Abstract Gastric adenocarcinomas are tumours of decreas-ing incidence in the Western world, although they are still the fourth leading cause of cancer mortality. The purpose of these clinical guidelines is to provide recommendations for the diagnosis and treatment of this disease based on the best available evidence. Regarding resectable gastric can-cer, the various potential therapeutic options are discussed (adjuvant or perioperative chemotherapy, and adjuvant or neoadjuvant chemoradiotherapy). With regard to advanced or metastatic disease, different alternative combinations of conventional cytotoxic agents including a platinum agent (cisplatin or oxaliplatin) and a fluoropyrimidine (5-FU, capecitabine or S1), with or without a third drug (epiru-bicin or docetaxel), as well as their integration with new biological agents (trastuzumab in HER2+ tumours), are discussed. Finally, an outline is provided of the main lines of research and development of therapies for this disease.

Keywords Gastric adenocarcinoma · Diagnosis · Treatment · Clinical guidelines

Introduction

Gastric cancer (GC) is a major health problem given its high incidence and mortality. It accounts for 10% of all malignant tumours and it is the second leading cause of death from cancer in the world [1]. In Europe, 159,900 new cases were diagnosed and 118,200 patients died of GC in 2006, making it the fourth leading cause of death from cancer. There are large geographical differences in its incidence, which is very high in Asia and South America. In the United States, Western Europe and Australia there has been a marked reduction in distal GC over the last 50 years and, since the 1980s, this evolution has coincided with an increase in the incidence of adenocarcinomas in the lower third of the oesophagus and oesophagogastric junction (EGJ) [2]. Except for Japan, which has screening programmes, the prognosis of patients with GC is still very poor, with 5-year overall survival (OS) rates below 30% in Western countries, including Spain.

GC is more frequent among males and its incidence increases with age (peak presentation is between 65 and 74 years old). Risk factors can be genetic/familial or envi-ronmental. The familial cancer syndromes with the greatest incidence of GC include hereditary diffuse gastric cancer (HDGC) syndrome, hereditary nonpolyposis colon cancer (HNPCC), Li-Fraumeni syndrome, familial gastric poly-posis, familial adenomatous polyposis and Peutz-Jeghers syndrome. Mutations in the germline of the E-cadherin (CDH1) gene are associated to HDGC but no mutations have yet been identified that increase the risk of intestinal gastric carcinoma.

It is worth noting that EGJ adenocarcinomas [which are subclassified as Siewert type I (predominantly oe-sophageal), Siewert II (equidistant from oesophagus and stomach) and Siewert III (predominantly gastric)] are included in these GC guidelines but these tumours could be also considered as oesophageal cancers. Environmental factors differ according to tumour location: the main risk factors of adenocarcinomas of the distal oesophagus and

F. Rivera ()Servicio de Oncología MédicaHospital Universitario Marqués de ValdecillaAvda. Valdecilla, s/nES-39008 Santander, Spaine-mail: oncrhf@humv.es

C. GrávalosServicio de Oncología MédicaHospital Universitario 12 de octubreMadrid, Spain

R. García-CarboneroServicio de Oncología MédicaHospital Universitario Virgen del RocíoSevilla, Spain

Clin Transl Oncol (2012) 14:528-535DOI 10.1007/s12094-012-0836-9

C L I N I C A L G U I D E S I N O N C O L O G y

SEOM clinical guidelines for the diagnosis and treatment of gastric adenocarcinoma

Fernando Rivera · Cristina Grávalos · Rocío García-Carbonero

Received: 4 May 2012 / Accepted: 2 June 2012

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EGJ are reflux oesophagitis, Barrett’s oesophagus, obesity and smoking, while gastric body and distal GCs are as-sociated to Helicobacter pylori infections, the intake of food in bad condition or unrefrigerated, excess nitrates and atrophic gastritis. Proximal and distal GCs are different in their epidemiology, biology, histology and clinical expres-sion. Although they are still therapeutically managed as a single entity, there is increasing evidence indicating that in the near future they should be addressed separately. Table 1 summarises the main clinical-pathological differences between the two groups.

