The role of systemic therapy for localised gastric cancer

educational session New directions in the systemic treatment of GI cancer Chair

Andrés Cervantes Hospital Clinic University, University of Valencia, Department of Hematology/Medical Oncology, Valencia, Spain

Co-Chair

Nuri Aykan Institute of Oncology, University of Istanbul, Department of Medical Oncology, Istanbul, Turkey

the role of systemic therapy for localized gastric cancer David Cunningham The Royal Marsden Hospital, Section of Medicine, Sutton, United Kingdom

the integration of targeted agents into systemic therapy of advanced colon cancer Dirk Arnold University of Halle, Department of Hematology and Oncology, Halle/Saar, Germany

a multimodality approach to localized rectal cancer Andrés Cervantes Hospital Clinic University, University of Valencia, Department of Hematology/Medical Oncology, Valencia, Spain

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Speakers

Annals of Oncology 17 (Supplement 10): x115–x121, 2006 doi:10.1093/annonc/mdl248

The role of systemic therapy for localised gastric cancer N. Starling1 & D. Cunningham2 1

Royal Marsden Hospital; 2Gastrointestinal and Lymphoma Units, Royal Marsden Hospital, Sutton, Surrey, UK

introduction

adjuvant systemic therapy Adjuvant systemic therapy aims to treat occult residual micro-metastatic disease post-resection and has proved to be a successful strategy resulting in improved survival in several tumour types including colorectal cancer. However, the use of adjuvant chemotherapy alone in gastric cancers has been disappointing. Several negative randomised phase III studies have reported utilising a number of the older chemotherapy regimens ranging from mitomycin C based combinations, 5-fluorouracil(5-FU)/anthracycline-based combinations, the 5-FU/cisplatin regimen and other 5-FU-based regimens [5, 6]. Only a handful of studies have indicated a prolonged survival for adjuvant chemotherapy compared to a control arm in comparison to the multitude of negative studies [5, 6]. However, given the small numbers of patients in these studies, conflicting results between studies and the evaluation of suboptimal chemotherapy regimens by today’s standards, it has been difficult to provide a consensus opinion on the issue of adjuvant systemic chemotherapy. Notably, recruitment to these studies has often been problematic and is a reflection, in part, of the physical demands of gastro-oesophageal surgery and the subsequent potentially difficult recovery. Several meta-analyses have been undertaken to address the issue of adjuvant chemotherapy for gastric cancer and have each ª 2006 European Society for Medical Oncology

neoadjuvant therapy

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Gastric cancer represents a major cause of cancer-related morbidity and mortality. Worldwide, it represents the second most commonly diagnosed cancer and is responsible for 12.1% of all cancer-related deaths [1]. Surgical resection remains the definitive treatment for early stage (T1 and T2) gastric cancer with 5-year survival rates between 70–95% [2, 3]. However, localised tumours that extend beyond the submucoa are associated with worse outcomes and a 5-year survival around 20–30% [4]. In this latter group the rate of relapse following resection of gastric cancer is high and this is largely due to occult micro-metastatic disease and to residual tumour in the resection bed. Strategies have been developed directed at eliminating both of these thereby aiming to reduce the risk of relapse and to improve survival following resection of localised gastric cancer. A number of approaches utilising a systemic approach to resectable cancer have been evaluated and are the focus of this review.

indicated a small survival benefit in favour of adjuvant chemotherapy. A combined analysis of the odds ratios (OR) from 11 studies performed between 1980 and 1991 comparing adjuvant chemotherapy with surgery alone found a small survival benefit [OR 0.88; 95% confidence interval (CI) 0.78 to 1.08] [7]. Earle et al. reported a meta-analysis of 13 randomised controlled trials in Western countries including 1990 patients also indicating a survival benefit for adjuvant therapy over surgery alone (OR = 0.80; 95% CI 0.66 to 0.97) and Mari et al. reported an 18% reduction in the risk of death following an analysis of the hazard ratios from 20 randomised studies involving 3658 patients (OR = 0.82; 95% CI 0.75 to 0.89; P < 0.001) [8, 9]. Another meta-analysis of 21 randomised studies of adjuvant therapy also reported a small survival benefit for adjuvant chemotherapy (OR = 0.84; 95% CI 0.74 to 0.96) but on subset-analysis the survival benefit only applied to studies performed in Asia and not Western countries [10]. However, heterogeneity between these meta-analyses in terms of methodological approaches, literature-based review as opposed to pooling of individual patient data and assessment of different older chemotherapy regimens make conclusive recommendations difficult. Based on this and the negative phase III reports, adjuvant systemic chemotherapy alone has not been adopted as a standard approach to localised gastric cancer.

