Management of advanced gastric cancer

Abstract

The management of advanced gastric cancer has only evolved a little over the last 15 years: platinum and fluoropyrimidine chemotherapy remains the backbone of therapy with ongoing debate as to the benefit of triplet therapy with either an anthracycline or taxane. Recently published trials of biological agents, in particular those targeting the Her2 receptor, have provided some signs of improvement. This article summarizes the relevant literature, discusses the role of these agents, as well as geographical variations in use, and provides recommendations regarding both ‘standard chemotherapy’ and the role of biological agents in advanced gastric cancer. Given the relative lack of progress for gastric cancer over the last 15 years, the focus for the next 5 years should be on an improved understanding of the molecular basis of gastric cancer, thus allowing rational integration of new molecular agents.

Keywords::

• chemotherapy
• EGFR
• gastric cancer
• HER2
• review
• VEGF

Medscape: Continuing Medical Education Online

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Expert Reviews Ltd. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.

Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journals/expertgastrohep; (4) view/print certificate.

Release date: 29 February, 2012; Expiration date: 1 March, 2013

Learning objectives

Upon completion of this activity, participants will be able to:

• • Describe standard chemotherapy for the management of AGC

• • Describe additional chemotherapy options for the management of AGC

• • Describe biological therapy options for the management of AGC

Financial & competing interests disclosure

EDITOR

Elisa Manzotti,Publisher, Future Science Group, London, UK

Disclosure:Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Laurie Barclay, MD,freelance writer and reviewer, Medscape, LLC

Disclosure:Laurie Barclay, MD, has disclosed no relevant financial relationships.

AUTHORS

Timothy J Price, MD,Haematology Oncology Unit, The Queen Elizabeth Hospital and University of Adelaide, Woodville, Southern Adelaide, Australia

Disclosure:Timothy J Price, MD, has disclosed the following relevant financial relationships: writing assistance funded as part of an unconditional grant from Roche Australia; attendance at the meeting was funded by an unconditional grant from Roche Australia.

Jeremy D Shapiro, MD,Cabrini Medical Centre and Monash University, Melbourne, Australia

Disclosure:Jeremy D Shapiro, MD, has disclosed the following relevant financial relationships: writing assistance funded as part of an unconditional grant from Roche Australia; attendance at the meeting was funded by an unconditional grant from Roche Australia.

Eva Segelov, MD,St Vincent’s Clinical School, University of New South Wales and Clinical Academic Medical Oncologist, St Vincent’s Hospital, Darlinghurst, New South Wales, Australia

Disclosure:Eva Segelov, MD, has disclosed the following relevant financial relationships: writing assistance funded as part of an unconditional grant from Roche Australia; attendance at the meeting was funded by an unconditional grant from Roche Australia.

Christos S Karapetis, MD,Department of Medical Oncology, Flinders Medical Centre, Southern Adelaide, Australia

Disclosure:Christos S Karapetis, MD, has disclosed the following relevant financial relationships: writing assistance funded as part of an unconditional grant from Roche Australia.

Nick Pavlakis, BSc, MBBS, MMed(Clin Epi), FRACP,Department of Medical Oncology, Director, NSCCHS Cancer Trials Network, Department of Medical Oncology, NSCCHS Cancer Trials Network, Royal North Shore Hospital, New South Wales, Australia

Disclosure:Nick Pavlakis, BSc, MBBS, MMed(Clin Epi), FRACP, has disclosed the following relevant financial relationships: writing assistance funded as part of an unconditional grant from Roche Australia.

Eric Van Cutsem, MD PhD,Digestive Oncology Unit, University Hospital Gasthuisberg, Belgium

Disclosure:Eric Van Cutsem, MD PhD, has disclosed the following relevant financial relationships: writing assistance funded as part of an unconditional grant from Roche Australia.

Manish A Shah, MD,Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan–Kettering Cancer Center, New York, New York, USA

Disclosure:Manish A Shah, MD, has disclosed the following relevant financial relationships: writing assistance funded as part of an unconditional grant from Roche Australia.

Yoon-Koo Kang, MD,Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea

Disclosure:Yoon-Koo Kang, MD, has disclosed the following relevant financial relationships: writing assistance funded as part of an unconditional grant from Roche Australia.

Niall C Tebbutt, MD,Austin Health, Studley Rd, Heidelberg, Victoria, Australia

Disclosure:Niall C. Tebbutt, MD, has disclosed the following relevant financial relationships: writing assistance funded as part of an unconditional grant from Roche Australia; attendance at the meeting was funded by an unconditional grant from Roche Australia.

