Although the incidence and mortality of gastric cancer has been steadily decreasing in Canadian men and women, this disease remains a global health problem, accounting for 10% of all new cancer cases and 12% of all cancer deaths worldwide (1). In Canada, the annual percent change in age-standardized incidence between 1996 and 2005 is -2.3% and -1.9% in males and females, respectively. The corresponding numbers for the change in agestandardized mortality between 1995 and 2004 is -3.6% and -3.1% for males and females, respectively (2). In Ontario in 2009, there will be an estimated 1090 new incident cases of stomach cancer (38% of new incident stomach cancer cases in Canada) and 670 deaths from stomach cancer (36% of stomach cancer deaths in Canada). The five-year relative survival ratio is 23% (95%CI: 21-24%) for males and females combined (2). However, the 5-year survival rate is much higher (about 75%) for patients with localized disease without regional lymph node involvement in whom the cancer is managed with surgery alone (3). Because the prognosis worsens with progressive lymph node involvement, there is interest in finding ways to improve the treatment results for this group of patients.
Although many clinical trials and meta-analyses have explored the value of neoadjuvant or adjuvant chemotherapy and radiation therapy in gastric cancer, these studies have produced conflicting results (4)(5)(6), making the role of neoadjuvant and adjuvant therapy controversial. Results of gastric cancer treatment have tended to be better for studies carried out in Asian countries, possibly because of etiologic or biologic differences in the disease or different practices such as screening for early stage cancer, the use of extended lymph node dissection, and the commencement of chemotherapy immediately after surgery.
This guideline is an update of Evidence-based Series (EBS) #2-14, which was originally developed in 2000 and then updated in 2003. The Gastrointestinal DSG believed that this further update was warranted, given the existence of new evidence published that could change the recommendations provided in the previous guideline.
The EBS guidelines developed by Cancer Care Ontario's Program in Evidence-Based Care (PEBC) use the methods of the Practice Guidelines Development Cycle (7). For this project, the core methodology used to develop the evidentiary base was the systematic review. Evidence was selected and reviewed by one member of the PEBC Gastrointestinal DSG and a methodologist.
The systematic review is a convenient and up-to-date source of the best available evidence on neoadjuvant or adjuvant therapy for resectable gastric cancer. The body of evidence in this review is primarily comprised of mature randomized controlled trial (RCT) data and meta-analyses of RCTs. That evidence forms the basis of the recommendations developed by the Gastrointestinal DSG.
The systematic review and companion recommendations are intended to promote evidence-based practice in Ontario, Canada. The PEBC is supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source.

# Literature Search Strategy
The MEDLINE (January 2002 to June week 3 2010), EMBASE (2002 to 2010 week 25), and Cochrane Library (February 2010), databases were systematically searched using revised literature search strategies (Appendix 1). In MEDLINE, the Medical Subject Heading (MeSH) "stomach neoplasms" and associated text words were combined with treatment-related terms, including the MeSH terms "chemotherapy, adjuvant," "radiotherapy, adjuvant," and "neoadjuvant therapy" and the text words "adjuvant," "neoadjuvant," "preoperative," and "postoperative." These terms were then combined with a search filter designed to identify randomized trials, systematic reviews, and meta-analyses adapted from a strategy developed by the Scottish Intercollegiate Guidelines Network (SIGN), available at www.sign.ac.uk. Modifications were made to the search terms, where appropriate, for use in EMBASE. The proceedings of the 2002 to 2010 American Society of Clinical Oncology (ASCO) and the 2002 to 2009 American Society for Therapeutic Radiology and Oncology (ASTRO) annual meetings were also searched for abstract reports of relevant studies. Reference lists of relevant reviews were searched for additional relevant reports.