The rationale for administering systemic chemotherapy prior to surgery for localised gastric cancer is based on several considerations. Firstly, there is the possibility of downstaging the primary tumour, which may facilitate an R0 resection, that is, surgery with no evidence of gross or microscopic residual tumour with R1 denoting microscopic residual tumour and R2 indicating macroscopic residual disease. Secondly, the early use of systemic therapy may begin to treat and potentially eliminate occult micro-metastatic disease at an earlier time point than any planned adjuvant therapy. Both of these effects could clearly impact upon and improve disease-free and overall survival in this disease. Other possible benefits include the rapid resolution of tumour-associated symptoms such as dysphagia, cachexia and pain in advance of major surgery and the demonstration of in-vivo cytotoxicity of the neoadjuvant chemotherapeutic agents, which would reinforce their use as part of an adjuvant strategy. In addition, recovery from surgery can be protracted

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Gastric, gastroesophageal junctional and lower oesophageal adenocarcinoma

S

CSC

Within 6 weeks

ECF 3 cycles 3 weekly

Resection

3 to 6 week break Resection 6 to 12 week break

ECF 3 cycles 3 weekly Follow-Up Abbreviations: CSC = Peri-operative therapy with neoadjuvant and adjuvant systemic chemotherapy S = Surgery Alone ECF = Epirubicin, Cisplatin, 5-Fluorouracil

Figure 1. The Medical Research Council (MRC) MAGIC randomised phase III trial schema.

combination. However, a recent Cochrane meta-analysis supported the addition of an anthracycline to CF in the advanced disease setting [20]. In the MAGIC trial 503 patients were randomised with 253 patients in the surgery alone arm and 250 in the peri-operative chemotherapy arm. Initially, only patients with gastric cancer were enrolled but the protocol was later amended to include gastroesophageal junctional and lower oesophageal tumours. In the chemotherapy arm 86% of patients completed neoadjuvant chemotherapy and 88% proceeded to surgery compared to 95% in the surgery alone arm. Pathological assessment of the resected specimens between the two groups showed significantly smaller tumours (3.0 versus 5.0 cm P < 0.001), lower T stage (P = 0.01) and lower N stage (P = 0.01) in the chemotherapy versus the surgery alone group suggesting effective tumour downstaging. Importantly peri-operative morbidity and mortality were not increased in the chemotherapy group with post-operative death and complication rates of 6% and 46% respectively in both groups. The proportion of patients commencing post-operative chemotherapy was 55% which is similar to that observed in the US Intergroup 113 study of perioperative chemotherapy for oesophageal cancer with the main reasons for failing to start treatment being early progression of disease or early death. With a median follow-up of at least 3 years, the median overall survival with chemotherapy was 24 months versus 20 months for the surgery alone arm (Overall survival: hazard ratio [HR], 0.75; 96% CI 0.60–0.93; P = 0.009) and 5-year survival rates were 36% and 23%, respectively. Peri-operative chemotherapy also significantly improved progression-free survival (HR, 0.66; 96% CI, 0.53–0.81;

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such that not all patients are suitable for adjuvant therapy thereby missing the opportunity for systemic treatment of potential micro-metastatic disease or even for local therapies such as chemoradiation. Potential drawbacks of a neoadjuvant approach include delaying the definitive treatment and the risk of disease progression therein and the potential for increased surgery-related morbidity secondary to chemotherapy-related toxicity. In the former scenario, progressive disease in this period is likely to indicate aggressive tumour biology and that the chances of failure with early relapse are likely to have been high even if primary radical treatment had been undertaken. Furthermore, accurate pathological tumour staging is difficult to determine after pre-operative therapy and this may confound the assessment of adequate surgical margins and lymph node dissection. Initial phase II studies of neoadjuvant therapy for localised gastric cancers confirmed the feasibility and safety of this approach with no apparent increase in surgical morbidity or mortality and R0 resection rates of 72 to 78% [11–13]. In a randomised trial of the Dutch Gastric Cancer Group, patients were allocated to surgery alone (n = 30) or treatment with four cycles of pre-operative 5FU, doxorubicin and methotrexate (FAMTX, n = 29) [14, 15]. The trial closed early due to poor accrual with a total of 59 patients. In the surgery alone group 62% of patients had R0 resections versus 56% of patients in the neo-adjuvant chemotherapy group. While this trial is statistically underpowered to detect significant differences in efficacy parameters, it is notable that in the chemotherapy arm 17/27 patients did not achieve tumour downstaging and this is likely to reflect the poor activity of this chemotherapy regimen in gastric cancers. The final results of the UK Medical Research Council MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) phase III randomised trial of 503 patients were presented at the 2005 American Clinical Oncology Annual Meeting. These indicated that compared to surgery alone, the use of systemic perioperative treatment using both a neoadjuvant and adjuvant strategy, improves survival for patients with resectable gastric cancers as well as for gastroesophageal junctional and lower oesophageal adenocarcinomas [16]. In this trial patients were randomised to treatment with three cycles of the ECF regimen (epirubicin 50 mg/m2 day 1, cisplatin 60 mg/m2 d1 and 5-FU by continuous protracted venous infusion 200 mg/m2/day every three weeks) pre-operatively followed by three cycles of ECF post-operatively or to surgery alone (Figure 1). An interval of 4–6 weeks following neoadjuvant chemotherapy was mandated and adjuvant therapy had to commence within three months of surgery. The surgical procedure employed was at the discretion of the operating surgeon but in practice most patients had lymph node dissections similar to the D2 extent. The rationale for the choice of ECF as the preferred chemotherapy regimen was based on its activity in the advanced disease setting where it is a reference regimen in the UK and other parts of Europe; in two randomised trials ECF was shown to consistently result in response rates in the region of 40% and proved to be superior to FAMTX in the first trial and equivalent to MCF but with significantly better global quality of life scores in the second [17–19]. Criticism has been raised with regard to the relative contribution of epirubicin to the cisplatin/5-FU (CF)

Annals of Oncology

Curatively Resected Gastric or Gastroesophageal Junctional Adenocarcinoma

5-FU/LV

ECF

5-FU RT

5-FU RT

5-FU/LV

ECF

Abbreviations: ECF = Epirubicin, Cisplatin and Capecitabine 5-FU/LV = 5-Fluorouracil/ Leucovorin RT = Radiotherapy

Figure 2. Schema for the CALGB 80101 Intergroup Study.

