Introduction

Gastric cancer (GC), including adenocarcinoma of the distal esophagus and the esophagogastric junction (EGJ), is a major global health problem. Around 1 million new cases and 750,000 deaths occur per year worldwide, accounting for 10 % of all deaths due to cancer [1, 2]. The highest incidence rates are found in East Asia, East Europe, and parts of South America, while the lowest rates occur in North America [2–4] (Fig. 1).

Fig. 1
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Age-adjusted gastric cancer incidence per 100,000 inhabitants (according to Lozano et al. [2])

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In Europe and North America, the overall 5-year survival for GC is approximately 25 % [3], while superior outcomes with 5-year-survival rates of approximately 60 % are reported in East Asia [5]. Early diagnosis due to well-established screening programs, careful surgical lymph node dissection in localized disease, and consistent use of postoperative adjuvant chemotherapy may explain some of the differences in patient outcomes [3, 6, 7]. Epidemiological studies indicate a progressive decrease in the intestinal type of gastric cancer and an increase in the diffuse type [8], while intestinal-type tumors still predominate in East Asia and East Europe. As our understanding of gastric cancer biology has improved, differential treatment approaches for specific subtypes of gastric cancer have emerged [9]. HER2-positive advanced GC is now treated by the addition of the monoclonal antibody trastuzumab to standard chemotherapy [10] (Fig. 2). More molecular characteristics are being identified and more specific and targeted treatments are being studied [11].

Fig. 2
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HER2 testing and treatment algorithm in advanced gastric cancer. IHC immunohistochemistry, ISH in situ hybridization

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Methods

References for this review were identified through searches of PubMed with the search terms “chemotherapy,” “gastric cancer,” “esophagogastric junction cancer,” “advanced,” “metastatic,” and “quality of life” from 1990 until April 2013. Articles were also identified through searches of the major oncology congress abstract search machines (American Society of Clinical Oncology Annual Meetings 2010–2013, European Society of Medical Oncology and European Cancer Organization Annual Meetings 2010–2012).

The benefit of chemotherapy in advanced gastric cancer

In this review, the term “advanced” indicates a disease extent that is no longer amenable to curative surgical treatment. It has been shown that chemotherapy can prolong survival in this setting [12]. This is true for first-line treatment as well as for second- and further-line chemotherapy (Table 1) [13–17]. Symptom control and quality of life have also been looked at in some studies, and have been demonstrated to be improved by chemotherapy.

Table 1 Phase III trials of chemotherapy versus best supportive care (BSC) for advanced gastric cancer
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For the first-line treatment of GC, it has been shown that combination chemotherapy is, in principle, more efficacious than monotherapy [12, 18, 19]. It should be noted that the benefit observed in the Cochrane review was rather marginal [hazard ratio (HR) for survival of 0.82; 95 % CI 0.74–0.90]. In addition, toxicity increases with combination schedules. Therefore, careful evaluation of the patient’s performance status and the different toxicity profiles of the treatment regimens should be performed before choosing the therapy. Although the majority of patients are ≥65 years old, elderly patients are generally underrepresented in clinical trials, mainly due to concerns regarding toxicity. Moreover, elderly patients who are enrolled in clinical studies may not represent the typical characteristics of an elderly GC population. Analyzing data from three randomized controlled trials, there were no significant differences in the incidence of grade 3/4 toxicity between younger and elderly adults. In terms of response rates, failure-free and overall survival elderly patients did benefit from chemotherapy to a similar degree as younger patients. In a multivariate analysis, independent prognostic factors for survival were performance status and locally advanced disease, but not age [20]. Nevertheless, careful assessment of functional status and comorbidities before the start of therapy is highly recommended, and the selection of sequential one-, two-, or three-drug regimens should be evaluated individually.

Systemic chemotherapy can prolong survival, improve symptom control and stability, and potentially improve quality of life. Combinations are more effective than single-agent chemotherapy and can also be recommended for elderly patients after proper evaluation of performance status and comorbidities. A combination comprising a platinum compound and a fluoropyrimidine can be regarded as an accepted first-line practice.

Which platinum compound should be used?