# Study Selection Criteria
The study inclusion and exclusion criteria used in the original systematic review (Section 2B) were modified for the updated review. Articles were selected for inclusion if they:
- were published abstracts or fully published reports of RCTs comparing preoperative or postoperative chemotherapy and/or radiotherapy versus potentially curative surgery alone or another preoperative or postoperative therapy approach. Syntheses of RCTs in the form of systematic reviews or meta-analyses were also included.  were studies of adults with resectable gastric cancer. Trials of gastric cancer that also including patients with tumours of the gastroesophageal junction were included.  included reports of OS data.
Articles were excluded if they:
- were studies of immunotherapy, immunochemotherapy, intraperitoneal chemotherapy, or intra-arterial chemotherapy.  were published in a language other than English, due to unavailability of translation services.  were abstract reports of preliminary or interim data only.  were abstract reports of studies that were subsequently fully published.  reported results of RCTs or meta-analyses in the form of a letter or editorial.  included a majority of patients with esophageal tumours and did not report data separately for patients with gastric or GEJ tumours.

# Study Quality Appraisal
The quality of the systematic reviews and meta-analyses was assessed using the AMSTAR tool (8). Randomized trials were assessed for key methodological characteristics, using information provided in the trial reports. The following elements were assessed: generation of allocation sequence, allocation concealment, blinding, intention-to-treat analysis, withdrawals, loss to follow-up, funding source, statistical power calculations, length of follow-up, differences in baseline patient characteristics, and early termination.

# Synthesizing the Evidence
No data pooling was conducted in this review due to the availability of published meta-analyses comparing postoperative chemotherapy to surgery alone, postoperative CRT to either surgery alone or postoperative chemotherapy, and preoperative radiotherapy to surgery alone.

# Literature Search Results
The updated search of MEDLINE and EMBASE yielded 1129 articles, of which 149 were retrieved for full-text review following title and abstract screening (Appendix 2). One hundred nineteen of the 149 articles were subsequently excluded because they were either duplicate citations or did not meet the inclusion criteria. One further meta-analysis conducted in Japan and that only included oral fluoropyrimidine trials was also excluded (9). Thirty-three abstracts from the ASCO annual meeting proceedings and six abstracts from the ASTRO proceedings were retrieved for review; 14 initially met the inclusion criteria. However, five of these 14 abstracts were reports of RCTs or meta-analyses that were subsequently fully published and are not discussed further. Two were meta-analyses conducted in Japan and that only included studies of oral fluoropyrimidines are not discussed further (10,11). No additional relevant studies were identified in a search of the Cochrane Library. Overall, 22 RCTs (12-33), 13 meta-analyses (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46), and two secondary analyses that report survival data (47,48) are included in this systematic review. One article reported the results of two RCTs (17). Six systematic reviews without meta-analyses were identified, but none were included in this report as meta-analytic data was available. Table 1 provides a summary of the original evidence and new evidence used in this guidance document. 

# Randomized Controlled Trials
Postoperative Chemotherapy vs. Surgery alone vs. Other postoperative Chemotherapy 30   

# Postoperative Chemotherapy (a) Study/Trial Design and Quality
Five of the 17 RCTs identified were terminated early before reaching target accrual, four for poor accrual (16,17,19) (Nitti (17) reports on two trials) and one for early evidence of benefit after an unplanned interim analysis (26). An additional RCT was discontinued after evidence of benefit at a planned interim analysis, and the results were reported before the planned follow-up was completed (20). Target accrual was met for this trial. Randomization methods appeared adequate in most trials; however, some did not report allocation concealment. None of the trials reported that patients or healthcare providers were blinded to treatment allocation, although one trial reported blinded outcome adjudication (20) (Appendix 3).
The GASTRIC group (41) meta-analysis was an individual patient data (IPD) metaanalysis. Well-conducted IPD meta-analyses are superior to well-conducted published literature meta-analyses, and this meta-analysis scored well on the AMSTAR scale. It included most of the items deemed necessary for a well-conducted meta-analysis except a list of excluded studies, which few meta-analyses provide, and an assessment of the likelihood of publication bias (Appendix 4).