These clinical guidelines aim to offer succinct, practical recommendations for diagnosis, treatment and follow-up of GC.

Diagnosis and staging

Diagnosis

For diagnosis, an upper GI endoscopy is essential as well as a biopsy of the suspect lesions. Ninety percent of GCs are adenocarcinomas. The histological study should also include the Lauren classification (intestinal and diffuse). It is also advisable to determine overexpression of HER2, which will be indispensable in cases of advanced dis-ease for which administration of trastuzumab is being considered. Immunohistochemical (IHC) tests should be conducted and validated in accordance with the specific criteria established for GC [3] (which differ from those for breast cancer) and, in the case of IHC 2+, FISH should be conducted [4].

Staging

Once diagnosis has been established, and in order to stage the disease and decide on the best therapeutic strategy, the following additional examinations should be carried out [5]:

– Anamnesis, physical examination and blood tests (haemogram, hepatic and renal function tests). This should include an evaluation of the patient’s func-tional and nutritional status, as well as geriatric as-sessment in the elderly.

– Computerised axial tomography (CAT) of chest and abdomen: necessary to rule out distant metastasis.

– Upper GI series and endoscopic ultrasound±FNPA of suspect adenopathies: useful to analyse the locore-gional extension of the disease (T and N).

– Laparoscopy and positron emission tomography (PET) may be recommendable in potentially resect-able patients, although it must be remembered that mucinous and diffuse tumours may be negative on a PET. [III, B]

– Other examinations shall be requested only if clini-cally indicated.

Staging should be conducted according to the 2010 TNM classification (Table 2). With regard to clinical man-agement, patients are generally classified into four major groups:

a) Early resectable disease (stages 0, I; 10% of patients in our setting); OS at 5 years ~70%.

b) Locally advanced resectable disease (stages II–IIIC, 40% of patients); OS at 5 years ~30%.

c) Locally advanced unresectable disease (20% of patients); OS at 5 years <5%, median OS 12–14 months.

d) Metastatic disease (stage IV, 30% of patients upon diagnosis) or relapse (60% of resected patients); OS at 5 years <5%, median OS ~9–11 months.

Treatment

The main therapeutic strategies for GC are surgery, sys-temic therapies and radiotherapy (RT). Active palliation also comprises an important part of treatment and includes placing an endoprosthesis, bypass surgery and support measures. Both diagnosis and treatment of GC require a multidisciplinary approach [6]. A treatment algorithm for gastric cancer is showed in Fig. 1

Treatment of localised disease

In early resectable disease (stage I), surgery is the treat-ment of choice. Stages IA do not require any additional treatment whereas in some select stages IB treatment may be considered.

In locally advanced resectable or resected disease (stag-es II–IIIC) we recommend administering treatment in addi-tion to surgery. For gastric tumours not involving the EGJ, there are currently three therapeutic approaches that have proven increased survival: adjuvant chemotherapy (CT), adjuvant chemo-radiotherapy (CT-RT) and perioperative CT. These three options have not been compared head-to-head and, although initially the three could be valid [I, A], perioperative CT is probably the one that offers the greatest potential theoretical advantages and the one most widely

Table 1 Clinical-pathological differences between cancer of the EGJ/cardias and of the gastric body

EGJ/cardias Body

Incidence Increasing DecreasingHelicobacter pylori + ++++Histology Diffuse type Intestinal type DNA content Diploid AneuploidDissemination pattern Haematogenous Locoregional

530 Clin Transl Oncol (2012) 14:528-535

used in European countries [IV, B]. For EGJ tumours there is a fourth therapeutic option: preoperative CT-RT [I, B].

SurgeryThe existing learning curve in GC surgery conditions treat-ment outcomes. It is advisable that, in those units where surgery for this type of tumour is not frequent, patients be referred to a reference unit [III, B]. There is no unanimous consensus on unresectability criteria, although experienced surgical teams generally consider tumours invading the head

of the pancreas, the hepatic hilum, the transverse mesoco-lon, the mesenteric artery or the aorta to be unresectable.