Cisplatin has been an integral part of GC reference regimens globally [12]. Due to its specific side effects, including nephrotoxicity, ototoxicity, and emetogenicity, other platinum salts have been studied. Carboplatin did not exhibit sufficient activity in phase II studies and was therefore not studied any further in randomized controlled trials [21]. In contrast, oxaliplatin, which had improved the efficacy of 5-fluorouracil (5-FU) treatment in colorectal cancer, was extensively studied in GC. Following promising phase II study results [22–24], oxaliplatin was compared with cisplatin in two randomized controlled trials. Both studies were designed to prove the non-inferiority of oxaliplatin compared with cisplatin. The Randomized ECF for Advanced and Locally Advanced Esophagogastric Cancer-2 (REAL-2) study had a two-by-two design. One thousand two patients were included, who received epirubicin/cisplatin plus either 5-FU (ECF) or capecitabine (ECX) or epirubicin/oxaliplatin plus either 5-FU (EOF) or capecitabine (EOX). For the oxaliplatin–cisplatin comparison, the hazard ratio for the oxaliplatin group [0.92 (95 % confidence interval CI, 0.80–1.10)] proved that oxaliplatin is non-inferior to cisplatin. As compared with cisplatin, oxaliplatin was associated with lower incidences of neutropenia, alopecia, renal toxicity, and thromboembolism, but with slightly higher incidences of diarrhea and neuropathy [25]. At the same time, the German Arbeitsgemeinschaft Internistische Onkologie (AIO) compared 5-FU/leucovorin and cisplatin (FLP) with 5-FU/leucovorin and oxaliplatin (FLO) [26]. The AIO study found a trend towards improved progression-free survival (PFS) with FLO versus FLP in 220 randomized patients, but no significant difference in overall survival (OS). Remarkably, FLO was associated with significantly less toxicity, including anemia, nausea, vomiting, alopecia, fatigue, renal toxicity, thromboembolic events, and other serious treatment-related adverse events. Sensory neuropathy was more common in the oxaliplatin group. In patients aged >65 years (n = 92), treatment with oxaliplatin resulted in significantly superior PFS (6.0 vs. 3.1 month; P = 0.029) and improved OS (13.9 vs. 7.2 months) as compared with cisplatin.

Cisplatin plus S-1 (CS) is the standard first-line treatment regimen for advanced gastric cancer in Japan [19]. Oxaliplatin plus S-1 (SOX) showed non-inferiority to CS in PFS [27]. The median PFS was 5.5 months for SOX vs. 5.4 months for CS (hazard ratio 1.00; 95 % CI, 0.84–1.20). The response rate was 56 % for SOX and 52 % for CS (χ 2 test, P = 0.37). The most common grade 3/4 toxicities in SOX vs. CS were neutropenia 19.5 vs. 41.5 %, thrombocytopenia 9.5 vs. 10.4 %, febrile neutropenia 0.9 vs. 6.9 %, and anorexia 14.8 vs. 18.5 %, respectively. Accordingly, SOX is considered a new standard option for first-line treatment in Japan.

In conclusion, oxaliplatin is generally less toxic than cisplatin. In view of its non-inferior efficacy, oxaliplatin can substitute for cisplatin in the treatment of advanced GC. Elderly patients may derive a particular benefit from treatment with oxaliplatin instead of cisplatin. However, oxaliplatin has not been approved in Europe, North America, or Japan by the medicine agencies and is therefore not reimbursed for the treatment of GC in some countries. In Korea, capecitabine–oxaliplatin or 5-FU, leucovorin, plus oxaliplatin is reimbursed and frequently used as first-line treatment for advanced GC.

Can oral fluoropyrimidines substitute for 5-FU?

Intravenous 5-FU has been the standard combination partner for platinum salts and other cytotoxic compounds in the treatment of GC.

