not gained wide acceptance. Different variations of this regimen have reduced toxicity without compromising efficacy and have re-popularized the addition of taxanes as a third agent in Europe and North America [27,28]. S1 was evaluated in a randomized trial in the United States and Europe based on promising results from Asia where patients with advanced gastric/gastroesophageal adenocarcinoma were treated with S1/cisplatin or 5FU/cisplatin. The study was the first phase III study of S1 conducted outside of Japan. Unfortunately, the trial did not meet its primary endpoint in improving OS with no difference in RR and PFS [29]. However, S1/cisplatin was better tolerated and compared favorably to the findings of the SPIRITS trial. These results will need to be interpreted with caution given the lower cisplatin dose in the S1 arm. Also, the S1 dose in FLAGS is much lower than that routinely used in Japan possibly compromising efficacy. Interestingly, based on this study, S1 was not approved in the United States but was approved by the European Commission on March 14, 2011 because it

420

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Table 3 Summary of selected taxane and irinotecan based trials in AGC. No. of patient

Study arms

Response rates (%)

Median response duration (months)

Median overall survival (months)

Van Cutsem et al. [4] 445

A: DCF vs B: CF

A: 37 vs B: 25 (p = 0.01)

TTP: A: 5.6 vs B: 3.7 (HR: 1.47; 95% CI: 1.19–1.82; log-rank p = 0 .001)

A: 9.2 vs B: 8.6 (HR: 1.29; 95% CI: 1.0–1.6; log-rank p = 0.02)

Gadgeel et al. [30]

27

Paclitaxel + Carboplatin

33

PFS:4.9

7.5

Kornek et al. [66]

45

Paclitaxel + Cisplatin

44

TTP:7.0

11.2

Dank et al. [67]

333

A: Irinotecan, folinic acid, 5FU vs B: Cisplatin + 5FU

A: 31.8 vs B: 25.8 (p = 0.23)

TTP: A: 5.0 vs B: 4.2 (HR:1.23; 95% CI: 0.97–1.57, p = 0.088)

A: 9.0 vs B: 8.7 (HR = 1.08;95% CI: 0.86–1.35, p = 0.53)

Bouche et al. [68]

136

A: FU/LV vs B: 5FU/LV + vs C: FOLFIRI

A: vs 24 B: 30 vs C: 40

PFS: A: 3.2 vs B: 4.9 vs C: 6.9

A: 6.8 vs B: 9.5 vs C: 11.3

Guimbaud et a [52]

416

A: FOLFIRI  ECX vs B: ECX  FOLFIRI

TTF: A: 22.1 weeks vs B: 18.5 weeks (HR = 0.77; CI: 0.63–0.94; p = 0.008)

A: 9.7 vs B: 9.5 (HR = 1.01;CI: 0.82–1.24)

Lee at al [31]

48

FOLFOXIRI

66.7

TTP: 9.6

14.8

Cao et al. [32]

49

FOLFOXIRI

63

TTP: 7.3

11.9

PFS: progression free survival; TTP: time to progression; DCF: docetaxel, cisplatin, 5FU; CF: cisplatin, 5FU; ECF: epirubicin, cisplatin, 5FU; DC: docetaxel, cisplatin; DCF: docetaxel, cisplatin, 5FU; FOLFIRI: 5FU, leucovorin, irinotecan; ECX: epirubicin, cisplatin, capecitabine; FOLFOXIRI: 5FU, leucovorin, irinotecan, oxaliplatin.

was felt that combination (S1) therapy was as effective as a comparator regimen, with an acceptable safety profile. Other doublets (cisplatin/carboplatin with paclitaxel) and triplet combinations with irinotecan have been evaluated for efficacy in early phase clinical trials (Table 3). A non-5-FU based combination using carboplatin and paclitaxel showed promising activity in a phase II single institutional trial [30]. Also, the combination of 5-FU, irinotecan, and oxaliplatin produced relatively high response rates (66%) but associated toxicities may limit further development of this regimen [31,32]. 3.4. Discussion on regional differences in first line treatment The current standard of care for frontline treatment of AGC is a combination chemotherapy regimen which includes a fluopyrimidine and a platinum agent. In some regions such as the United Kingdom (UK) and Australia, a third agent such as anthracycline is added. In the US and other parts of Europe, docetaxel is usually added for patients with good performance status. In Asia doublets are preferred especially in combination with S1. Recent data from the TOGA study supports the role of biologic therapy in a first line setting. This is a landmark study demonstrating for the first time the benefit of a molecular targeted agent in metastatic gastric cancer. HER2 positivity was significantly associated with tumor location (20.9% stomach vs 33% gastro-oesophageal junction; p < 0.001) and differentiation type (32.5% intestinal vs 6.0% diffuse; p < 0.001). [33] The use of trastuzumab in combination with infusional