As for the type of gastrectomy, current recommenda-tions include resection with negative margins (proximal, distal and radial) avoiding total routine gastrectomy, dis-tal pancreatectomy or splenectomy, unless necessary to achieve free margins. Thus, in a high percentage of cases, conducting a proximal (proximal or EGJ tumours) or sub-total (distal tumours) gastrectomy is usually considered sufficient [III, A]. Splenectomy may also be indicated in

Table 2 TNM staging (7th ed, 2010)

T: primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Tis Carcinoma in situ: intraepithelial tumour without invasion of the lamina propria T1 Tumour invades lamina propria, muscularis mucosae or submucosa T1a Tumour invades lamina propria or muscularis mucosae T1b Tumour invades submucosa T2 Tumour invades muscularis propria T3 Tumour invades subserosa T4 Tumour invades serosa (visceral peritoneum) or adjacent structures T4a Invades serosa (visceral peritoneum) T4b Invades adjacent structures N: regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No evidence of regional lymph node metastasis N1 Metastasis in 1-2 regional lymph nodes N2 Metastasis in 3-6 regional lymph nodes N3 Metastasis in more than 6 regional lymph nodes N3a Metastasis in 7-15 regional lymph nodes N3b Metastasis in more than 15 regional lymph nodes M: distance metastasis MX Distance metastasis cannot be assessed M0 No evidence of distance metastasis M1 Distance metastasis

Stages of GC

Stage 0 Tis N0 M0Stage IA T1 N0 M0Stage IB T1 N1 M0 T2 N0 M0Stage IIA T1 N2 M0 T2 N1 M0 T3 N0 M0Stage IIB T1 N3 M0 T2 N2 M0 T3 N1 M0Stage IIIA T2 N3 M0 T3 N2 M0 T4a N1 M0Stage IIIB T3 N3 M0 T4a N2 M0 T4b N1 M0 T4b N0 M0Stage IIIC T4a N3 M0 T4b N3 M0 T4b N2 M0Stage IV Any T Any N M1

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proximal tumours located in the greater curvature or gastric fundus to allow the proper lymphadenectomy of the splenic hilum. In very early well differentiated gastric tumours, <2 cm and confined to the mucosa, more limited surgical resections may be considered or even endoscopic resection by experienced teams [III, B].

Lymphadenectomy must include ≥15 lymph nodes and be at least D1 (perigastric lymph nodes). Japanese surgeons advocate D2 lymphadenectomy (coeliac axis vessels), but two European randomised studies found higher periopera-tive morbidity-mortality with D2 vs. D1, with no increase in survival [I, A]. This is why, although some surgeons are in favour of D2, it is not considered a requirement in the West. Another type of lymphadenectomy is the modified D2, which avoids pancreatectomy and splenectomy.

Studies conducted by experienced teams suggest that a laparoscopic approach could provide tumour control similar to that of an open laparotomy with less morbidity-mortality. Nonetheless, a meta-analysis of the randomised studies conducted concluded that surgery time was longer and the number of resected adenopathies was lower with a laparoscopic approach than with open surgery [I, A]. Therefore, at present it should still be considered an ex-perimental approach.

Adjuvant treatmentChemotherapy. In Western countries, no randomised study has definitively proven the efficacy of adjuvant CT com-pared to observation, although several meta-analyses, the most recent one published in 2010 [7], suggest a long-term survival benefit of 3–6% in absolute terms.

In an Asian population, the administration of S-1 [an oral fluoropyrimidine consisting of a combination of tega-fur, a pro-drug of 5-fluorouracil (5FU), and two metabo-lism modulators, oteracil and gimeracil] for 1 year signifi-

cantly improved survival vs. surgery alone (OS at 3 years 80% vs. 70%, HR 0.68; p=0.003) [8] and it has become the standard treatment in Japan. Given that tumour biol-ogy and pharmacokinetics may be different in Eastern and Western populations, these data should be validated in our setting (Western population). In another Asian Phase III study (CLASSIC), which included 1035 patients, XELOX (Capecitabine-oxaliplatin) as adjuvant treatment follow-ing surgery was superior in terms of disease-free survival (DFS) to observation; follow-up was still too short to draw any conclusions in terms of OS [9].