The REAL-2 study compared capecitabine, an orally available 5-FU prodrug, with intravenous 5-FU [25]. The fluoropyrimidine comparison in REAL-2 showed non-inferiority of capecitabine with a hazard ratio for death of 0.86 (95 % CI, 0.80–0.99). The ML17032 study was performed in parallel in Korea and included 316 patients who were randomly assigned to receive either cisplatin/5-FU or cisplatin/capecitabine. The response rate was significantly higher in the capecitabine group (42 vs. 32 %, p = 0.02). The survival analysis proved the non-inferiority of capecitabine [28]. In a combined analysis of REAL-2 and ML17032, OS was even superior in patients treated with capecitabine combinations compared with patients treated with 5-FU; HR 0.87 (95 % CI 0.77–0.98, P = 0.02) [29]. However, the reported substantial toxicity of hand foot syndrome (HFS), which 22 % experienced with capecitabine compared to only 4 % with 5FU in the ML17032 study [28], and 46 % compared to 29 % all-grade HFS with capecitabine compared to 5FU in the REAL-2 study [25], may undercut the potential advantage of oral over continuous infusion administration.

Another oral fluoropyrimidine, S-1, is now approved in East Asia and Europe for the treatment of advanced GC. S-1 contains tegafur/gimeracil/oteracil potassium in a molar ratio of 1.0:0.4:1.0. Gimeracil reduces the degradation of 5-FU and oteracil improves its gastrointestinal tolerability. S-1 in combination with cisplatin has been established as the standard first-line chemotherapy in advanced GC in Japan (SPIRITS trial) [19]. S-1 was also shown to be non-inferior to infusional 5-FU when both were given as single agents [30]. With a dose established in a Western patient population [31] and with the hypothesis that cisplatin/S-1 could improve overall survival, safety, and convenience compared to cisplatin/5-FU, a randomized comparison was attempted in a non-Asian phase III trial into which 1053 patients were enrolled. The median OS was 8.6 months in the cisplatin/S-1 arm and 7.9 months in the cisplatin/5-FU arm, showing no significant difference. However, significant safety advantages were observed with S-1/cisplatin for the rates of complicated neutropenia, stomatitis, hypokalemia, and treatment-related deaths [32]. Note that cisplatin was administered at a reduced dosage in the S-1 arm (75 mg/m2) compared to the standard arm (100 mg/m2), possibly explaining the more favorable toxicity profile with S1/cisplatin. The results of a randomized trial proving the efficacy of S-1 and oxaliplatin in Japanese patients treated for advanced gastric cancer has already been reported [33]. Nevertheless, due to considerable pharmacokinetic differences when used in non-Asians, clinical experience with S-1 in Western countries suggests a different toxicity than that reported in Asian populations. Several polymorphisms have been identified in genes encoding drug-metabolizing enzymes, which may explain this differential toxicity of fluoropyrimidines between Asian and Western populations [34].

Oral fluoropyrimidines can substitute for intravenous 5-FU and are now subsidized for advanced GC in most countries. Although no superior survival was shown with the combination cisplatin/S-1, significant safety advantages were observed compared to cisplatin/5-FU. Cisplatin and capecitabine has become the standard backbone chemotherapy in trials investigating monoclonal antibodies in GC [10, 35, 36]. In the treatment of elderly or frail patients, or in cases where platinum agents are contraindicated, single-agent fluoropyrimidine, although not as effective as doublet regimens, should also be considered an option [37, 38].

Doublets or triplets—the rationale for adding a third cytotoxic drug

Triplet combination chemotherapy comprising an anthracycline or a taxane in addition to a platinum compound and a fluoropyrimidine has resulted in higher response rates and a modest improvement in overall survival compared with doublet combinations, but it also exposes patients to more serious side effects [12, 19]. A variety of treatment regimens have been established in randomized phase III studies which are the standard of care in different parts of the world, but not globally (Table 2).

Table 2 First-line treatment regimens developed in randomized controlled trials in advanced gastric cancer
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Anthracycline-containing triplet combinations

The literature is inconsistent regarding the potential value of anthracyclines. In the UK and in some other countries, the incorporation of anthracyclines into the palliative medical treatment of gastric cancer has become common practice. According to the Cochrane analysis, randomized studies have proven the value of anthracyclines given in addition to platinum and 5-FU [12]. However, the evidence to support the activity of an anthracycline-based triplet [i.e., epirubicin, cisplatin, and 5-fluorouracil (ECF)] is provided by only three randomized studies, with a total sample size of 501 patients [12]. Note that the largest study included in this meta-analysis is a comparison between ECF and another triplet (mitomycin C plus CF, MCF) [39], which may lead us to question the conclusion that the addition of an anthracycline improves outcome, presuming that mitomycin C had a negative effect on CF efficacy. More recently, a relatively small randomized trial from Korea could not demonstrate improved efficacy upon the addition of epirubicine to cisplatin and capecitabine (ECX) compared to only cisplatin and capecitabine (CX) [40]. Despite the uncertainty regarding the value of adding an anthracycline to cisplatin and 5-FU, this anthracycline triplet remains the standard treatment in the UK. The combination of epirubicine, oxaliplatin, and capecitabine (EOX regimen) has shown superior survival compared with ECF in the randomized REAL-2 study (ECF) [25] (9.9 vs. 11.2 months; HR: 0.8; p = 0.02); however, a comparison to common two-drug regimens such as CF is lacking.