5FU or capecitabine with cisplatin in patients with Her2 overexpression resulted in increases in RR and median OS but no significant increase in toxicities compared to chemotherapy alone. In patients with high Her2 expression (immunohistochemistry (IHC) staining 2+ and FISH positive or IHC 3+), the survival benefit was extended further from 11.8 to 16 months [33]. More importantly, this study highlights the significant heterogeneity of gastric cancer as Her-2 was more common in proximal intestinal gastric cancer compared to distal diffuse gastric cancer. Thus, Her-2 positive gastric cancer is most prevalent in places like China and Japan where intestinal gastric cancer is the most common type. As a consequence of these results, routine determination of HER2 overexpression is considered mandatory, independent of region, and the addition of trastuzumab to palliative chemotherapy should be considered for every patient with HER2 + gastric adenocarcinoma. Regional tolerability differences to fluoropyrimidine have been well documented and reported. For example in colon cancer, more neutropenia and gastrointestinal toxicities associated with fluoropyrimidine have been reported in the US patients compared to non-US patients [34]. Regional disparities may be potentially attributed to differences in dietary folate intake [35]. 5-FU metabolites are stable in the presence of reduced folate causing prolonged exposure to the drug and potentially increasing toxicity. In gastric cancer, the toxicities of S1 have been reported to be more severe, likely resulting in less robust efficacy in Caucasians as compared to Asians [36]. The differences in drug tolerability are thought to be reflective of differences in CYP2A6 gene polymorphisms existing between Asians and Caucasians, affecting

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S1 to 5FU conversion. It is postulated that this enzyme is more efficacious in whites than in Asians, converting S1 to 5FU at a greater rate and achieving a higher AUC of 5FU at much lower doses of S1 [36]. This pharmacogenomic difference may be the reason why a lower dose of S1 was used in the FLAG study compared to Japanese studies. However, the lower dose was used despite the higher body surface of Western patients compared to Japanese patients which may in turn have potentially compromised efficacy. Interestingly, subset analysis of the FLAG study demonstrated that S1 is more effective in diffuse type gastric cancer, which expresses much higher dihydropyrimidine dehydrogenase (DPD) than the intestinal subtype [29]. DPD is an enzyme responsible for up to 90% of 5FU catabolism. Given that S1 contains 5 chloro-2,4 dihydroxyphridine (CDHP), a reversible inhibitor of DPD, it is postulated that S1 may be more active than 5FU in patients with diffuse type gastric cancer which is more prevalent in the Western Hemisphere. Based on the high expression of DPD in the diffuse type, the DIGEST study was designed to compare S-1/Cisplatin to 5FU/Cisplatin in untreated patients with metastatic diffuse type gastric/esophagogastric junction cancer throughout the Western Hemisphere (http://clinicalTrials.gov: NCT01285557).

4. Second line chemotherapy Based on pooled data of 1080 patients from phase III studies testing 5-FU based regimens and other studies about 20–50% of patients with AGC who progress on first line treatment will go on to receive second line treatment [37–39]. There are several phase II trials published using various chemotherapy agents showing activity in second line gastric cancer. These agents include 5-fluorouracil (5-FU), docetaxel, oxaliplatin, S1, cisplatin, irinotecan, and taxanes either in a combination or as a single agent (Table 4). The results of these regimens are modest with no single or combination regimen showing clear superiority [40]. The response rates range from 3% to 30% with overall survival between 5 and 8 months. Most of these published studies are limited by small sample size, selection bias, lack of a control arm and contain heterogeneous populations of patients receiving different types of first line chemotherapy. Until recently there has been no established second line therapy or data to support chemotherapy over BSC in the second line setting in AGC. Two prospective studies demonstrated an indicating survival advantage of chemotherapy over BSC [6]. A prospective study in Korea randomized patients to docetaxel or irinotecan vs BSC in patients who failed 5-FU and platinum. The trial met its primary endpoint and there were 2.5 months (5.3 months vs 3.8 months) of overall survival advantage favoring the chemotherapy arm. Another smaller randomized study conducted in Europe also showed overall survival of irinotecan over BSC [41]. Median survival improved from 2.4 months to 4 months