Writing assistance was provided by Linda A Crofts of Complete Medical Group Australia, and funded as part of an unconditional grant from Roche Australia.

Gastric adenocarcinoma (GC) is the fourth most common cancer worldwide (7.8% of cancers) but the second leading cause of cancer death (9.7% of cancer deaths) [1]. In Australia, there are approximately 1900 new cases of GC each year (1.9% of all cancers), representing 2.8% of total cancer deaths [2].

Although the prognosis for very early stage GC is good, it is predominantly seen only in Asian countries, partly owing to active screening programs. Complete resection remains the only curative therapy, with evidence for increased survival with the addition of perioperative chemotherapy or adjuvant chemotherapy with or without radiation (40% 5-year survival) [3–5]. In Western countries, however, 80–90% of patients are ultimately either diagnosed at an advanced stage when the tumor is inoperable or develop recurrence within 5 years after surgery was initially performed with curative intent [6]. The 5-year survival for advanced/metastatic gastric cancer (AGC) is less than 10% and, despite the recent development of new chemotherapy regimens and the introduction of biologic therapy, median overall survival (OS) remains less than 1 year [7].

In AGC, it is accepted that chemotherapy improves survival and quality of life (QoL) compared with best supportive care (BSC) alone (hazard ratio [HR] = 0.37) [6], although this evidence is based on studies limited to patients with good performance status (PS). The addition of targeted agents has also been recently investigated. However, there remains no internationally accepted standard regimen and current best practice varies widely between East Asia, Europe and North America.

Significant regional differences in patient outcomes in AGC have been observed, with better outcomes in East Asia compared with Western countries. Despite a common conception that this is due to differences in tumor biology, there is currently no evidence to support this. Some of the perceived difference probably relates to regional variation in the prevalence of different GC subtypes, and associated differences in prognosis. Proximal tumors, for example, have a poorer prognosis than distal tumors, as well as a significantly increasing incidence in industrialized nations [8]. The incidence of these tumor subtypes varies across populations from different geographic locations, and racial and socioeconomic groups, with no evidence that patient outcomes for proximal GC differ between regions [8]. Of the two main histologic subtypes, intestinal and diffuse, intestinal-type tumors predominate in high-risk geographic areas, such as East Asia, eastern Europe and Central and South America, and account for much of the global variation in GC [8]. Early diagnosis may also explain some of the differences in patient outcomes as population screening programs and the frequency of postsurgical surveillance vary widely across regions.

Although AGC is considered incurable, prolonged survival (more than 2 years) is possible and large retrospective studies have highlighted baseline PS as the single common factor having an independent effect on survival [7,9]. Other adverse prognostic factors include the location of metastasis (in particular peritoneal or liver), two or more metastatic sites and low albumin [9]. Early detection and treatment of AGC, even asymptomatic disease, while PS is still good, may enable improved outcomes over and above lead-time bias.

This article reviews the clinical trial evidence and current best practice with a focus on regional differences to produce an Australian perspective on the optimal systemic management of AGC. The review follows a formal consensus meeting between Australian specialist clinicians and three eminent international GC experts (from the USA, Asia and Europe). We have focused on gastric cancer, but it should be noted that there would be a crossover into gastroesophageal junction adenocarcinoma, as many trials include both.

First-line treatment of AGC

Backbone chemotherapy

No prior treatment

Combination chemotherapy regimens tend to be the backbone of current practice as there is strong evidence for an improvement in patient outcomes in AGC compared with single-agent chemotherapy (HR for survival of 0.82; 95% CI: 0.74–0.90) based on a reported meta-analysis [6]. However, the preferred combination regimen varies widely globally.

Doublet chemotherapy is current standard practice in many Asian countries, with preferred regimens comprising a platinum compound, typically cisplatin (C), in combination with either infusional 5-fluorouracil (F; cisplatin plus 5-fluorouracil is denoted as CF) or an oral fluoropyrimidine, such as capecitabine (X; cisplatin plus capecitabine is denoted as CX) or S-1 [10,11]. Oral fluoropyrimidines have been shown to be noninferior to infusional 5-fluorouracil, appear not to confer higher toxicity, and thus are often preferred [10,12]. In randomized studies these regimens have resulted in median progression-free survival (PFS) times of 5–6 months and OS of approximately 10–13 months [10,11]. Many patients prefer oral fluoropyrimidine regimens to infusional 5-fluorouracil regimens owing to their convenience; however, careful patient selection and education is required to optimize compliance and avoid conditions likely to reduce drug absorption.