Docetaxel-containing triplet combinations

The randomized controlled TAX 325 trial showed a significantly improved overall survival (median 9.2 vs. 8.6 months; HR 1.29; P = 0.0021) for the addition of docetaxel (DCF) compared with cisplatin/5-FU (CF). Secondary endpoints were response rate (37 vs. 25 %) and time to progression (5.6 vs. 3.7 months; HR1.47; P = 0.0004), which were also in favor of DCF [41]. The median age of the patients included was 55 years, with only 24 % of patients aged ≥65. The majority of the patients had a good Karnofsky performance status (≥90:64 %). However, DCF was associated with substantial toxicity, particularly myelosuppression, with a 29 % incidence of febrile neutropenia, and gastrointestinal side effects were markedly increased (49 % grade 3/4). As a consequence, half of the patients discontinued treatment with DCF for either adverse events or patient refusal. Given that patients in clinical trials are usually carefully selected to be of a younger age and to have near-optimal organ and functional status, and thus do not necessarily reflect the geriatic and frail patients more commonly treated in clinical practice, the routine use of this toxic DCF regimen is rather questionable [41]. Due to the high rates of hematologic and other toxicities observed with the original DCF regimen, alternative docetaxel-containing regimens have been investigated in several phase II studies (Table 3). The principle of splitting docetaxel from 3-weekly into weekly or bi-weekly administration has led to a considerable decrease in hematological toxicity. Although evidence from phase III studies is lacking, the modification of DCF by alternative scheduling has decreased the toxicity, apparently without compromising the efficacy. Therefore, if docetaxel-based first-line treatment is considered, one should refrain from using classic DCF and choose an alternative treatment protocol such as Gastro-Tax [42], FLOT [43], or ATTAX [44]. Regarding the use of an intensive docetaxel-based triplet combination in elderly patients (≥65 years), the FLOT combination appears to be feasible and effective but no better than FOLFOX, although toxicity was markedly increased and quality of life was negatively impacted in a significant proportion of patients during the first 8 weeks of treatment [45]. Therefore, despite all of the associated improvements, docetaxel-containing treatment regimens should be only considered in fit and compliant patients, and proper patient selection—including critical evaluation of performance status and comorbidities, as well as access to frequent assessment of toxicity—should be performed before the onset of therapy. An alternative highly active and tolerable doublet chemotherapy regimen is the combination of docetaxel and S-1, which showed a promising median overall survival of 14.3 months and a median TTP of 8.3 months in a single center in Asia [46]. This trial was the basis for the randomized phase III START trial comparing docetaxel/S-1 with S-1 in patients with advanced gastric cancer. An updated analysis presented at ESMO 2012 showed an improved median survival time of 12.5 months in the combination therapy group compared to 10.8 months in patients who received S-1 alone (p = 0.0319) [47]. Another Japanese approach involving a triplet regimen was evaluated in a phase I/II trial in which patients received S-1, docetaxel (40 mg/m2 on day 1), and cisplatin (60 mg/m2 on day 1) (DCS), or S-1 (80–120 mg/day), 2 weeks on, 2 weeks off, every 4 weeks [48]. The most commonly observed grade 3/4 toxicity was neutropenia in 70 % of patients. The gastrointestinal toxicities were very low. The median PFS was 8.7 months and the median survival was 18.5 months. DCS is also being compared with CS in an ongoing phase III trial in Japan (JCOG 1013), from which known HER2-positive patients are excluded. The study aims to recruit a total of 740 patients and the primary endpoint is overall survival. The patients will be stratified according to institution, number of metastatic sites, measurable or nonmeasurable, and diffuse or intestinal type. The key secondary endpoint is survival by histology.