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around designing a trial in which neoadjuvant chemotherapy is added to adjuvant chemoradiation, such a study design would prove difficult in the US where the pattern of referral is postsurgical. Other investigational possibilities include the incorporation of newer cytotoxic agents or targeted therapies such as bevacizumab, which will be discussed later.

potential for new cytotoxics A number of newer cytotoxics are now available which may be more active than previously evaluated agents in the treatment of gastric cancer and which are already under investigation in the advanced disease setting. These include oxaliplatin, a third generation platinum compound, irinotecan, a topoisomerase inhibitor, taxanes including docetaxel and capecitabine, the oral pro-drug for 5-FU. The usual convention has been to select agents or cytotoxic regimens that appear to be most active in the advanced disease setting for evaluation in the neoadjuvant/ adjuvant arena. On this basis a few key studies in the advanced disease setting are likely to inform future phase III trials of systemic therapy for localised gastric cancer. The recently reported UK National Cancer Research Institute (NCRI) REAL-2 phase III study evaluated the substitution of capecitabine for 5-FU and oxaliplatin for cisplatin in the ECF regimen [24]. The use of capecitabine (X) avoids the potential morbidity associated with protracted venous infusion 5-FU associated central venous catheters and offers the potential for increased patient convenience. Oxaliplatin (O) is a newer generation platinum with a different toxicity profile to cisplatin. 1002 patients with gastro-oesophageal cancer were randomised between four arms; the reference ECF, ECX, EOF and EOX. Capecitabine was shown to be non-inferior to 5-FU (HR 0.86 95% CI 0.8, 0.99) and oxaliplatin was shown to be non-inferior to cisplatin (HR 0.92 95% CI 0.8, 1.1) for the primary endpoint of one year survival in the per-protocol two by two factorial comparison. In the individual arm comparisons in the intentto-treat populations median and one year survivals were highest for EOX (46.8% and 11.2 months) compared to a one year and median survival for ECF of 37.7% and 9.9 months respectively (p=0.02). Response rates were 40.7%, 46.4%, 42.4% and 47.9% for ECF, ECX, EOF and EOX respectively. Capecitabine and oxaliplatin therefore offer alternatives to 5-FU and cisplatin in the treatment of oesophago-gastric cancers and the former has been incorporated into new studies of systemic therapy for localised gastric cancer. Several phase II studies have indicated encouraging response rates for irinotecan in combination regimens [25–26]. However, in a phase III study of 337 patients with advanced gastric cancer irinotecan in combination with bolus 5-FU and infused 5-FU over 22 hrs (IF) did not result in statistically significant improvement in time to progression (the primary endpoint) or overall survival compared to CF [27]. Nonetheless, small studies evaluating irinotecan-based neoadjuvant therapy are currently underway. Final results of the TAX325 randomised phase III study were recently reported and confirm activity for docetaxel in gastric cancer [28]. 427 patients with advanced gastric cancer were randomised between treatment with the standard arm CF (cisplatin 100 mg/m2 on day 1 and 5-FU 1000 mg/m2/days

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P = 0.0001). The magnitude of these benefits is similar to that observed for the use of systemic neoadjuvant cisplatin/5-FU in the MRC OE02 trial in resectable oesophageal cancer [21]. The MAGIC trial represents the first study to demonstrate a survival advantage for a peri-operative systemic approach to the treatment of localised gastric cancer. The other established approach in this disease is the use of postoperative chemoradiation considered the standard of care in the United States based on the results of the pivotal Intergroup INT-0116 trial [22]. In this study, the use of adjuvant chemoradiation compared to surgery alone resulted in an improvement in median overall survival (35 versus 26 months, HR 1.31; 95% CI 1.08–1.61; P = 0.006) and disease-free survival (30 versus 19 months, HR 1.52; 95% CI 1.25–1.85; P < 0.001) with a median follow-up of 6 years [22, 23]. There are now, therefore, two possible treatment strategies for localised gastric cancer raising the obvious question of which is the preferred option? Caution should be exercised in attempting a cross-trial comparison primarily as patients entered these two trials at very different points in their diagnostic/treatment journey; in MAGIC patients were identified at the point of diagnosis and operability/treatment plans formulated within multidisciplinary meetings whereas in INT-0116 patients were identified post-operatively. The latter therefore represents a highly selected group of patients and this is likely, in part, to account for the higher median overall survival seen in this study. Additionally, differences in patient eligibility and study design also confound comparison. It appears unlikely that a head to head comparison of perioperative chemotherapy versus post-operative chemoradiation will ever be undertaken. Instead current trials are underway or in evolution aiming to build upon each strategy. An ongoing Intergroup study, CALGB 80101, is adding a post-operative systemic chemotherapy component using ECF to adjuvant chemoradiation (Figure 2). Although discussion has occurred