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demonstrating that irinotecan prolonged survival in the second line setting. Targeted therapy drugs have also been tested in the second line setting. This has been covered extensively in other review articles with mostly modest results [40,42]. The era of targeted agents as second line therapies is approaching according to a press release from 10/15/2012 indicating that ramucirumab, an antibody targeting VEGF receptor-2, met its primary endpoint of improved overall survival and also showed prolonged progression-free survival. This was a randomized phase III trial comparing ramucirumab vs placebo in refractory AGC. Based on these 3 phase III studies we can argue that second line chemotherapy should be considered standard of care for patients as it provides a modest but significant improvement in survival in patients with good performance status. Targeted therapy such as ramucirumab may also play a role in this setting but we are still awaiting details from the clinical trial. 4.1. Discussion on regional differences in second line therapy The type of chemotherapy used in the second line setting does not differ much from region to region. Most patients receive either irinotecan or taxanes depending on the first line chemotherapy used. Currently, there is no evidence to support combination chemotherapy over single agent irinotecan or taxanes in this setting. A randomized phase III study of irinotecan vs weekly paclitaxel in unresectable or recurrent gastric cancer refractory to combination therapy of fluorouracil plus platinum (WJOG 4007G) was recently published in Japan [43]. The results did not show superiority of irinotecan over paclitaxel. However, there was a trend toward longer OS with paclitaxel. Future trials will most likely use weekly paclitaxel or irinotecan as a backbone in second line therapy. Using platinum alone has fallen out of favor due to frequent use in the first line setting. In Asia taxanes or irinotecan as a single agent or combination such as FOLFIRI or FOLFOX are commonly used [44–48]. In Japan, paclitaxel is the most widely used second line therapy [49]. In the US and certain parts of Europe taxanes (docetaxel) are commonly used as a first line therapy. As such, irinotecan as a single agent or in a combination such as FOLFIRI is most commonly used [41,50]. In the United Kingdom second line therapy for patients with AGC is not considered standard of care. Even though types of chemotherapy do not differ much, the pattern of practice for second line therapy differs from region to region. Higher proportions of patients with gastric cancer in Asia receive second line therapy compared to US and Europe. This is evident considering that most of the aforementioned second line trials were conducted in Japan and Korea. Additionally, use of second line therapy may contribute to the fact that median survival in phase III trials conducted in Asia is longer than in Western countries. In the SPIRIT study over 70% of patients received second line

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Table 4 Selected second line phase II studies in AGC. No. of patient

Study arms

Response rates (%)

Median response duration (RD) (months)

Median overall survival (months)

Cascinu et al. [69]

36

22.2

RD: 5

8

Lee et al. [45]

49

Paclitaxel 225 mg/m2 every 3 weeks Docetaxel 75 mg/m2 every 3 weeks

18

8.3

Chun et al. [44]

35

20

Jeung et al. [70] Kim DY et al. [48] Kim SG et al. [47] Assersohn et al. [50] Park et al. [71]

30 23 40 38 48

Irinotecan weekly × 4 weeks S-1 FOLFOX mFOLFIRI FOLFIRI Docetaxel plus cisplatin every 3 weeks

RD: 4.5 months TTP: 2.5 months TTP: 2.6

12 26 27 29 23

PFS: 11 weeks TTP: 4.3 FFS: 3.7 TTP: 3.7 TTP: 3.9

5.2 33 weeks 7.3 6.4 6.4 5.8

FFS: failure free survival.

chemotherapy compared to 31% in the FLAG study [29,17]. These findings were consistently seen in other global studies as well. The trials conducted in Japan had 83% of patients receiving second line therapy while the rate in the REAL-2 study was only 15% [3,16]. Interestingly, in the subset analysis of the TOGA study, addition of trastuzumab did not influence survival in Asia but produced a marked influence in South America [33]. Since second line therapy is rarely offered in South America, it may have masked the benefit of trastuzumab in Asia. Another first line study, AVGAST, produced similar findings. This was a phase III trial of capecitabine/5FU and cisplatin with or without bevacizumab in first line advanced gastric cancer. The trial did not meet its primary endpoint of improvement in OS compared to chemotherapy alone, but addition of bevacizumab resulted in significant improvement in RR (37% vs 46%, p = 0.03) and median PFS (5.3 vs 6.7 months, p = 0.004) [51,55]. However, OS and PFS benefit was greatest for patients in pan-America, less in Europe and virtually absent in Asia. Possible reasons for this intriguing observation include lead time bias and benefit of second line therapy. The question remains, is this phenomenon due to tumor biology, patient selection or is it because more patients in Asia receive second line therapy negating the potential benefit seen in the Western population. Sequencing of chemotherapy may play an important role in contributing to better outcomes. The concept of sequential therapy has been studied prospectively in AGC. The FFCD-GERCOR-FNCLCC 03-07 study, a randomized trial using non-5-FU, a non-platinum based regimen, was presented at ESMO in 2010 (Table 3) [52]. 416 patients were randomized to arm A: ECX until progression, followed by FOLFIRI in the second line vs arm B: the reverse sequence. Time to treatment failure (TTF), the primary endpoint of this study, was achieved with a higher TTF in the latter arm but no differences in OS [52]. Another similar study used docetaxel (arm T) or irinotecan 180 mg/m2 (arm C) with bolus/44-h infusion of 5-FU/LV (day 1 every 2 weeks)

and switched to the other arm after 4 weeks [53]. Medial survival was nearly identical to 11 months in both arms supporting a role for sequential therapy in gastric cancer. Even though 5-FU/platinum is the preferred frontline regimen, similar results can be achieved using regimens that either do not have 5FU and a platinum based regimen in the frontline setting.