Table 3 Docetaxel-containing combination regimens: phase II/III
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Irinotecan-containing regimens

Irinotecan-based combination regimens have been studied as a first-line alternative to platinum-based chemotherapy. The first phase II study results suggested that irinotecan and 5-fluorouracil combinations had promising anti-tumoral activity and efficacy [49, 50]. A randomized controlled phase III trial failed to show the superiority of irinotecan and high-dose 5-fluorouracil over only cisplatin and 5-fluorouracil [51]. However, quality of life tended to be better during treatment with irinotecan and 5-fluorouracil. Due to the lack of superior efficacy, irinotecan was not approved for the first-line treatment of gastric cancer in many health systems, but can be used as a “reserve regimen” with proven efficacy. Capecitabine could substitute for 5-fluorouracil as a combination partner of irinotecan [52].

Recommended regimens

Both doublet and triplet drug-regimens based on a platinum compound and a fluoropyrimidine can be used for the medical treatment of advanced GC. However, careful consideration of the potential toxic complications, impairment of the patient’s quality of life, and the relative benefit should be undertaken. An indication for using three drugs in the first-line treatment is the presence of severe tumor symptoms, life-threatening tumor manifestations leading to the need for an instant tumor response, and the patient’s preference for receiving the most active drug combination (and acceptance of enhanced side effects). Preferred regimens are the anthracycline-containing EOX regimen and the different modifications of DCF.

If doublet chemotherapy is chosen, one should be aware of the considerable toxicity associated with older high-dose cisplatin-based regimens. The CF regimen used in the control arm of the TAX 325 trial and other trials, cisplatin 100 mg/m2 and a 5-day infusion of 1000 mg/m2 5-FU every 4 weeks, was associated with substantial grade 3/4 toxicity, mainly neutropenia (57 %), stomatitis (27 %), diarrhea (8 %), nausea (17 %), and vomiting (17 %). Newer modified regimens using a weekly or biweekly infusion schedule of 5-FU combined with either biweekly cisplatin (50 mg/m2) or oxaliplatin (85 mg/m2) demonstrated markedly reduced toxicity [26] (Table 2), indicating that these regimens should be preferred in the treatment of advanced GC. Cisplatin/capecitabine (XP), cisplatin/S-1 or oxaliplatin plus a fluoropyrimidine (FLO, CapOx, or SOX) also represent more tolerable alternatives (Table 2), with dose reductions and various supportive measures considered in the case of severe toxicity.

Alternatively, although not as effective as combination therapy, single-agent fluoropyrimidines show activity in GC, and thus first-line fluoropyrimidine monotherapy (oral or infusional) should be considered as a reasonable option in the treatment of elderly patients or patients in whom platinum agents are contraindicated.

Quality of life

There are few reliable data on the quality of life associated with cytotoxic treatment of advanced GC. An analysis from the TAX-325 study shows that—despite being associated with considerable toxicity—DCF led to a prolongation of the time until definitive deterioration of the “global health status” as assessed by the European Organization of Research and Treatment of cancer (EORTC) quality of life C30 questionnaire [53]. This indicates that, in advanced GC, the global health status is very much influenced by the burden of disease. Comparing docetaxel-based triplet chemotherapy with anthracycline-based therapy indicated a higher treatment burden and a worse health status/QOL for docetaxel compared to anthracycline-based therapy [54]. Several studies with ECF confirmed that improved global QOL scores were obtained compared to DCF or MCF therapy in the first 6 months of treatment [39, 54]. Nevertheless, high treatment intensity over longer periods of time in patients with GC may again worsen health status and quality of life. Therefore, the clinical concept of starting with intensive induction regimens that reduce the disease burden followed by less intensive and better tolerated maintenance regimens that prolong the time to symptomatic tumor progression should be explored.

Biologically targeted therapy

Only modest progress has been made with novel chemotherapy agents such as oxaliplatin, docetaxel, capecitabine, and S1. Therefore, in order to further improve outcome, the identification of certain pathways that are key to cancer development is of the utmost importance. A number of biological therapies aim to inhibit components of signal transduction pathways that are amplified or functionally activated by specific genetic or epigenetic alterations. Pathways with targeted therapies where data are available or which are currently under clinical evaluation comprise HER2, VEGF, EGFR, mTOR, and c-Met.