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future directions Important progress has been made in the treatment of localised gastric cancers but rates of cure are still poor when compared to other tumour types. As the limitations of what can be achieved with manipulations of cytotoxic combinations, dosing and schedules are reached, there appears a clear need to develop alternative/additional strategies to improve outcomes for patients with localised gastric cancer. Here, the expanding field of molecular oncology in gastrointestinal malignancies is likely to play a crucial role. As further molecular mechanisms governing carcinogenesis and tumour progression are elucidated, novel molecular targets and predictive/prognostic markers are emerging. In colorectal cancer both the epidermal growth factor receptor (EGFR) axis and vascular endothelial growth factor (VEGF) receptor signalling pathways have been successfully therapeutically exploited with the use of the monoclonal antibodies cetuximab/panitumumab and bevacizumab respectively. Although at a molecular level issues around target characterisation, validation and mechanism of action of these drugs present challenges, these so-called targeted biologic therapies have demonstrated clinical efficacy in various tumour types and are under assessment in the adjuvant and neo-adjuvant settings.

incorporating biologic targeted therapies in gastric cancer The development of biologic targeted therapies in gastric and oesophageal cancer has been slower than in other gastrointestinal malignancies and is so far limited to early phase studies in the advanced disease setting. Both matuzumab (EMD 72000) a humanised monoclonal antibody against EGFR and

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bevacizumab, directed against VEGF, are in phase II clinical evaluation in gastric cancers. The EGFR is an attractive molecular target in gastric cancers; EGFR is highly expressed in gastric tumours, the EGFR gene is amplified in a small proportion of intestinal type gastric cancers and its expression is associated with poor prognosis [29–31]. Matuzumab is a high-affinity humanised monoclonal antibody against EGFR. In phase I evaluation it was shown to have a prolonged half life with some responses seen in patients with gastric cancer [32, 33]. A subsequent phase I study of varying dose levels of matuzumab in combination with the epirubicin, cisplatin, capecitabine (ECX) regimen in patients with gastric and lower oesophageal adenocarcinomas indicated feasibility and safety of the combination [34]. Responses were seen in all dose cohorts and the maximum tolerated dose had not been reached. A European randomised study of ECX plus or minus matuzumab in patients with gastric and lower oesophageal adenocarcinoma is currently ongoing. A number of single arm phase II studies have addressed the potential activity of small molecule tyrosine kinase inhibitors such as gefitinib/erlotinib in patients with gastric cancer [35]. These have shown limited single-agent activity but it should be noted that the patient populations under investigation were mostly pre-treated and that one study suggested a possible differential therapeutic effect in gastroesophageal junctional compared to gastric adenocarcinomas [36]. At the present time it is too early to say whether suppression of the EGFR axis as part of a systemic or local therapeutic approach will be of utility in the adjuvant/ neoadjuvant setting for gastric cancer but as EGFR inhibitors continue their clinical development in gastric cancer; this question is likely to arise. Vascular endothelial growth factor (VEGF), a key mediator in tumour angiogenesis, and its receptor (VEGFR/KDR) are also overexpressed in gastric cancer and associated with tumour progression and prognosis [37–39]. Bevacizumab, a humanised monoclonal antibody against VEGF has so far only been evaluated in a phase II study in combination with irinotecan and cisplatin in patients with advanced gastric and gastroesophageal junctional cancers where an encouraging response rate of 65% was observed in 34 response-evaluable patients (95% CI 46 to 80%). The primary endpoint of median time to progression was 9 months (95% CI 5.7, 9.9 months) with an overall survival of 12.3 months (95% CI 11, 17 months) [40]. Possible bevacizumab-related grade 3/4 toxicities included hypertension (30%) GI hemorrhage (2%), gastrointestinal perforation (6%) and thromboembolism (30%). However, without a comparator arm it is difficult to determine the relative contribution of bevacizumab to the latter three events over and above the disease- and chemotherapy-background risk. For instance, the rate of thromboembolic events was similar in a phase II study by the same investigators of cisplatin plus irinotecan alone in a similar patient population. There are several theoretical advantages to the application of bevacizumab peri-operatively as an adjunct to systemic or localised therapy. As part of a neoadjuvant strategy, bevacizumab may improve response rates to concurrently administered cytotoxics through such potential mechanisms as tumour vasculature normalisation. Anti-vascular effects may also play a role [42]. It should be noted that in the advanced

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continuously on days 1 to 5) or to DCF (docetaxel 75 mg/m2 day 1, cisplatin 75 mg/m2 day 1 and 5-FU 750 mg/m2/day continuously on days 1 to 5). The primary endpoint of progression-free survival was significantly better for DCF compared to CF (5.6 months versus 3.7 months; HR 0.68, 95% CI 0.55–0.84; P = 0.0004) as was overall survival (9.2 months versus 8.6 months; HR 0.77, 95% CI 0.62–0.96; P = 0.02) and 2-year survivals were 18.4% and 8.8%, respectively. The overall response rate was also significantly better with DCF (36.7% versus 25.4%, P = 0.01). Notably, grade 3 and 4 toxicities were higher in the DCF arm compared to the CF arm, with at least one grade 3 or 4 toxicity experienced in 81.4% and 75.4% of patients respectively. Haematologic toxicity also appeared to be an issue with grade 3/4 neutropenia observed in 82.3% versus 56.8% of patients in the DCF and CF arms respectively with associated rates of febrile neutropenia of 30.0% and 13.5%. While docetaxel is clearly active in combination in gastric cancer, haematologic toxicity in particular may hinder the applicability of this regimen to the curative setting as part of a systemic approach. Of note an ongoing Swiss/Italian trial with a projected accrual of 240 patients is randomising patients with locally advanced operable gastric cancer to four cycles of either preoperative or postoperative DCF.