In Europe and the USA, fluoropyrimidine and platinum-based combinations with or without the addition of a third drug, typically docetaxel (D) or epirubicin (E), are the most widely used chemotherapy combinations for first-line AGC. The evidence to support the activity of an anthracycline-based triplet (i.e., epirubicin, cisplatin and 5-fluorouracil [ECF]) is provided by two randomized studies [13,14]. A meta-analysis also suggested a small survival benefit with the addition of an anthracycline over a CF backbone [6]; however, as the largest study included in this meta-analysis is a comparison between ECF and another triplet (mitomycin-C plus CF) [13], some have questioned the conclusion, although one would have to presume mitomycin-C had a negative effect on CF activity for this to be relevant. Uncertainty regarding the value of adding an anthracycline also comes from two small randomized Phase II trials of CF/CX versus ECF/epirubicin, cisplatin and capecitabine (ECX), respectively, which did not demonstrate a benefit with the anthracycline triplet therapy over the doublet chemotherapy [15,16]. A recent updated report of an individual patient data meta-analysis of 22 studies involving 4245 patients also questions the survival benefit of the addition of an anthracycline, although the full publication is pending [17]. In the UK, however, an anthracycline triplet, often E plus oxaliplatin (O) plus X (EOX), which was shown to confer superior survival compared with ECF in the REAL-2 trial (9.9 vs 11.2 months; HR: 0.8; 95% CI: 0.660–0.97; p = 0.02) [11], is still favored as a first-line therapy for AGC.

In the USA, docetaxel is the preferred agent for use in combination with CF (i.e., DCF), based on the V325 trial in which improved survival was observed with DCF compared with CF (HR: 0.77; p = 0.02) [18]. The DCF regimen was, however, associated with excessive toxicity, particularly myelosuppression with a 29% incidence of febrile neutropenia, and DCF triplet chemotherapy is thus typically considered only in carefully selected patients with good PS. In Europe also, with the exception of the UK, a taxane triplet is today generally preferred and various modified DCF regimens are being investigated to reduce toxicity while maintaining activity. For example, encouraging activity with reduced hematological toxicity is observed when the taxane is administered more frequently at a reduced dose [19,20].

Other treatment approaches have included the use of newer fluoropyrimidines and platinum agents. Two trials have established the noninferiority of capecitabine (X) to infusional 5-fluorouracil (F), and oxaliplatin (O) to cisplatin (C), in the combination regimens CX, OX, ECX, EOX and EOF [8,11]. In a meta-analysis of these two studies, capecitabine-containing chemotherapy resulted in longer OS and improved response rate (RR) compared with the 5-fluorouracil combinations (HR for survival: 0.87; p = 0.02) [21].

For reasons that are as yet unclear, regional differences exist in fluoropyrimidine tolerability, with more frequent treatment-related toxicity reported in the USA compared with the rest of the world for bolus F/leucovorin (F/LV) and capecitabine in colon cancer studies [22]. In addition, clinical experience with S-1 in Western countries suggests greater toxicity compared with that reported in Asian populations, and polymorphisms have been identified in genes encoding drug-metabolizing enzymes that may explain this differential toxicity of fluoropyrimidines between Asian and Western populations [23]. Thus, infusional 5-fluorouracil is currently the fluoropyrimidine backbone of choice in the USA (and to a lesser degree in Europe), although capecitabine is an accepted alternative.

The use of oxaliplatin, however, is dependent on its availability and government subsidization policies in individual countries. Infusional 5-fluorouracil in combination with oxaliplatin is commonly used as a first-line regimen in the USA, and in some European countries docetaxel is also added along with granulocyte growth factor support [23–25].

Irinotecan is generally considered a second-line drug in AGC; however, the results of a Phase III study comparing two sequences of chemotherapy (ECX first-line until progression, then folinic acid/5-fluorouracil/irinotecan (FOLFIRI) second-line versus the reverse sequence) show that FOLFIRI is a better tolerated first-line treatment than ECX, with a longer time to failure, and thus may be a more suitable platform for the addition of targeted therapies in future trials [26].

In Australia, current practice typically follows that of the UK. The standard chemotherapy regimen for AGC is ECF/ECX, or CF/CX in patients who cannot tolerate triplet therapy, although the use of epirubicin in triplet chemotherapy may decrease in the future based on data emerging from new combination regimens with biological agents, excluding anthracyclines. Nausea associated with cisplatin use is less of an issue than in the past owing to the availability of newer antiemetics such as aprepitant. Oxaliplatin is less commonly used as it is not subsidized, despite being registered for use in AGC. In selected patients not suitable for cisplatin, carboplatin may be used, although there is little evidence to confirm its efficacy [27]. Capecitabine is an accepted alternative to infusional 5-fluorouracil and is now subsidized for AGC in most countries, although only in combination with cisplatin in some regions, despite the results of the REAL-2 study demonstrating comparable efficacy of oxaliplatin and cisplatin [11].