5. Discussion on biomarkers The relative contribution of biological vs practice pattern in explaining the disparity in outcome has been a subject of intense debate. Proponents of the theory that tumors in Asians are less aggressive proposed that this difference had a genetic basis; however, studies published to date have failed to find a genetic difference between clinically comparable gastric cancers in eastern and the western countries. The ultimate goal is to personalize treatment for each patient by way of taking into account the heterogeneity of gastric cancer and identifying predictive markers for treatment efficacy and/or toxicity. Currently in clinical practice the only predictive marker in AGC is the Her2neu status. Several other predictive markers are being evaluated. Many gene abnormalities and growth factors have been found to be involved in gastric cancer. Over-expression of the excision repair cross-complementing 1 (ERCC1) gene, which is essential for the repair of cisplatin (CDDP)-DNA adducts, has been found to negatively influence the effectiveness of CDDP-based therapy in various malignancies including gastric cancer. Recently, specific ERCC1 gene polymorphisms have been shown to be predictive of patient outcomes on platinum based regimens [54]. SWOG has launched a pilot randomized phase II study S1201 to prospectively validate ERCC level as a predictive marker in AGC patients using FOLFOX and docetaxel/irinotecan in patient with both high and low ERCC levels (http://clinicalTrials.gov: NCT01498289).

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Over-expression of thymidylate synthase (TS) and thymidine phosphorylase(TP) may lead to 5FU resistance while DPD overexpression increases 5FU catabolism to inactive metabolites, reducing cytotoxicity [55,56]. In a retrospective biomarker study from the SPIRITS trial, high mRNA levels of TP and TS and low mRNA levels of orotate phosphoribosyltransferase (OPRT) detected through real-time PCR in tumor tissues were found to be significant predictors of longer OS in patients receiving S1 monotherapy [57]. A group from Singapore published a study analyzing gene expression profiles for 37 gastric cancer cell lines [58]. They identified two intrinsic subtypes, intestinal (G-INT) or diffuse (G-DIF), and then validated this in the primary tumors of 521 patients. They identified a 171-gene set that classified tumors into two subtypes (G-INT and G-DIF) and in vitro sensitivity to 3 chemotherapy drugs was done. Interestingly the G-INT cell lines were significantly more sensitive to 5-fluorouracil (5-FU) and oxaliplatin, but more resistant to cisplatin, than were the G-DIF cell lines. This allows for classification of gastric cancer based on intrinsic subtypes to be used to determine prognosis and to customize therapy.

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Finally, several studies have explored the molecular classification of gastric cancer through gene expression analysis to determine whether genomic signatures could significantly differentiate gastric cancer subtypes solely based on anatomic and histopathologic characteristics. Tan et al. performed gene expression profiling on gastric cancer cell lines, identifying 2 major genomic gastric cancer subtypes based on distinct patterns of expression. These patterns were found to be associated with overall survival and chemotherapy response [58]. Shah et al. conducted a similar study finding different gene expression profiles for cancers arising in the distal vs proximal stomach, and diffuse vs non-diffuse histology [63]. Tay et al. looked at comparative genomic hybridization (CGH), microsatellite instability (MSI) assays, and expression microarrays to molecularly subclassify a common set of gastric tumor samples [64]. Based on the expression profile they were classified as “tumorigenic,” “reactive,” and “gastric-like”. Patients with gastric-like tumors exhibited a significantly better overall survival compared to the other two classes (p < 0.05) potentially providing a tool for prognostication in gastric cancer.