Annals of Oncology

selection of therapy based on predictive and prognostic factors Clinico-pathological characteristics have traditionally been correlated with patient outcome and factors such as TMN stage do currently determine selection of treatment in terms of operability and potentially on selection of systemic treatments such as neoadjuvant chemotherapy. However, differences in individual tumour behaviour and pharmacogenomics are also likely to influence outcome and response to systemic therapy. At the present time there are no validated prognostic or predictive

Adenocarcinoma of the stomach or gastroesophageal cancer

ECX 3 cycles 3 weekly

ECX + BV 3 cycles 3 weekly Resection

ECX 3 cycles 3 weekly

ECX + BV 3 cycles 3 weekly Bevacizumab x 6 cycles

Abbreviations: ECX = Epirubicin, Cisplatin, Capecitabine BV = Bevacizumab (Dose 7.5 mg/kg)

Figure 3. The intended study schema for the Medical Research Council (MRC) STO3 trial.

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markers, either molecular or imaging parameters, by which to select patients for systemic or local therapy for localised gastric cancer. Clearly such an approach is warranted given the poor prognosis of the disease and the potential for significant morbidity associated with radical approaches. Furthermore, as the paradigm shifts towards more personalised therapeutic approaches, prognostic and predictive markers for operable disease and for targeted therapies have taken centre stage. The former may help define good and bad prognosis groups and facilitate treatment stratification accordingly and the latter will help to rationalise resources and optimise development of these agents by enriching investigational populations with potential responders. A number of small, usually retrospective series, have reported on potential molecular prognostic/predictive markers in advanced and resectable gastric cancers. Possible candidate genes and/or their protein products include VEGFR and EGFR as discussed earlier, platelet derived growth factor A, ErbB2, p53 and cyclin D2 to name just a few [5]. The VEGF axis in particular has generated interest with several studies indicating correlation of survival and tumour stage with both serum and tumour expression of VEGF [38, 39, 44, 45]. The identification and development of a serum prognostic/predictive marker would be particularly appealing in terms of utility within the clinic. Recently, tumoral VEGF-D and VEGFR-3 which mediate lymphangiogenesis, were suggested as independent novel prognostic markers for patients with resectable gastric cancer [46]. This suggests, perhaps unsurprisingly, that the lymphangiogenic axis may also be important in predicting patients with a worse prognosis. In terms of predictive markers for resectable gastric cancers, the evidence is more limited. There are reports correlating p53 protein negative (by immunohistochemistry) gastric tumours with response to 5-FU/cisplatin-based neoadjuvant or mitomycin-C-based adjuvant systemic chemotherapy [47, 48]. Intact p53-dependent apoptosis modulates the cytotoxicity of several agents including cisplatin and 5-FU [49]. Inactivation of p53 through events such as gene mutation or deregulation can lead to disruption of this pathway, tumourigenesis, accumulation of mutant p53 protein and resistance to chemotherapy [50, 51]. However, conflicting reports also argue against any association between response to neoadjuvant cisplatin-based therapy and p53 mutation or protein expression status [52] or conversely that p53 mutation/overexpression correlates with improved response to neoadjuvant therapy [53]. Confounding factors such as heterogeneity of p53 mutations and the resultant functional consequences, the multitude of functions of p53, differences in mechanism of actions of the cytotoxic regimens used and the small numbers of patients in these studies may help to explain these differences. Thymidylate synthase (the target enzyme of 5-FU) overexpression appears to correlate with resistance to 5-FU-based chemotherapy [54] and ERCC1 expression (involved in nucleotide excision repair) is associated with chemoresistance in patients receiving 5-FU/platinum-based chemotherapy [55]. Whilst these studies are hypothesis driven the results do require prospective validation within clinical trials of systemic peri-operative therapy in gastric cancers to determine clinical utility as predictive markers. Currently, studies correlating gene polymorphisms (either tumour or germline) with outcomes to

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disease setting in combination with chemotherapy bevacizumab has tended to be associated with a 10% improvement in response rates. In the pivotal phase III trial in metastatic colorectal cancer of IFL (irinotecan and bolus 5-FU) versus IFL plus bevacizumab, while response rates were improved from 34.8% to 44.8% the larger increment in efficacy was for survival, which was improved from 15.6 to 20.3 months (HR 0.66, P = 0.001). The addition of bevacizumab to adjuvant systemic therapy is therefore also attractive and has the potential to abrogate the angiogenic switch in small volume micrometastatic disease [43]. The UK MRC MAGIC-B (ST03) randomised phase III trial due to launch this year is building on the systemic therapeutic approach employed in MAGIC and will randomise patients with resectable type III gastroesophageal junctional and gastric cancer to three cycles of ECX pre- and post-operatively plus or minus bevacizumab (Figure 3). Of note, the 5-FU used in the MAGIC schema has been substituted by capecitabine, its oral pro-drug, to avoid the need for indwelling central venous catheters and their associated potential complications and for patient convenience. Bevacizumab will be administered at a dose of 7.5 mg/kg every three weeks and an adequate interval has been incorporated between the last dose of bevacizumab and surgery to minimise the risk of wound healing and bleeding complications.