Although not as effective as combination therapy, single-agent fluoropyrimidine has activity in GC, and thus first-line fluoropyrimidine monotherapy (oral or infusional) may have a place in the treatment of the elderly or patients in which platinum agents are contraindicated [28,29]. Treatment decision-making should involve consideration of patient comorbidities, fitness and personal preferences, with oral fluoropyrimidines arguably preferable to infusional 5-fluorouracil. It is sometimes not appreciated that total gastrectomy does not appear to affect absorption of capecitabine (or S-1) [30,31], and that tablets may be crushed for patients with dysphagia. Monitoring for toxicity, which is more unpredictable with oral fluoropyrimidines than with infusional 5-fluorouracil, is important.

Relapse post-adjuvant therapy

The clinical scenario of relapse post-perioperative chemotherapy, primarily CF or ECF, is relatively new, as this treatment modality has become routine practice only within the past 5 years. Patients relapsing less than 3 or 6 months after adjuvant therapy (depending on the chosen definition) are usually considered to have failed owing to drug resistance, and here the treatment options are similar to those of second-line therapy in the advanced setting (discussed below), where agents of known activity may be tried in selected patients or patients are enrolled in clinical trials. If the relapse is more than 3 or 6 months post-adjuvant therapy, the ideal regimen is again not defined but re-challenge with the same platinum-based schedule may be considered. Avoidance of additional anthracycline owing to cumulative drug exposure and cardiotoxicity concerns should be considered.

The role & timing of radiotherapy

In AGC, palliative radiation therapy (RT) is usually reserved for symptom control, especially pain or uncontrolled bleeding. There are few reports defining the optimal RT treatment schedule, with various dose fractionations reported [32–34]. In a recent retrospective series of 30 patients with uncontrolled gastrointestinal blood loss treated with RT, 22 patients (73%) responded, with re-bleeding occurring in 11 (50%) of these patients (median time to re-bleeding 3.3 months). Twelve patients received concurrent chemoradiotherapy (mostly fluoropyrimidines) and had a significantly lower re-bleeding rate than patients undergoing RT alone (four out of 11 vs seven out of 11 patients; p = 0.001) [35].

The role of RT in lymph node recurrent GC after curative gastrectomy is not clearly defined and, as such recurrences would usually be considered incurable, treatment is often reserved for symptom control. A small retrospective study confirmed the palliative value of RT in this setting and suggested that, in patients with isolated nodal metastases, aggressive local RT may prolong survival [36]. Prospective evaluation in a randomized controlled study will be required to confirm this observation.

Finally, the use and timing of RT in patients with AGC should be discussed in multidisciplinary meetings, where possible, in order to gain most insight for individual patients.

Biologic therapies

Agents targeting HER2

Trastuzumab

HER2 positivity has been reported in approximately 15–20% of gastroesophageal cancers, although positivity rates differ according to tumor location and histological subtype – being higher in gastroesophageal junction cancer (GOJC) than stomach cancer (33.2 vs 20.9%; p < 0.001) and in intestinal histology compared with that of diffuse histology (32.2 vs 6.1%; p < 0.001) – likely explaining the observed differences in HER2-positivity rates between countries [37]. HER2 positivity has been correlated with poor outcomes and more aggressive disease in prior reports; however, more recent data have suggested that HER2 status may not be prognostic [38,39].

Trastuzumab, a monoclonal antibody (MAb) directed against HER2, has proven beneficial in the management of HER2-positive breast cancer. Recently, the first international Phase III randomized trial of trastuzumab in HER2-positive AGC/GOJC (ToGA) demonstrated a significantly improved median OS with trastuzumab in combination with chemotherapy (CX or CF) compared with chemotherapy alone (13.8 vs 11.1 months; HR: 0.74; p = 0.0046), and improved median PFS (6.7 vs 5.5 months; HR: 0.71; p = 0.0002) [40]. Time to progression (TTP), overall RR (ORR) and duration of response were also significantly improved with the addition of trastuzumab. Exploratory subgroup analysis suggested that in patients with the highest levels of HER2 protein expression on immunohistochemistry (HER2 2+ and FISH positive, and HER2 3+ and FISH positive), trastuzumab conferred an even greater survival benefit than that observed for the intention-to-treat population (16.0 vs 11.8 months; HR: 0.65). This treatment combination is the first to result in a median survival beyond 1 year and will change the standard of care for HER2-positive GC. Based on these data, trastuzumab has been approved for the treatment of HER2-positive AGC in combination with doublet CT in several countries, including in Australia where it is approved (but not yet subsidized) for first-line HER2-positive AGC/GOJC in combination with cisplatin and either 5-fluorouracil or capecitabine. The pattern of HER2 amplification/overexpression in GC tissue (heterogeneous and frequently focal), and the scoring system used to assess it, differ from that in breast cancer and consequently HER2 testing protocols used for breast cancer specimens require modification to be used for GC specimens [41,42].