Chemoradiotherapy. In 2001, the Phase III study SWOG 9008/INT 0116 was published, which proved that adjuvant CT-RT with 5FU and leucovorin (LV) sig-nificantly increased DFS and OS vs. observation [I, A] (Table 3) [10]. In an unplanned subgroup analysis [11] the survival benefit remained similar in patients with lymph node dissections D0 (54% of patients) and D1 (36%), but it was more questionable in lymphadenectomy D2 (10% of patients). The influence of the histological type was also analysed and clear differences were found in favour of the arm with CT-RT in the subgroup with intestinal type, but not in the diffuse type.

In order to define the best CT regime, the Phase III study CALGB-80101 randomised 546 resected patients to two postoperative chemoradiotherapy regimes: the control arm with 5FU/LV and the experimental one with ECF (epirubicin, cisplatin and 5FU in continuous infusion). No significant differences were observed in terms of DFS or OS [12].

The Korean study ARTIST assessed the role of adju-vant CT vs. adjuvant CT-RT in 458 patients with resected GC, comparing a regime with cisplatin-capecitabine (XP) associated to RT vs. the same regime of CT alone. There

Treatment of gastric adenocarcinoma

Early resectableStages 0, IA

Relapsedor metastatic

ResectableStages IB-IIIC

Unresectable Locally advanced

Surgery

Follow-up

Surgery +- Postoperative CT*- Postoperative CT/RT - Perioperative CT- Preoperative CT/RT (only in cardias)

*Option with little acceptance in the West

If HER2+ (IHC +++ or IHC ++ with FISH+):- Cisplatin+ capecitabin/5FU + trastuzumabIf HER2–: Several options possible:- Cisplatin/oxaliplatin + capecitabine/5FU- Triplets with epirubicin (ECF, ECX, EOF, EOX)- Triplet with docetaxel (DCF)*Assess surgical rescue if there is a response

CT: chemotherapy; CT/RT: chemoradiotherapy; IHQ: immunohistochemistry; RT: radiotherapy.

Fig. 1 Treatment algorithm

532 Clin Transl Oncol (2012) 14:528-535

was a tendency to longer DFS in the CT-RT arm and this difference was statistically significant in the subgroup of pN+ patients [13].

Perioperative treatmentThe theoretical advantages of preoperative treatment are the potential increase of the tumour’s resectability, a higher probability of treatment compliance, less toxicity, early treatment of micrometastases and a better scenario to re-search new additional treatments.

Chemotherapy. In the randomised Phase III studies MAGIC [14] and FFCD 9703 [15], perioperative CT sig-nificantly increased survival of patients with resectable gastric or EGJ adenocarcinomas [I, A] (Table 3).

Two studies are evaluating the role of associating a monoclonal antibody to CT. The UK Phase III study MAG-IC B, which plans to include 1100 patients, compares ECX (epirubicin, cisplatin and capecitabine) with the experimen-tal arm ECX+bevacizumab. In turn, the Spanish Phase II study NEOXH aims to assess the efficacy of adding trastu-zumab to XELOX perioperatively in resectable HER2+ GC.

Chemoradiotherapy. The value of associating postop-erative RT to perioperative CT shall be evaluated by the Dutch Phase III study (CRITICS), which is designed to randomise nearly 800 patients to receive perioperative ECX vs. preoperative ECX and postoperative capecitabine/RT.

Neoadjuvant treatmentChemotherapy. A study by the EORTC, which randomised 144 patients with locally advanced GC to initial surgical resection or to neoadjuvant cisplatin/5FU (CF) followed by surgery, found an increase in the rate of R0 resection among patients treated with CT, however no statistically significant difference in survival was reached [16]. This study, nonetheless, is small and patient follow-up is still insufficient.

Chemoradiotherapy. In adenocarcinomas of the oe-sophagus and the cardias, preoperative CT-RT is an estab-lished treatment. However, it is still an experimental proce-dure in nocardia stomach tumours.