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conclusions Significant progress has been made in the treatment of localised gastric cancer through both systemic therapy as exemplified by the MAGIC trial and through localised approaches as demonstrated in the INT-0116 trial. Both should be considered standard treatment options for localised gastric cancer. However, even with these advances, the rates of relapse following resection remain high and survival is still depressingly low. Future applications of newer cytotoxics, targeted therapies and integration of molecular determinants of tumour behaviour, prognosis and response to therapy may ultimately help to improve on current standards and facilitate the delivery of more tailored therapeutic interventions. While progress in the treatment of gastric cancers has traditionally lagged behind that of other tumour types, the next few years are likely to witness exciting developments as several ongoing trials report and other innovative trials are launched.

references 1. Parkin DM, Pisani P, Ferlay J. Global Cancer Statistics. CA Cancer J Clin 1999; 49 (1): 33–64. 2. Sue-Ling HM, Johnston D, Martin IG et al. Gastric Cancer: a Curable Disease in Britain. BMJ 1993; 307 (6904): 591–596. 3. Sasako M, Sano T, Katai H et al. Radical Surgery. Sugimura, T. and Sasako, M. Gastric Cancer. Oxford University Press; 1997. pp. 223–248. 4. Siewert JR, Bottcher K, Roder JD et al. Prognostic Relevance of Systematic Lymph Node Dissection in Gastric Carcinoma. German Gastric Carcinoma Study Group. Br J Surg 1993; 80 (8): 1015–1018. 5. Catalano V, Labianca R, Beretta GD et al. Gastric Cancer. Crit Rev Oncol Hematol. 2005; 54 (3): 209–241. 6. Lim L, Michael M, Mann GB, Leong, T. Adjuvant Therapy in Gastric Cancer. J Clin Oncol 2005; 23 (25): 6220–6232.

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7. Hermans J, Bonenkamp JJ, Boon MC et al. Adjuvant Therapy After Curative Resection for Gastric Cancer: Meta-Analysis of Randomized Trials. J Clin Oncol 1993; 11 (8): 1441–1447. 8. Earle CC, Maroun JA. Adjuvant Chemotherapy After Curative Resection for Gastric Cancer in Non-Asian Patients: Revisiting a Meta-Analysis of Randomised Trials. Eur J Cancer 1999; 35 (7): 1059–1064. 9. Mari E, Floriani I, Tinazzi A et al. Efficacy of Adjuvant Chemotherapy After Curative Resection for Gastric Cancer: a Meta-Analysis of Published Randomised Trials. A Study of the GISCAD (Gruppo Italiano Per Lo Studio Dei Carcinomi Dell’Apparato Digerente). Ann Oncol 2000; 11 (7): 837–843. 10. Janunger KG, Hafstrom L, Glimelius B. Chemotherapy in Gastric Cancer: a Review and Updated Meta-Analysis. Eur J Surg 2002; 168 (11): 597–608. 11. Ajani JA, Ota DM, Jessup JM et al. Resectable gastric carcinoma. an evaluation of preoperative and postoperative chemotherapy. Cancer 1991; 68 (7): 1501–1506. 12. Ajani JA, Mayer RJ, Ota DM et al. Preoperative and Postoperative Combination Chemotherapy for Potentially Resectable Gastric Carcinoma. J Natl Cancer Inst 1993; 85 (22): 1839–1844. 13. Crookes P, Leichman CG, Leichman L et al. Systemic Chemotherapy for Gastric Carcinoma Followed by Postoperative Intraperitoneal Therapy: a Final Report. Cancer 1997; 79 (9): 1767–1775. 14. Hartgrink HH, van de Velde CJ, Putter H et al. H. Neo-Adjuvant Chemotherapy for Operable Gastric Cancer: Long Term Results of the Dutch Randomised FAMTX Trial. Eur J Surg Oncol 2004; 30 (6): 643–649. 15. Songun I, Keizer HJ, Hermans J et al. Chemotherapy for Operable Gastric Cancer: Results of the Dutch Randomised FAMTX Trial. The Dutch Gastric Cancer Group (DGCG). Eur J Cancer 1999; 35 (4): 558–562. 16. Cunningham D, Allum WH, Stenning SP et al. Perioperative chemotherapy in operable gastric and lower oesophageal cancer: final results of a randomised, controlled trial (the MAGIC trial, ISRCTN 93793971). Proc Am Soc Clin Oncol 23 (16S). 2005. Abstr. 4001. 17. Ross P, Nicolson M, Cunningham D et al. Prospective Randomized Trial Comparing Mitomycin, Cisplatin, and Protracted Venous-Infusion Fluorouracil (PVI 5-FU) With Epirubicin, Cisplatin, and PVI 5-FU in Advanced Esophagogastric Cancer. J Clin Oncol 2002; 20 (8): 1996–2004. 18. Waters JS, Norman A, Cunningham D et al. Long-Term Survival After Epirubicin, Cisplatin and Fluorouracil for Gastric Cancer: Results of a Randomized Trial. Br J Cancer 1999; 80 (1–2): 269–272. 19. Webb A, Cunningham D, Scarffe JH et al. Randomized Trial Comparing Epirubicin, Cisplatin, and Fluorouracil Versus Fluorouracil, Doxorubicin, and Methotrexate in Advanced Esophagogastric Cancer. J Clin Oncol 1997; 15 (1): 261–267. 20. Wagner AD, Grothe W, Behl S et al. Chemotherapy for Advanced Gastric Cancer. Cochrane Database Syst Rev 2005; (2): CD004064. 21. Medical Research Council Oesophageal Cancer Working Party. Surgical Resection With or Without Preoperative Chemotherapy in Oesophageal Cancer: a Randomised Controlled Trial. Lancet 2002; 359 (9319): 1727–1733. 22. Macdonald JS, Smalley SR, Benedetti J et al. Chemoradiotherapy After Surgery Compared With Surgery Alone for Adenocarcinoma of the Stomach or Gastroesophageal Junction. N Engl J Med 2001; 345 (10): 725–730. 23. Macdonald JS, Smalley S, Benedetti J et al. Postoperative combined radiation and chemotherapy improves disease-free survival (DFS) and overall survival (OS) in resected adenocarcinoma of the stomach and gastroesophageal junction: Update of the results of Intergroup Study INT-0116 (SWOG 9008). Proc Am Soc Clin Oncol 2004; 23: Abstr 6. 24. Cunningham D, Rao S, Starling N et al. Randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric (OG) cancer: The REAL 2 trial. Proc Am Soc Clin Oncol 24 (18S). 2006. Abstr. LBA4017. 25. Ajani JA, Baker J, Pisters PW et al. CPT-11 Plus Cisplatin in Patients With Advanced, Untreated Gastric or Gastroesophageal Junction Carcinoma: Results of a Phase II Study. Cancer 2002; 94 (3): 641–646. 26. Blanke CD, Haller DG, Benson AB et al. A Phase II Study of Irinotecan With 5-Fluorouracil and Leucovorin in Patients With Previously Untreated Gastric Adenocarcinoma. Ann Oncol 2001; 12 (11): 1575–1580.