Lapatinib

Lapatinib, an orally active tyrosine kinase inhibitor (TKI) of both EGF receptor (EGFR) type 1 and 2 (HER2), is being evaluated in the treatment of advanced AGC/GOJC. The results of a Phase III study comparing lapatinib in combination with weekly paclitaxel with paclitaxel alone in previously treated AGC are awaited (ClinicalTrials.gov identifier: NCT00486954) [101].

Agents targeting EGFR

Cetuximab & panititumab

Tumor overexpression of EGFR has been associated with a poorer prognosis in GC [43]. Anti-EGFR MAb therapy has proven activity in several other cancer types, and promising early Phase II studies in advanced gastroesophageal cancer [44–47] have led to further evaluation of cetuximab and panitumumab in randomized studies: EXPAND (ClinicalTrials.gov identifier: NCT00678535; Phase III; CX ± cetuximab), ATTAX 3 (AGITG:AG0607OG; Phase II; DCF ± panitumumab) and REAL-3 (ClinicalTrials.gov identifier: NCT00824785; Phase III; EOX ± panitumumab) [101]. At present, none of these trials are restricted to patients with wild-type KRAS tumors as the frequency of KRAS mutations in GC is expected to be low (∼5%) [48], and there are currently no data to suggest that KRAS gene mutation is predictive of lack of response to EGFR-targeted MAb therapy in this tumor type.

Gefitinib & erlotinib

The efficacy of the EGFR TKI gefitinib has been studied in Phase II trials in metastatic gastroesophageal cancers [49,50]. Observed RRs were low (<15%), although disease control rates, which included stable disease, were higher but still less than 40%. A second EGFR TKI, erlotinib, has been tested as first-line therapy in 70 patients with unresectable or metastatic adenocarcinoma originating in the gastro–esophageal junction (GOJ) or stomach [51]. Objective response was observed in six patients (9%), all with GOJ tumors; no responses were observed in GC. No molecular parameters of EGFR expression or mutations were predictive of clinical outcome. The reason for the apparent differential sensitivity of GOJ and gastric carcinomas to EGFR blockade using erlotinib is unclear.

Agents targeting VEGF

Elevated serum and tumor levels of VEGF have been associated with more rapid GC progression and poorer prognosis [52,53].

Bevacizumab

The anti-VEGF MAb bevacizumab has been associated with improved outcomes when combined with chemotherapy in metastatic colorectal cancer, breast cancer and non-small-cell lung cancer. A Phase II study of bevacizumab combined with irinotecan and cisplatin in metastatic gastric or GOJ adenocarcinoma revealed a high RR and TTP compared with historical controls [54], although in another Phase II study the addition of bevacizumab to cisplatin and docetaxel did not appear to prolong TTP or survival compared with a series of chemotherapy alone [55].

A randomized Phase III trial of bevacizumab in combination with chemotherapy (CX) in AGC (AVAGAST) recently demonstrated significant improvement in the secondary efficacy end points of PFS (6.7 vs 5.3 months; HR: 0.80; p = 0.0037) and ORR (46 vs 37%; p = 0.0315) with bevacizumab, but did not meet the primary end point of OS [56]. An unplanned subgroup analysis demonstrated a survival benefit in patients from the Americas (a fifth of enrolled patients) but not in patients from Asia. The reasons for this variance are not clear. No excess gastrointestinal bleeding was observed in the bevacizumab group. Anti-VEGF therapy is currently not indicated in advanced gastric or esophageal cancer.

Sunitinib & sorafenib

Phase II studies of the multi-targeted TKIs sunitinib and sorafenib suggest that these agents may have activity in AGC; however, without randomized controlled trial evidence, their benefits remain uncertain [57,58].