The Phase III study POET [17] compared preoperative CT with preoperative CT-RT in cardia adenocarcinomas (Table 3). A trend was observed, with no statistical signifi-cance, of an increase in survival and local control with CT-RT, with no differences in the rate of R0 resections. In the RT arm, a trend was observed of higher surgical mortality. Some elements of this study worth noting are the limited number of patients (n=114), the fact the comparison was only with preoperative CT and not perioperative, and that patient selection was very strict (ECOG 0-1).

Taking into account that in the above adjuvant CT, post-operative CT-RT and perioperative CT studies, a significant number of EGJ tumours were included, many authors be-lieve that the four therapeutic strategies may be considered valid options for the management of these patients [I, A], while others lean towards preoperative CT-RT as the treat-ment of choice in cardia cancer [IV, D].

Additional treatment recommendations for resectable diseaseThe two currently accepted options for additional treatment of resectable tumours in Western countries are postop-erative CT-RT (SWOG 9008/INT 0116 regime) and peri-operative CT [I, A]. Many authors, especially in the USA, continue accepting postoperative CT-RT with 5FU/LV as standard, while in Europe most authors prefer periopera-tive CT. This is, furthermore, the ideal scenario to study the role of new biological treatments.

Treatment of advanced gastric cancer (AGC)

This includes both treatment of metastatic disease and unresectable locally advanced disease. In the latter case,

Table 3 Phase III studies of resectable disease

N OS DFS

INT 0116 [4] 566 3 yrs: 50% vs. 41% 3 yrs: 48% vs. 31%Postoperative 5FU-LV/RT vs. surgery alone HR 1.35 HR 1.52 p=0.005 p=0.005MAGIC [6] 503 3 yrs: 43% vs. 32% 3 yrs: 41% vs. 26%Perioperative ECF vs. surgery alone HR 0.75 HR 0.66 p=0.009 p<0.05FFCD 9703 [7] 224 5 yrs: 38% vs. 37% 5 yrs: 34% vs. 21%Perioperative CF vs. surgery alone HR 0.69 HR 0.65 p=0.002 p=0.003EORTC 40954 [8] 144 2 yrs: 73% vs. 70% 2 yrs: 59% vs. 48%Preoperative PFL vs. surgery alone HR 0.84 HR 0.66 p=0.48 p=0.20POET [9] (cardias) 119 3 yrs: 47% vs. 27%Preoperative PFL vs. preoperative PFL→PE/RT HR 0.67 p=0.07

N, number of patients; yrs, years; ECF, epirubicin, cisplatin, 5FU; CF, cisplatin, 5FU; PLF, cisplatin, 5FU, LV; PE, cisplatin, etoposide

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the prognosis is slightly better and some form of locore-gional treatment may be added (especially rescue surgery if a response is achieved following CT). This is why many authors consider they should be assessed separately, with specific studies for each one of these two subgroups.

Several randomised studies and a meta-analysis [18], comparing palliative CT with the best supportive care (BSC), have demonstrated that CT increases median sur-vival (3–4 vs. 7–10 months) and improves the quality of life of patients with AGC.

First-lineChemotherapy based on cisplatin. In the late 1990s, it was proven that regimes based on cisplatin were superior to other older regimes without cisplatin. Both CF and ECF became standard regimes and there are no randomised head-to-head comparison studies.

Although these regimes result in response rates of 20–40%, these responses are of limited duration, with median time to progression (TTP) of around 4–5 months, exceptional complete response (~5%) and median survival of only 7–10 months [19].

Benefits are generally limited to patients in a good gen-eral condition and should be assessed in light of the signifi-cant toxicity and inconvenience associated to this regime.

Chemotherapy based on docetaxel. In the Phase III study V-325 [20], DCF (docetaxel, cisplatin, 5FU) was compared with CF. The study was positive for its main endpoint, TTP (median 5.6 vs. 3.7 months), and DCF was also significantly superior in OS, survival at 2 years and response rate. Grade 3–4 neutropenia, febrile neutropenia and diarrhoea were more frequent with DCF, although it should be noted that febrile neutropenia under DCF de-creased from 30% to 12% with the prophylactic adminis-tration of colony-stimulating factors.