The human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20 % of GC patients. In HER2-positive advanced GC, the international phase III Trastuzumab for Gastric Cancer (ToGA) study showed a significant improvement in the median OS of patients upon the addition of trastuzumab to cisplatin and fluoropyrimidine backbone therapy [10]. Trastuzumab in combination with chemotherapy is now a new reference treatment for the first-line treatment of HER2-positive GC. Note that the appropriate selection of patients for anti-HER2 treatment is highly dependent on the quality of HER2 assessment by immunohistochemistry (IHC) and on the evaluation of HER2 gene amplification by in situ hybridization (ISH) techniques. Testing for HER2 in GC has its pitfalls and challenges. Optimal tumor samples should be used, and testing should be done in well-trained and quality-assured pathology laboratories [55, 56]. The greatest benefitof using trastuzumab may be gained by patients with the highest degree of HER2 overexpression: those that are IHC 3+ or IHC 2+ and FISH+.

Lapatinib, an oral tyrosine kinase inhibitor against both EGFR and HER2, has modest single activity in the first-line setting [57]. Results of the randomized phase III TRIO-013/Logic trial were recently presented [58]. The Logic trial could not demonstrate a statistically significant improvement in overall survival (primary endpoint) with the addition of lapatinib to capecitabine plus oxaliplatin (CapeOx) as the first-line treatment of advanced or metastatic HER2+ gastric or gastroesophageal adenocarcinoma (12.2 vs. 10.5 months; HR: 0.91 (95 % CI 0.73, 1.12, p = 0.35)). However, pre-specified subgroup analyses showed significant improvements in OS in Asian patients (HR = 0.68) and those under 60 years (HR = 0.69). With regard to toxicity, lapatinib in combination with CapeOx showed an increased rate of grade 3 diarrhea (12 vs. 3 %) and a higher rate of skin toxicity. The next steps in HER2 blockade for GC may follow the developments in breast cancer, with evaluation of TDM-1, a conjugate molecule combining trastuzumab with an antimicrotubule agent; the combination of trastuzumab and lapatinib; and first-line integration of pertuzumab in metastatic disease and the investigational use of HER2 inhibitors in the neoadjuvant setting. RTOG trial 1010 is currently evaluating preoperative chemoradiotherapy in esophageal and GEJ cancers that are HER2+, randomizing patients to receive chemoradiotherapy alone or chemoradiotherapy plus trastuzumab followed by adjuvant trastuzumab after surgery.

In contrast to the success obtained with trastuzumab in advanced GC, monoclonal antibodies that target HER1 (epidermal growth factor receptor, EGFR) have failed to improve outcome in biologically unselected GC patients [36, 59]. It remains to be elucidated from tumor tissue analyses if a small proportion of GC patients may benefit from anti-EGFR targeted therapy, e.g., in the case of EGFR gene amplification [60]. The negative results obtained with cetuximab (EXPAND study) and panitumumab (REAL3 study) emphasize the need to have a biologically meaningful target before studying targeted agents in larger populations. The importance of combining targeted agents with an appropriate chemotherapy backbone is also highlighted. As the REAL3 study taught us, the combination of a triplet chemotherapy (EOX) regimen with panitumumab is suboptimal and associated with inferior survival, probably due to the excessive toxicity experienced when using this chemotherapy backbone.

Other potential targets, including hepatocyte growth factor receptor (c-Met), insulin-like growth factor receptor 1 (IGF-1R), fibroblast growth factor receptor (FGFR), proteins involved in cell cycle regulation, the proteasome, chaperone proteins, matrix metalloproteinases, histone deacetylases, and other structures, are under evaluation. Novel drugs directed against those specific targets are under clinical investigation.