5.1. Biomarkers associated with targeted agents 6. Conclusion A full discussion of targeted agents is beyond the scope of this article. We will briefly discuss potential biomarkers associated with targeted agents. Biomarker analysis of the AVAGAST trial revealed overall survival to be greatest for patients with high plasma VEGF-A receiving bevacizumab (HR = 0.72; p = .07). Tissue neuropilin (NRP) expression was both prognostic and predictive. Patients with low levels had poorer prognosis but appeared to benefit more from bevacizumab. Patients with low tumor NRP on bevacizumab had an OS treatment hazard ratio (HR) numerically better than those with high NRP (low NRP HR: 0.75; 95% CI: 0.59–0.97; high NRP HR: 1.07; 95% CI: 0.81–1.40). Additionally, a higher proportion of patients with diffuse/signet ring type gastric cancer had lower NRP levels compared to intestinal type gastric cancer or proximal/GEJ tumors. The predictive value of these markers in gastric cancer patients holds promise but will need prospective validation [59]. Studies conducted with anti-EGFR (epidermal growth factor receptor) monoclonal antibodies in AGC were mostly disappointing. One study suggested that, in an unselected population, addition of anti-EGFR monoclonal antibody to chemotherapy was associated with worsening of OS [60]. There seems to be a correlation between the intensity of EGFR expression and overall outcome suggesting that certain patients may benefit from anti-EGFR drugs [61]. Identification of a potential biomarker for mTOR inhibitors was undertaken in Korea. One small study showed that high expression of pS6(Ser240/4) at baseline in the tumor was significantly associated with higher DCR (p = 0.043) and prolonged PFS (p = 0.001) in patients who received everolimus [62].

Patterns of treatment and types of chemotherapy used in AGC vary from region to region. Combination of 5FU (including oral fluoropyrimidines S1 or capecitabine) with a platinum analog (cisplatin and oxaliplatin) remains the most widely accepted reference regimen. All patients with AGC should be tested for Her 2 expression and be offered trastuzumab and platinum based doublets if her2neu overexpression is demonstrated with either FISH or IHC based on the TOGA study. S1 and capecitabine is at least as effective as 5FU and more convenient for patients. Addition of third agents such as anthracycline or taxane can be considered as an option for frontline therapy provided the patient has good performance status. Evidence exists to support second line therapy for AGC. Either irinotecan or taxanes are reasonable options depending on what was used as the first line therapy. Targeted therapy ramucirumab may also play a role in the second line setting. The question remains, is the variation of outcomes in gastric cancer due to disease biology or differences in management? In this era of genomics, the question in gastric cancer should shift from describing regional differences in treatment to an individualized approach based on the molecular profile of the tumor. Recent results from genomic analysis clearly indicate that gastric cancer is not one disease and that subtypes exist and may explain observed differences in response to therapy and prognosis. It should be noted that there are still differences in management including surgical techniques, health care systems and usage of second line therapy. The next challenge in drug development in AGC will be to develop trials that account for the molecular heterogeneity of the disease.

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Future trials should focus on biomarkers, further exploring genes associated with growth signal transduction like VEGF, EGFR and various protein tyrosine kinases, as well as enzymes involved in 5FU metabolism. These studies must take regional differences into account and consider more approaches based on histology, a strategy that has already entered into trials of patients with advanced gastric cancer (i.e. DIGEST study). Finally gastric cancer is a heterogeneous disease with different molecular drivers; demanding individualized therapies.

Funding No funding has been received for preparation of this manuscript.

Conflicts of interest Dr. Kim receives an honorarium from BMS. There are no conflicts of interest of any of the authors with publication of the manuscript or an institution or product that is mentioned in the manuscript and/or is important to the outcome of the review presented.

Reviewers Dr. Tanios S. Bekaii-saab, Assistant Professor, The James, The Ohio State University, College of Medicine, 320 W 10th Avenue, Columbus, OH 43210, United States. Professor Hans-Joachim Schmoll, Martin-LutherUniversitat Halle-Wittenberg, Innere Med. IV, Ernst-Grube-Strasse 40, D-06120 Halle, Germany.

References [1] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA: A Cancer Journal for Clinicians 2011;61:69–90. [2] Wagner AD, Unverzagt S, Grothe W, et al. Chemotherapy for advanced gastric cancer. Cochrane Database of Systematic Reviews 2010. CD004064. [3] Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. New England Journal of Medicine 2008;358:36–46. [4] Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 study group. Journal of Clinical Oncology 2006;24:4991–7. [5] Webb A, Cunningham D, Scarffe JH, et al. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. Journal of Clinical Oncology 1997;15:261–7. [6] Kang JH, Lee SI, Lim do H, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. Journal of Clinical Oncology 2012;30:1513–8.