Meeting summary: recommendations for first-line treatment of AGC

• • Platinum-containing doublet chemotherapy: CF/CX or OX;

• • Triplet chemotherapy in selected suitably-fit patients;

• • Epirubicin, cisplatin or oxaliplatin, 5-fluorouracil or capecitabine, or a modified DCF regimen;

• • Capecitabine and oxaliplatin combination chemotherapy regimens;

• • Evidence supports the use of either oxaliplatin or cisplatin; capecitabine is an accepted alternative to infusional 5-fluorouracil;

• • Targeted therapies: Herceptin^® (Roche) is recommended for HER2-positive patients (registered for use in combination with CF/CX);

• • Table 1 summarizes key Phase III trials of first-line therapy in AGC.

Second-line treatment of AGC

Almost all patients with AGC will develop progressive disease after first-line therapy, and the benefit of second-line chemotherapy until recently has remained controversial. A number of agents have previously demonstrated second-line activity in AGC in Phase II trials, with modest benefit; however, no single regimen has shown superior activity [59–64]. Several Phase II trials assessing the benefit of targeted second-line therapies have demonstrated ability to achieve disease stabilization (everolimus/RAD001 [65], ramucirumab/IMC-1121B [66], sunitinib [67], cetuximab [68] and lapatinib in HER2-positive disease [69]) and there are a number of ongoing randomized trials assessing the impact of such agents on survival outcomes. The variation in first-line chemotherapy regimens in AGC, and the consequent use of a variety of second-line regimens, has meant that interpreting study data is difficult.

A pooled analysis of three Phase III trials of 5-fluorouracil-based first-line chemotherapy (1080 patients) reported that only approximately 20% of patients went on to receive second-line therapy, with ORR of 13.3% and a median survival of 5.6 months from the start of second-line therapy [70]. This rate of second-line therapy, together with the lack of significant advances in first-line therapy, may go some way to explain why the median OS for GC remains under 12 months. In more recent Phase III trials, the percentage of patients receiving second-line therapy has ranged from 14% to as high as 42–45% [8,40].

In practice, second-line treatment is increasingly being used, particularly in Asia, despite a lack of randomized trial data to support it. In the AVAGAST study, for example, 66% of Asian patients went on to receive second-line therapy compared with only 31% in Europe and 21% in the Americas [56]. The improved survival observed in the Asian subgroup may, in part, be due to lead-time bias, but it may also provide indirect evidence for the benefit of second-line treatment. Commonly used second-line treatment approaches include re-challenge with cisplatin and fluorouracil (if progression occurs more than 3–6 months after first-line therapy), taxane monotherapy, irinotecan monotherapy or FOLFIRI/folinic acid/fluoropyrimidine/oxaliplatin (FOLFOX) [59]. There is currently little evidence to support combination schedules over single agents [59]. Table 2 summarizes some the evidence on some of the available options.

Despite multiple second-line Phase II trials there has been a lack of Phase III trials until recently. The AIO trial, which closed prematurely owing to poor accrual, was the first Phase III study to investigate second-line chemotherapy in AGC [71]. While PFS was similar in both arms, median survival favored irinotecan over BSC (123 vs 3 days; HR: 0.42; p = 0.023). A second, larger Phase III trial comparing second-line chemotherapy (either single-agent docetaxel or irinotecan) plus BSC with BSC alone in medically fit patients pretreated with fluoropyrimidines and platinum has also shown that second-line chemotherapy is tolerated and significantly improved OS (5.1 vs 3.8 months; p = 0.009) when added to BSC [72].

These two positive second-line Phase III trials argue for second-line chemotherapy to become an accepted standard of care in suitably fit patients. The question of the optimum sequence of chemotherapy will now be discussed. A recent randomized Phase II study has attempted to assess this question in AGC. Patients were randomized to either docetaxel/F/LV or irinotecan/F/LV regimen, and were switched after four cycles. Second-line activity was observed for both schedules and there was no difference in outcome by sequence. The median OS with planned second-line therapy was close to 12 months (11.5 and 10.6 months) [73]. Another crossover study comparing ECX and FOLFIRI had a lower OS and also failed to demonstrate a difference in outcome by sequence (9.5 vs 9.7 months, respectively; p = 0.95), although FOLFIRI first-line provided longer TTF than ECX first-line therapy (4.2 vs 5.1 months, respectively; p = 0.008) [74]. It should be noted that these studies might be a truer reflection of real practice as patients were enrolled at diagnosis rather than being assessed for fitness for second-line therapy at progression. As a result, a significant number would not have been considered fit for second-line treatment in a second-line treatment trial, and drop-out rates were high with only 48% and 39% proceeding to second-line therapy. This is then reflected in the lower-than-expected OS.