Chemotherapy based on oxaliplatin. The study REAL2 [21] compared four different regimes, replacing cisplatin with oxaliplatin and 5FU with capecitabine. No statistically significant differences were observed in the response rate or in progression-free survival (PFS), but EOX (epirubicin, oxaliplatin, capecitabine) was superior to ECF in OS (11.2 vs. 9.9 months, p=0.02). Response rates were 41%, 46%, 42% and 48% for the regimes ECF, ECX, EOF (epirubicin, oxaliplatin, 5FU) and EOX, respectively.

In another Phase III study [22], 220 patients with AGC were randomised to receive FLC (5FU/LV and cisplatin) or FLO (5FU/LV and oxaliplatin). A trend was observed towards improved PFS in the oxaliplatin group (median 5.8 vs. 3.9 months, p=0.07). The FLO regime also showed a superior response rate (34% vs. 25%) with a more positive tolerability profile.

Oral fluoropyrimidines. In the study REAL2, no infe-riority was found when replacing 5FU with capecitabine. In another non-inferiority Phase III [23] study (primary

endpoint PFS), 316 patients with metastatic gastric ad-enocarcinoma were randomised to receive either cisplatin/capecitabine (XP) or cisplatin/5-FU (CF). The XP regime was clearly not inferior to CF, with median PFS of 5.6 and 5 months, respectively. Furthermore, XP improved median OS (10.5 vs. 9.3 months) and response rate (41% vs. 29%), and it showed a similar safety profile except for hand-foot syn-drome, which was more frequent in the XP arm (22%) than in the CF arm (4%). In a meta-analysis that included both studies [24], OS was superior with capecitabine combina-tions compared with 5-FU combinations (HR 0.87, p=0.02).

The randomised Phase III study FLAGS [25] compared the combination of cisplatin and S1 with a control arm of CF. In terms of efficacy, the combination demonstrated its non-inferiority vs. the comparator, and it was more benefi-cial in terms of convenience and toxicity. For this reason, the European Medicines Agency (EMA) recently issued (December 2010) a positive opinion for its marketing in Europe for this indication. In this study, the S1 arm was more beneficial for the subgroup of patients with tumours of diffuse histology. Consequently, a new Phase III study is being initiated to compare cisplatin-S1 with CF, focusing on patients with this histological subtype. Other cytostatic agents. The combination of irinotecan/5FU/LV (FOLFIRI) can be an alternative for select patients [26]. There are sev-eral Phase II studies with various combinations that include paclitaxel or UFT with interesting results, although their true role should be established in Phase III studies.

Anti-HER2 therapies. HER2 is overexpressed in 13–25% of patients with GC and it can be associated to a worse prognosis [27]. This overexpression is more frequent in in-testinal tumours and those located in the EGJ [28].

In the Spanish Phase II clinical trial GASTROHER2 [29], there was a response rate of 32% and a disease con-trol rate of 64%, with good tolerability, in 22 patients with AGC HER2+ treated with cisplatin and trastuzumab, a monoclonal anti-HER2 antibody.

In the Phase III study TOGA [30], HER2 status was analysed in 3807 patients with advanced EGJ or gastric adenocarcinoma; 22% were HER2+ and 584 patients were randomised to receive CT alone (XP or CF) or with tras-tuzumab. In the trastuzumab group, a significant increase was noted in OS (primary endpoint) (HR 0.74; p=0.0048), PFS and response rate. No significant increase in toxicity due to CT was observed and there was no statistical sig-nificance in congestive heart failure symptoms. An analysis of the subgroups showed that the survival benefit appeared to be concentrated in patients with IHC 3+ or IHC 2+ and FISH+ (HR 0.65). Therefore, trastuzumab combined with XP or CF is now the gold standard treatment for advanced HER2+ disease (while adequate determination of HER2 is essential for the selection of patients).

With regard to other HER2 inhibitors, there are cur-rently Phase III studies ongoing to examine lapatinib as-sociated to CT in patients with AGC HER2+ as first-line (LOGIC) or second-line (TyTAN).