[7] Schwarz RE, Zagala-Nevarez K. Ethnic survival differences after gastrectomy for gastric cancer are better explained by factors specific for disease location and individual patient comorbidity. European Journal of Surgical Oncology 2002;28:214–9. [8] Sasako M, Sakuramoto S, Katai H, et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. Journal of Clinical Oncology 2011;29:4387–93. [9] Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. New England Journal of Medicine 2006;355:11–20. [10] Noguchi Y, Yoshikawa T, Tsuburaya A, Motohashi H, Karpeh MS, Brennan MF. Is gastric carcinoma different between Japan and the United States? Cancer 2000;89:2237–46. [11] Kattan MW, Karpeh MS, Mazumdar M, Brennan MF. Postoperative nomogram for disease-specific survival after an R0 resection for gastric carcinoma. Journal of Clinical Oncology 2003;21:3647–50. [12] Strong VE, Song KY, Park CH, et al. Comparison of gastric cancer survival following R0 resection in the United States and Korea using an internationally validated nomogram. Annals of Surgery 2010;251:640–6. [13] Japanese Gastric Cancer A. Japanese gastric cancer treatment guidelines 2010 (ver 3). Gastric Cancer 2011;14:113–23. [14] Bonenkamp JJ, Hermans J, Sasako M, et al. Extended lymph-node dissection for gastric cancer. New England Journal of Medicine 1999;340:908–14. [15] Songun I, Putter H, Kranenbarg EM, Sasako M, van de Velde CJ. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncology 2010;11:439–49. [16] Boku N, Yamamoto S, Fukuda H, et al. Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study. Lancet Oncology 2009;10:1063–9. [17] Koizumi W, Narahara H, Hara T, et al. S-1 plus cisplatin versus S1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncology 2008;9:215–21. [18] Fujii M, Satoh T, Kim YH, et al. Randomized phase III study of S-1 alone versus S-1 plus docetaxel (DOC) in the treatment for advanced gastric cancer (AGC): the START trial update. Journal of Clinical Oncology 2011;29 [suppl; Abstract 4016]. [19] Koizumi W, Nakayama N, Tanabe S, et al. A multicenter phase II study of combined chemotherapy with docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer (KDOG 0601). Cancer Chemotherapy and Pharmacology 2012;69:407–13. [20] Koizumi W, Takiuchi H, Yamada Y, et al. Phase II study of oxaliplatin plus S-1 as first-line treatment for advanced gastric cancer (G-SOX study). Annals of Oncology 2010;21:1001–5. [21] Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig WE. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. Journal of Clinical Oncology 2006;24: 2903–9. [22] Ross P, Nicolson M, Cunningham D, et al. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. Journal of Clinical Oncology 2002;20:1996–2004. [23] Al-Batran SE, Hartmann JT, Probst S, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. Journal of Clinical Oncology 2008;26:1435–42. [24] Okines A, Verheij M, Allum W, Cunningham D, Cervantes A. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2010;21(Suppl. 5):v50–4. [25] Ajani JA, Moiseyenko VM, Tjulandin S, et al. Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and

R. Kim et al. / Critical Reviews in Oncology/Hematology 88 (2013) 416–426

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40] [41]

[42]

fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: the V-325 Study Group. Journal of Clinical Oncology 2007;25:3205–9. Ajani JA, Moiseyenko VM, Tjulandin S, et al. Quality of life with docetaxel plus cisplatin and fluorouracil compared with cisplatin and fluorouracil from a phase III trial for advanced gastric or gastroesophageal adenocarcinoma: the V-325 Study Group. Journal of Clinical Oncology 2007;25:3210–6. Shah M, Stoller R, Shibata S, et al. Random assignment multicenter phase II study of modified docetaxel, cisplatin, fluorouracil (mDCF) versus DCF with growth factor support (GCSF) in metastatic gastroesophageal adenocarcinoma (GE). Journal of Clinical Oncology 2010;28(15s) [suppl; Abstract 4014]. Al-Batran SE, Hartmann JT, Hofheinz R, et al. Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. Annals of Oncology 2008;19:1882–7. Ajani JA, Rodriguez W, Bodoky G, et al. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. Journal of Clinical Oncology 2010;28:1547–53. Gadgeel SM, Shields AF, Heilbrun LK, et al. Phase II study of paclitaxel and carboplatin in patients with advanced gastric cancer. American Journal of Clinical Oncology 2003;26:37–41. Lee J, Kang WK, Kwon JM, et al. Phase II trial of irinotecan plus oxaliplatin and 5-fluorouracil/leucovorin in patients with untreated metastatic gastric adenocarcinoma. Annals of Oncology 2007;18:88–92. Cao WG, Yang WP, Lou GY, et al. Phase II trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) as first-line treatment for advanced gastric cancer. Anti-Cancer Drugs 2009;20:287–93. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687–97. Haller DG, Cassidy J, Clarke SJ, et al. Potential regional differences for the tolerability profiles of fluoropyrimidines. Journal of Clinical Oncology 2008;26:2118–23. Lewis CJ, Crane NT, Wilson DB, Yetley EA. Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use. The American Journal of Clinical Nutrition 1999;70:198–207. Ajani JA, Faust J, Ikeda K, et al. Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma. Journal of Clinical Oncology 2005;23:6957–65. Chau I, Norman A, Ross P. Multivariate prognostic factor analysis and second-line treatment in locally advanced and metastatic oesophagogastric cancer – pooled analysis of 1080 patients from three multicentre randomised controlled trials using individual patient data. In: ASCO gastrointestinal cancers symposium. 2004 [Abstract 5]. Catalano V, Graziano F, Santini D, et al. Second-line chemotherapy for patients with advanced gastric cancer: who may benefit? British Journal of Cancer 2008;99:1402–7. Lee J, Lim T, Uhm JE, et al. Prognostic model to predict survival following first-line chemotherapy in patients with metastatic gastric adenocarcinoma. Annals of Oncology 2007;18:886–91. Wesolowski R, Lee C, Kim R. Is there a role for second-line chemotherapy in advanced gastric cancer? Lancet Oncology 2009;10:903–12. Thuss-Patience PC, Kretzschmar A, Bichev D, 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). European Journal of Cancer 2011;47:2306–14. Cappetta A, Lonardi S, Pastorelli D, Bergamo F, Lombardi G, Zagonel V. Advanced gastric cancer (GC) and cancer of the gastro-oesophageal