Patient selection is thus an important consideration, and several clinical factors have been associated with poor OS after second-line therapy [75]: low PS (two or more); hemoglobin ≤11.5 g/l; carcinoembryonic antigen level >50 ng/ml; the presence of three or more metastatic sites of disease; and TTP on first-line chemotherapy ≤6 months. Survival of AGC patients who received second-line chemotherapy was shown to be related to the number of adverse prognostic factors: median survival was 12.7 months (no risk factor), 7.1 months (one to two risk factors) and 3.3 months (three to five risk factors), respectively (p < 0.001).

Ongoing randomized trials are required to define the optimal second-line treatment schedule and define the role of targeted agents in this setting. Until then, AGC patients should be offered places in clinical trials investigating second-line therapies. Outside of clinical trials, patients may be carefully selected for second-line therapy based on PS, TTP on first-line therapy and disease extent, and treated with active agents not already used in first-line treatment, such as docetaxel or irinotecan [59,75].

Meeting summary: recommendations for second-line treatment of AGC

• • Single-arm Phase II trials indicate activity of second-line therapy;

• • Two randomized Phase III trials have reported a survival advantage with second-line single-agent docetaxel or irinotecan;

• • Ongoing trials are important to define the true overall role of second-line therapy, define the optimal therapy and explore new options to improve OS;

• • Clinicopathologic factors can be used to identify patients most likely to benefit from second-line therapy.

Role of supportive & palliative care

Given the poor prognosis for AGC patients, supportive and palliative care is an important part of a patient management plan from early on. Issues such as nutrition and control of diarrhea and postgastrectomy bowel disturbance need particular attention and can make the difference between patients being fit enough for active treatment or not. The inclusion of QoL measures in clinical trials in AGC would better enable such factors to be taken into account when making treatment decisions. The OS benefit of early formal palliative care intervention on patient outcomes in AGC has not been established; however, one can hypothesize a benefit based on results observed in a recent randomized study in non-small-cell lung cancer [76]. Here, early palliative care referral of advanced lung cancer patients led to significant improvements in both QoL and mood, and patients receiving early palliative care integrated with standard oncologic care had less aggressive care at the end of life and longer survival than patients receiving standard oncologic care alone [76]. Furthermore, early palliative care intervention in symptomatic AGC patients should play a significant role in relieving symptoms and improving QoL.

Expert commentary

There is definitive evidence that systemic chemotherapy has a role in improving survival over BSC in AGC patients with good PS. In general, a combination schedule, including at least a fluoropyrimidine and a platinum agent, would be considered the standard of care and, although there is variation around the world, the addition of either an anthracycline or a taxane could be considered for selected patients. Oral fluoropyrimidines and oxaliplatin can replace infusional 5-fluorouracil and cisplatin, respectively, given evidence for at least equivalence of these agents. For HER2-positive patients, the addition of trastuzumab to CF doublet chemotherapy is a new treatment standard. There is increasing evidence for the benefit of second-line therapy in fit patients, although large randomized trials, focusing on better patient selection as well as novel therapies, are still awaited to better define its role. Based on current evidence, irinotecan or a taxane would appear appropriate second-line therapies when not received in first-line treatment. Attention to supportive care, QoL and treatment toxicity is especially important in AGC and should be a focus in addition to chemotherapy options.

Five-year view

Over the next 5 years, the aims of investigators should focus on a better understanding of the molecular pathways crucial for gastric cancer proliferation and with this an exploration of agents targeting these pathways should follow. We have seen that the HER2 pathway is one target that has improved survival, but this is for a subset of patients. By contrast, the anti-VEGF agent bevacizumab appears to add little when combined with first-line platinum/fluorouracil chemotherapy, but a more targeted approach may again see a subset benefiting and recent results from colorectal cancer have suggested some potential biomarkers for anti-VEGF therapy, although these and others will need to be assessed specifically in gastric cancer. Results of trials assessing the role of anti-EGFR targeted agents will also be available in the near future, and the hope would be that these agents may add to the therapeutic armory if the trials are positive and show improvements in OS. The other major focus over the next 5 years will be to optimize second-line therapy or explore maintenance therapy to further improve OS. Furthermore, exploration of third-line therapy may also lead to further improvements.

Table 1. Selected Phase III trials of first-line chemotherapy in advanced/metastatic gastric cancer.