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systemic therapy in gastric cancer are limited and this represents an area for further investigation. With the rapid evolution of high-throughput screening technologies such as microarray-based gene expression profiling and array-comparative genomic hybridisation, new opportunities have arisen to identify potential predictive and prognostic markers through a hypothesis-generating as opposed to a candidate gene-driven approach. A recent study of paired tumour and normal mucosal biopsies from 18 patients with gastric cancers undergoing resection and no systemic or local peri-operative therapy identified a gene expression profile predictive of survival [56]. A survival prediction model based on three genes was developed after validation with semi-quantitative reverse transcriptase polymerase chain reaction. This supports the feasibility of applying a high throughput genome-based approach to the potential identification of predictive/prognostic markers. Again, validation of results would be required in larger studies thereby employing a similar phase I to II to III approach utilised in drug development studies. Ongoing studies in gastro-oesophageal cancers are addressing this investigational avenue further and importantly in situations where peri-operative systemic therapies are used.

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41.

42. 43. 44.

45.

46.

47.

48.

49. 50.

51. 52.

53.

54.

55.

56.

patients with metastatic gastric or gastroesophageal (GEJ) adenocarcinoma (NCI #6447). Proc Am Soc Clin Oncol 24 (18S). 2006. Abstr 4020. Shah MA, Ilson D, Kelsen DP. Thromboembolic Events in Gastric Cancer: High Incidence in Patients Receiving Irinotecan- and Bevacizumab-Based Therapy. J Clin Oncol 2005; 23 (11): 2574–2576. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004; 25 (4): 581–611. Folkman J, Hanahan D. Switch to the Angiogenic Phenotype During Tumorigenesis. Princess Takamatsu Symp 1991; 22: 339–347. Karayiannakis AJ, Syrigos KN, Polychronidis A et al. Circulating VEGF Levels in the Serum of Gastric Cancer Patients: Correlation With Pathological Variables, Patient Survival, and Tumor Surgery. Ann Surg 2002; 236 (1): 37–42. Hyodo I, Doi T, Endo H et al. Clinical Significance of Plasma Vascular Endothelial Growth Factor in Gastrointestinal Cancer. Eur J Cancer 1998; 34 (13): 2041–2045. Juttner S, Wissmann C, Jons T et al. Vascular Endothelial Growth Factor-D and Its Receptor VEGFR-3: Two Novel Independent Prognostic Markers in Gastric Adenocarcinoma. J Clin Oncol 2006; 24 (2): 228–240. Cascinu S, Graziano F, Del Ferro E et al. Expression of P53 Protein and Resistance to Preoperative Chemotherapy in Locally Advanced Gastric Carcinoma. Cancer 1998; 83 (9): 1917–1922. Fondevila C, Metges JP, Fuster J et al. P53 and VEGF Expression Are Independent Predictors of Tumour Recurrence and Survival Following Curative Resection of Gastric Cancer. Br J Cancer 2004; 90 (1): 206–215. Lowe SW, Ruley HE, Jacks T, Housman DE. P53-Dependent Apoptosis Modulates the Cytotoxicity of Anticancer Agents. Cell 1993; 74 (6): 957–967. Bartek J, Bartkova J, Vojtesek B et al. Aberrant Expression of the P53 Oncoprotein Is a Common Feature of a Wide Spectrum of Human Malignancies. Oncogene 1991; 6 (9): 1699–1703. Levine AJ. P53, the Cellular Gatekeeper for Growth and Division. Cell 1997; 88 (3): 323–331. Ott K, Vogelsang H, Mueller J et al. Chromosomal Instability Rather Than P53 Mutation Is Associated With Response to Neoadjuvant Cisplatin-Based Chemotherapy in Gastric Carcinoma. Clin Cancer Res 2003; 9 (6): 2307–2315. Bataille F, Rummele P, Dietmaier W et al. Alterations in P53 Predict Response to Preoperative High Dose Chemotherapy in Patients With Gastric Cancer. Mol Pathol 2003; 56 (5): 286–292. Lenz HJ, Leichman CG, Danenberg KD et al. Thymidylate Synthase MRNA Level in Adenocarcinoma of the Stomach: a Predictor for Primary Tumor Response and Overall Survival. J Clin Oncol 1996; 14 (1): 176–182. Metzger R, Leichman CG, Danenberg KD et al. ERCC1 MRNA Levels Complement Thymidylate Synthase MRNA Levels in Predicting Response and Survival for Gastric Cancer Patients Receiving Combination Cisplatin and Fluorouracil Chemotherapy. J Clin Oncol 1998; 16 (1): 309–316. Chen CN, Lin JJ, Chen JJ et al. Gene Expression Profile Predicts Patient Survival of Gastric Cancer After Surgical Resection. J Clin Oncol 2005; 23 (29): 7286–7295.