[43]

[44]

[45]

[46]

[47]

[48]

[49] [50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

425

junction (GEJ): focus on targeted therapies. Critical Reviews in Oncology/Hematology 2012;81:38–48. Ueda S, Yasui HS, Nishina H, et al. Randomized phase III study of irinotecan (CPT-11) versus weekly paclitaxel (wPTX) for advanced gastric cancer (AGC) refractory to combination chemotherapy (CT) of fluoropyrimidine plus platinum (FP): WJOG4007 trial. Journal of Clinical Oncology 2012;30 [suppl; Abstract 4002]. Chun JH, Kim HK, Lee JS, et al. Weekly irinotecan in patients with metastatic gastric cancer failing cisplatin-based chemotherapy. Japanese Journal of Clinical Oncology 2004;34:8–13. Lee JL, Ryu MH, Chang HM, et al. A phase II study of docetaxel as salvage chemotherapy in advanced gastric cancer after failure of fluoropyrimidine and platinum combination chemotherapy. Cancer Chemotherapy and Pharmacology 2008;61:631–7. Kodera Y, Ito S, Mochizuki Y, et al. A phase II study of weekly paclitaxel as second-line chemotherapy for advanced gastric cancer (CCOG0302 study). Anticancer Research 2007;27:2667–71. Kim SG, Oh SY, Kwon HC, et al. A phase II study of irinotecan with bi-weekly, low-dose leucovorin and bolus and continuous infusion 5-fluorouracil (modified FOLFIRI) as salvage therapy for patients with advanced or metastatic gastric cancer. Japanese Journal of Clinical Oncology 2007;37:744–9. Kim DY, Kim JH, Lee SH, et al. study of oxaliplatin, 5-fluorouracil and leucovorin in previously platinum-treated patients with advanced gastric cancer. Annals of Oncology 2003;14:383–7. Takiuchi H. Second-line chemotherapy for gastric cancer: a new issue lies ahead in global trials. Gastric Cancer 2011;14:206–11. Assersohn L, Brown G, Cunningham D, et al. Phase II study of irinotecan and 5-fluorouracil/leucovorin in patients with primary refractory or relapsed advanced oesophageal and gastric carcinoma. Annals of Oncology 2004;15:64–9. Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. Journal of Clinical Oncology 2011;29:3968–76. Guimbaud R, Louvet C, Bonnetain F, et al. Final results of the intergroup FFCD-GERCOR-FNCLCC 03-07 phase III study comparing two sequences of chemotherapy in advanced gastric cancers. Annals of Oncology 2010;21:250–60. Gubanski M, Johnsson A, Fernebro E, et al. Randomized phase II study of sequential docetaxel and irinotecan with 5-fluorouracil/folinic acid (leucovorin) in patients with advanced gastric cancer: the GATAC trial. Gastric Cancer 2010;13:155–61. Yin M, Yan JR, Martinez-Balibrea E, et al. ERCC1 and ERCC2 polymorphisms predict clinical outcomes of oxaliplatin-based chemotherapies in gastric and colorectal cancer: a systemic review and meta-analysis. Clinical Cancer Research 2011;17:1632–40. Yeh KH, Shun CT, Chen CL, et al. High expression of thymidylate synthase is associated with the drug resistance of gastric carcinoma to high dose 5-fluorouracil-based systemic chemotherapy. Cancer 1998;82:1626–31. Fukuda H, Takiguchi N, Koda K, Oda K, Seike K, Miyazaki M. Thymidylate synthase and dihydropyrimidine dehydrogenase are related to histological effects of 5-fluorouracil and cisplatin neoadjuvant chemotherapy for primary gastric cancer patients. Cancer Investigation 2006;24:235–41. Koizumi W, Tanabe S, Azuma M, et al. Impacts of fluorouracilmetabolizing enzymes on the outcomes of patients treated with S-1 alone or S-1 plus cisplatin for first-line treatment of advanced gastric cancer. International Journal of Cancer Journal International du Cancer 2010;126:162–70. Tan IB, Ivanova T, Lim KH, Ong CW, Deng N, Lee J, et al. Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology 2011;141:476–85, 85 e1–e11. Van Cutsem E, de Haas S, Kang YK, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a