With regards to angiogenesis, the phase III AVAGAST trial [35] could not demonstrate a survival benefit with the addition of bevacizumab, an inhibitor of the ligand for vascular endothelial growth factor receptor 2 (VEGFr2), VEGF-A, to chemotherapy, but it did show improved PFS and RR. However, looking at the American and European patients, there appears to be a modest benefit of using bevacizumab, which highlights how the biology of gastric cancer varies in different parts of the world. A subsequent report suggested that high serum levels of VEGF-A and low tumor neuropilin expression were correlated with the enhanced benefit resulting from treatment with bevacizumab, but only in Western patients treated in the trial [61]. Recently, ramucirumab, a monoclonal antibody directed against VEGFR2 [62], has been shown to prolong survival when used as a monotherapy compared with the best supportive care in the second-line treatment of advanced GC [63]. The phase III RAINBOW study, which is investigating ramucirumab in combination with paclitaxel in the second-line setting (http://clinicalTrials.gov/show/NCT01170663), has completed recruitment and results are awaited.

Another key regulator of cell proliferation, growth, survival, metabolism, and angiogenesis is the PI3K/Akt/mTOR pathway, which is dysregulated in 50–60 % of gastric cancers. Everolimus, an oral mTOR inhibitor, failed to improve OS in patients treated with 1 or 2 lines of systemic chemotherapy when given as monotherapy, but did improve PFS [64]. A phase III trial of the German Arbeitsgemeinschaft Internistische Onkologie (AIO-STO 0111) is currently evaluating paclitaxel with and without everolimus in patients with GC after initial treatment with a fluoropyrimidine-containing regimen (http://clinicalTrials.gov/show/NCT01248403).

The published randomized controlled trials involving molecularly targeted drugs in advanced gastric cancer are delineated in Table 4.

Table 4 Reported phase III trials investigating biologically targeted agents in advanced gastric cancer
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Another target in GC is the receptor tyrosine kinase MET. Met receptor overexpression is associated with poor prognosis for gastric cancer patients. Preliminary results of a randomized phase II trial with rilotumumab, a fully human monoclonal antibody against the Met receptor ligand hepatocyte growth factor, showed improved OS and PFS in patients with high MET expression when combined with ECX [65]. Phase III studies evaluating the clinical benefit of MET inhibitors are under underway.

Post-progression treatment

Post-progression chemotherapy is effective in advanced gastric cancer. Three randomized controlled trials showed superior survival of patients on either irinotecan or docetaxel monotherapy compared with those receiving best supportive care [16, 17, 66]. In the smallest study, which was performed in Germany, it was reported that post-progression chemotherapy not only prolonged survival but also led to better symptom control. Reports of appropriate quality-of-life measurements are, however, missing in these studies. A study from the West Japan Oncology Group has recently shown that weekly paclitaxel may also be used in second-line advanced GC [67]. Assessment of palliative treatment goals such as general health status, clinical benefit, and quality of life must be included in further studies [68].

Second-line chemotherapy is now considered a standard therapy option for patients who progress during or after first-line chemotherapy, who are defined as having Eastern Cooperative Group (ECOG) performance status 0–1(2), and who have motivation to be further treated with chemotherapy. Irinotecan administered every 2 or 3 weeks, docetaxel given once every 3 weeks, or weekly paclitaxel are potential options (Fig. 3). Ramucirumab has also been shown to prolong the survival time with a very reasonable side-effect profile [59], but this anti-angiogenic antibody is not yet on the market.

Fig. 3
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Indication for post-progression chemotherapy. ECOG PS Eastern Cooperative Group performance status

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Future outlook

The more we learn about the biological heterogeneity of gastric cancer, the more we can see that there is no single medical treatment that is the best option for all types of gastric cancers. Even with classical cytotoxic treatment, different sensitivities to specific agents may exist in intrinsic GC subtypes [9]. Histologically, distal gastric cancer is classified into intestinal, diffuse, and signet-ring types, and adenocarcinoma of the esophagogastric junction is now classified into three unique subsets of upper gastrointestinal adenocarcinoma. With regards to targeted therapy, the development of trastuzumab in HER2-overexpressing gastric cancer raises hope that further progress may be achieved. New targeted agents are under investigation, and some look promising; with better genetic or epigenetic characterization of GC, new and improved treatment options may become available in the future. The identification of biomarkers is essential in order to target the appropriate populations in the trials. Therefore, the collaboration between basic science and clinical research and the performance of well-designed bench-to-bedside studies will be key to achieving further progress in the treatment of advanced gastric cancer.