Study	Treatment	Patients (n)	ORR (%)	1-year OS (%)	Median OS (months)	p-value	Ref.
ML17032	CF CX	137 139	32 46	NA NA	9.3 10.5	NS	[8]
REAL-2	ECF ECX EOF EOX	249 241 235 239	40.7 46.4 42.4 47.9	37.7 40.8 40.4 46.8	9.9 9.9 9.3 11.2	0.02^†	[10]
V325	DCF CF	221 224	37 25	40 32	9.2 8.6	0.02	[16]
ToGA	CX/CF +trastuzumab CX/CF	294 290	47 35	NA NA	13.8 11.1	0.0046	[35]

^†EOX compared with ECF.

CF: Cisplatin, 5-fluorouracil; CX: Cisplatin, capecitabine; DCF: Docetaxel, cisplatin, 5-fluorouracil; ECF: Epirubicin, cisplatin, 5-fluorouracil; ECX: Epirubicin, cisplatin, capecitabine; EOF: Epirubicin, oxaliplatin, 5-fluorouracil; EOX: Epirubicin, oxaliplatin, capecitabine; NA: Not available; NS: Not significant; ORR: Overall response rate; OS: Overall survival.

Table 2. Selected Phase II trials of second-line chemotherapy in advanced/metastatic gastric cancer.

Treatment	Patients (n)	ORR (%)	Median TTP/PFS (months)	Median OS (months)	Ref.
Docetaxel (75 mg/m^2 every 3 weeks)	49	16	2.5	8.3	[63]
FOLFIRI (every 2 weeks)	38	29	3.7	6.4	[60]
Irinotecan (125 mg/m^2 weekly for 4 weeks on a 6-week cycle)	37	20	2.6	5.2	[61]
Irinotecan (160 mg/m^2) plus docetaxel (65 mg/m^2) every 3 weeks	49	20	2.7	8.9	[64]
Paclitaxel (80 mg/m^2 weekly for 3 weeks every 4-week cycle)	38	24	2.1	5	[62]

FOLFIRI: Folinic acid/5-fluorouracil/irinotecan; ORR: Overall/objective response rate; OS: Overall survival; PFS: Progression-free survival; TTP: Time to progression.

Key issues

• • The outlook for advanced gastric cancer remains poor, with median overall survival generally under 12 months.

• • There may be regional variations that impact on treatment choice and effectiveness in advanced gastric cancer.

• • Fluoropyrimidine and platinum chemotherapy remains the backbone of current therapy and does lead to an improvement in overall survival over best supportive care alone.

• • The addition of a third agent, anthracycline or taxane, adds a small survival gain but there are toxicity trade-offs.

• • The addition of Herceptin^® to HER2-positive gastric cancer has been shown to improve survival and should be considered a standard of care.

• • Currently, there is no evidence for a clinical benefit of adding other biological agents to standard chemotherapy.

• • Second-line chemotherapy, with a taxane or irinotecan depending on first-line regimen, can be considered an option in selected patients.

• • Future research should focus on a better understanding of molecular pathways specific to gastric cancer to allow rational trial design of better targeted agents.

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Website

• ClinicalTrials.gov. http://clinicaltrials.gov
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Management of advanced gastric cancer

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Activity Evaluation

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1. Your patient is a 68-year-old man with advanced gastric cancer (AGC). On the basis of the review by Dr Price and colleagues, which of the following statements about standard chemotherapy is most likely correct?

• □ A Current best-practice recommendations are the same throughout the world

• □ B Double-agent chemotherapy offers no improvement over single-agent chemotherapy

• □ C Fluoropyrimidine and platinum chemotherapy are still the backbone of current therapy

• □ D Oral fluoropyrimidines are not as effective as infusional 5-fluorouracil (5-FU)

2. On the basis of the review by Dr Price and colleagues, which of the following statements about additional chemotherapy options for management of the patient described in question 1 is most likely correct?

• □ A Adding anthracycline or taxane as a third agent offers no survival benefit

• □ B Depending on the first-line regimen, second-line chemotherapy with a taxane or irinotecan may be an option in selected patients

• □ C Adding anthracycline or taxane as a third agent is not associated with any additional toxicity

• □ D In the United States, mitomycin-C is the preferred third agent

3. On the basis of the review by Dr Price and colleagues, which of the following statements about biological therapy options for the management of AGC would most likely be correct?

• □ A Trastuzumab has not been approved in any country for the treatment of any type of AGC

• □ B Adding trastuzumab to chemotherapy for patients with HER2-positive gastric cancer may be considered a standard of care

• □ C In the first international phase 3 randomized trial of trastuzumab in HER2-positive AGC, overall survival was no better than with chemotherapy alone

• □ D Adding biological agents other than trastuzumab to standard chemotherapy is of significant clinical benefit