534 Clin Transl Oncol (2012) 14:528-535

Other new targeted drugs– Bevacizumab: In Phase III AVAGAST [31], 774 pa-

tients with GC or advanced EGJ were randomised to receive XP plus placebo vs. XP plus bevacizumab. The primary endpoint was OS and although a trend was noted in favour of bevacizumab, it did not reach statistical significance (HR 0.87, p=0.10).

– Anti-EGFR monoclonal antibodies: Two currently ongoing randomised studies will establish the value of adding CT to first-line cetuximab (EXPAND) or panitumumab (REAL-3). However, in a randomised Phase II study (MATRIX), adding matuzumab, an an-ti-EGFR humanised monoclonal antibody, to ECX did not increase the response rate or survival, therefore it will not be further evaluated in Phase III studies [32].

– Other targets: In patients with refractory GC, there are ongoing Phase III studies with everolimus (GRANyTE-1) and with ramucirumab (anti-VEGFR monoclonal antibody). Tyrosine kinase inhibitors are also being assessed, such as sunitinib, sorafenib, tela-tinib, gefitinib and erlotinib, and monoclonal antibod-ies such as nimotuzumab, catumaxomab and AMG 102, AMG 386, etc. The identification of response and/or toxicity predictive biomarkers would be highly desirable to allow for a better selection of patients in order to be able to provide more personalised therapy.

Second-lineThere are some Phase II studies that suggest second-line activity when a first line with CF fails, with irinotecan or docetaxel or oxaliplatin, and this type of treatment should be considered for selected patients depending on the treat-ment previously received. A Phase III study that compared irinotecan to BSC in this setting has also been recently communicated and, although it included only 40 patients, it showed increased survival (median: 4.1 vs. 2.4 months, HR 2.85; p=0.002) in favour of the irinotecan arm [33].

Treatment recommendations for advanced disease CT should be considered for all patients with advanced gastric carcinoma and good overall condition, as it pro-longs patient survival and improves quality of life [I, A]. There is no single regime at present that could be univer-sally considered the gold standard.

Adequate therapeutic regimes are those that combine a platinum agent (cisplatin or oxaliplatin) with a fluoropy-rimidine (5FU, capecitabine or S1). Other options are the triplets adding epirubicin or docetaxel to the above combi-nation [I, A]. Combining FU with irinotecan has a similar efficacy to combining it with cisplatin, therefore it may al-so be considered a valid therapeutic alternative in this con-text [I, A]. Choosing a therapeutic regime shall depend on a set of factors, including the patient’s functional status and comorbidity, the toxicity profile of the drugs to be used, the treatment objective (induce a response in potentially resec-table or highly symptomatic locally advanced tumours vs. prolong survival of an asymptomatic patient) and also the experience of the responsible medical team.

Finally, in patients with HER2+ tumours, trastuzumab should be added to the combination of cisplatin and fluoro-pyrimidines (capecitabine or 5FU) [I, A].

Follow-up

There is no evidence that regular intensive follow-up im-proves patient survival [4, 5]. Therefore, follow-up based on symptoms is considered adequate in most cases. In this regard, we recommend anamnesis and physical ex-amination every 3–6 months in the first three years fol-lowing surgical intervention and then every 6–12 months during years 4 and 5 [IV, B]. The benefit of following-up patients beyond year 5 is debatable. Conducting ad-ditional tests (CAT, gastroscopy, …) would only be indicated as per clinical suspicions. Patients should be monitored for any possible iron and/or vitamin B12 de-ficiencies and treated accordingly, if necessary [http://www.nccn.org].

Conflict of interest Fernando Rivera served on the advisory board and received travel and research Grants from Roche.

Clinical Guideline Working Group on behalf of the Spanish Society of Medical Oncology (SEOM) Executive Committee 2011-2013: Juan Jesús Cruz, Pilar Garrido, Agustí Barnadas, Pablo Borrega, Francisco Javier Barón, Elvira del Barco, Rocío García-Carbonero, Jesús García-Mata, Encarnación González, Pilar Lianes, Antonio Llombart and Fernando Rivera.

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