Downloaded from http://annonc.oxfordjournals.org/ at New York University on April 28, 2015

27. Dank M, Zaluski J, Barone C et al. Randomized phase 3 trial of irinotecan (CPT11) + 5FU/folinic acid (FA) vs CDDP + 5FU in 1st-line advanced gastric cancer patients. Proc Am Soc Clin Oncol 23 (16S). 2005. Abstr. 4003. 28. Moiseyenko VM, Ajani JA, Tjulandin SA et al. Final results of a randomized controlled phase III trial (TAX 325) comparing docetaxel (T) combined with cisplatin (C) and 5-fluorouracil (F) to CF in patients (pts) with metastatic gastric adenocarcinoma (MGC). Proc Am Soc Clin Oncol 2005; 23 (16S): Abstr 4002. 29. Jonjic N, Kovac K, Krasevic M et al. Epidermal Growth Factor-Receptor Expression Correlates With Tumor Cell Proliferation and Prognosis in Gastric Cancer. Anticancer Res 1997; 17 (5B): 3883–3888. 30. Tokunaga A, Onda M, Okuda T et al. Clinical Significance of Epidermal Growth Factor (EGF), EGF Receptor, and C-ErbB-2 in Human Gastric Cancer. Cancer 1995; 75 (6 Suppl): 1418–1425. 31. Hirono Y, Tsugawa K, Fushida S et al. Amplification of Epidermal Growth Factor Receptor Gene and Its Relationship to Survival in Human Gastric Cancer. Oncology 1995; 52 (3): 182–188. 32. Vanhoefer U, Tewes M, Rojo F et al. Phase I Study of the Humanized Antiepidermal Growth Factor Receptor Monoclonal Antibody EMD72000 in Patients With Advanced Solid Tumors That Express the Epidermal Growth Factor Receptor. J Clin Oncol 2004; 22 (1): 175–184. 33. Tabernero J, Rojo F, Jimenez E et al. A phase I PK and serial tumor and skin pharmacodynamic (PD) study of weekly (q1w), every 2-week (q2w) or every 3-week (q3w) 1-hour (h) infusion EMD72000, a humanized monoclonal antiepidermal growth factor receptor (EGFR) antibody, in patients (pt) with advanced tumors. Proc Am Soc Clin Oncol 2003; 22: Abstr 770. 34. Rao S, Starling N, Benson M et al. Phase I study of the humanized epidermal growth factor receptor (EGFR) antibody EMD 72000 (matuzumab) in combination with ECX (epirubicin, cisplatin and capecitabine) as first line treatment for advanced oesophagogastric (OG) adenocarcinoma. Proc Am Soc Clin Oncol 2005; 23 (16S): Abstr 4028. 35. Tabernero J, Macarulla T, Ramos FJ, Baselga J. Novel Targeted Therapies in the Treatment of Gastric and Esophageal Cancer. Ann Oncol 2005; 16 (11): 1740–1748. 36. Dragovich T, McCoy S, Urba SG et al. SWOG 0127: Phase II Trial of Erlotinib in GEJ and Gastric Adenocarcinomas. Proc Gastrointestinal Am Soc Clin Oncol Symposium 2005; Abstr. 5. 37. Maeda K, Chung YS, Ogawa Y et al. Prognostic Value of Vascular Endothelial Growth Factor Expression in Gastric Carcinoma. Cancer 1996; 77 (5): 858–863. 38. Takahashi Y, Cleary KR, Mai M et al. Significance of Vessel Count and Vascular Endothelial Growth Factor and Its Receptor (KDR) in Intestinal-Type Gastric Cancer. Clin Cancer Res 1996; 2 (10): 1679–1684. 39. Tanigawa N, Amaya H, Matsumura M, Shimomatsuya T. Correlation Between Expression of Vascular Endothelial Growth Factor and Tumor Vascularity, and Patient Outcome in Human Gastric Carcinoma. J Clin Oncol 1997; 15 (2): 826–832. 40. Shah MA, Ramanathan RK, Ilson D et al. Final results of a multicenter phase II study of irinotecan (CPT), cisplatin (CIS), and bevacizumab (BEV) in

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