426

[60]

[61]

[62]

[63] [64]

[65]

[66]

[67]

[68]

R. Kim et al. / Critical Reviews in Oncology/Hematology 88 (2013) 416–426 biomarker evaluation from the AVAGAST randomized phase III trial. Journal of Clinical Oncology 2012;30:2119–27. Waddell TS, Chau I, Barbachano Y, et al. A randomized multicenter trial of epirubicin, oxaliplatin, and capecitabine (EOC) plus panitumumab in advanced esophagogastric cancer (REAL3). Journal of Clinical Oncology 2012;39 [suppl; Abstract LBA4000]. Kim Y, Sasaki Y, Lee K, et al. Randomized phase II study of nimotuzumab, an anti-EGFR antibody, plus irinotecan in patients with 5-fluorouracil-based regimen-refractory advanced or recurrent gastric cancer in Korea and Japan: preliminary results. Journal of Clinical Oncology 2011;29(suppl 4) [Abstract 87]. Yoon DH, Ryu MH, Park YS, et al. Phase II study of everolimus with biomarker exploration in patients with advanced gastric cancer refractory to chemotherapy including fluoropyrimidine and platinum. British Journal of Cancer 2012;106:1039–44. Shah MA, Khanin R, Tang L, et al. Molecular classification of gastric cancer: a new paradigm. Clinical Cancer Research 2011;17:2693–701. Tay ST, Leong SH, Yu K, et al. A combined comparative genomic hybridization and expression microarray analysis of gastric cancer reveals novel molecular subtypes. Cancer Research 2003;63:3309–16. Fujii M, Satoh KHH. Randomized phase III study of S-1 alone versus S-1 plus docetaxel (DOC) in the treatment for advanced gastric cancer (AGC): the START trial update, 2011 ASCO Annual Meeting. Journal of Clinical Oncology 2011;29 [suppl; Abstract 4016]. Kornek GV, Raderer M, Schull B, et al. Effective combination chemotherapy with paclitaxel and cisplatin with or without human granulocyte colony-stimulating factor and or erythropoletin in patients with advanced gastric cancer. British Journal of Cancer 2002;86:1858–63. Dank M, Zaluski J, Barone C, et al. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Annals of Oncology 2008;19:1450–7. Bouche O, Raoul JL, Bonnetain F, et al. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic,gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study – FFCD 9803. Journal of Clinical Oncology 2004;22:4319–28.

[69] Cascinu S, Graziano F, Cardarelli N, et al. Phase II study of paclitaxel in pretreated advanced gastric cancer. Anti-Cancer Drugs 1998;9:307–10. [70] Jeung HC, Rha SY, Shin SJ, et al. A phase II study of S-1 monotherapy administered for 2 weeks of a 3-week cycle in advanced gastric cancer patients with poor performance status. British Journal of Cancer 2007;97:458–63. [71] Park SH, Kang WK, Lee HR, et al. Docetaxel plus cisplatin as second-line therapy in metastatic or recurrent advanced gastric cancer progressing on 5-fluorouracil-based regimen. American Journal of Clinical Oncology: Cancer Clinical Trials 2004;27:477–80.

Biography Dr. Richard Kim is an assistant professor in the section of Gastrointestinal Malignancies at the H. Lee Moffitt Cancer Center. He is board-certified in internal medicine and medical oncology. He completed a six-year, Bachelor of Science and medical degree program at the University of Miami School of Medicine and completed his residency in internal medicine at the University of Illinois at Chicago and a post-doctoral fellowship in hematology and medical oncology at Yale University Comprehensive Cancer Center, New Haven, Conn. Since the fellowship, he was a faculty member at Cleveland Clinic in Ohio then recently joined as a faculty at H. Lee Moffitt Cancer Center. He specializes in caring for patients with GI malignancies, in particular hepatobiliary, pancreatic and colorectal cancer. His expertise lies in the research focused on investigational anticancer agents including novel targeted drugs in an effort to develop therapeutic strategies for patients with cancers arising in the gastrointestinal tract. Currently he is a principal investor in many phase I, II, III clinical trials in gastrointestinal tumors.