# (b) Outcomes
Seven published literature meta-analyses were identified that compared postoperative chemotherapy versus surgery alone for patients with resected gastric cancer (34)(35)(36)(37)(38)(39)(40). Study inclusion criteria, literature search periods, and statistical methods differed between the seven meta-analyses although the basic research question was the same. There was considerable overlap in the studies included in each of these meta-analyses (Appendix 5). These seven meta-analyses will not be discussed further, owing to the availability of a recent IPD meta-analysis (41). These authors identified 31 eligible trials from 1970-2009 and were able to obtain IPD from 17 of them. An examination of the eligible studies does not indicate any bias with respect to studies for which the authors were and were not able to obtain the IPD. These authors used a fixed-effects model and determined that there is a modest advantage for postoperative chemotherapy for OS (HR, 0.82; 95% CI, 0.76 to 0.90; p<0.001) based on 17 trials and for DFS (HR, 0.82; 95% CI, 0.75 to 0.90; p<0.001) based on 14 trials. No heterogeneity was detected for either outcome measure. The GASTRIC group (41) subsequently conducted a sensitivity analysis for OS using IPD where available (17 trials) and published summary statistics for the other studies, where available (11 trials). The results of the sensitivity analysis were consistent with the main analysis for OS (HR, 0.82; 95% CI, 0.77 to 0.88; p<0.001).
The GASTRIC group report (41) does not include information about adverse events. However, searching through the individual studies demonstrates that the most common grade 3 and 4 hematologic toxicities are leucopenia, thrombocytopenia, and neutropenia, depending on the chemotherapy regimen. The most common grade 3 and 4 non-hematologic toxicities, other than alopecia, are nausea and/or vomiting, diarrhea, mucositis, and stomatitis, depending on the chemotherapy regimen. Not all of the studies reported toxicity or graded the toxicity if they did report it; this was especially apparent in the older trials.
The updated literature search identified 11 trial reports, representing 12 RCTs that compared postoperative chemotherapy with surgery alone (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). All of these studies, except one very recently published trial (22), were part of the meta-analyses described above and will not be discussed further. Kulig et al. (22) compared postoperative chemotherapy (etoposide, adriamycin, and cisplatin) to surgery alone. They report no survival advantage in the chemotherapy arm. Grade 3 or 4 toxicities were reported in 22% of patients, with leucopenia being the most common toxicity reported (6%).
Five RCTs compared postoperative chemotherapy versus another postoperative chemotherapy regimen (23)(24)(25)(26)(27). Study characteristics and results are summarized in Tables 2  and 3 below. Three trials did not demonstrate a difference in OS, DFS, or local recurrence between treatment arms 1 : one compared FAM vs. FM vs. 5-FU (23); one compared PELF vs. 5-FU (25); and one compared MfP vs. Mf (27). A small trial comparing PELF vs. EtLF for completely resected advanced gastric cancer (clinical stage 3 or 4, M0) reported a significant benefit for PELF in OS and DFS (24). Another trial comparing FOLFIRI/docetaxel/cisplatin vs. MMC was stopped early for evidence of a DFS benefit favouring FOLFIRI/docetaxel/cisplatin at an unplanned interim analysis. Therefore, the results should be interpreted with caution (26). Other than alopecia, hematologic toxicities (leucopenia, thrombocytopenia, and neutropenia) and nausea and vomiting were the most often reported grade 3 and 4 toxicities, especially for regimens involving cisplatin, etoposide, or epirubicin.

# Postoperative Radiotherapy
No meta-analyses or RCTs solely comparing postoperative radiotherapy vs. surgery alone for resectable gastric cancer were identified in the updated literature search.   

# Postoperative Chemoradiotherapy (a) Study/Trial Design and Quality
The one RCT found was terminated early for poor accrual, before reaching its target (28). These authors did conduct an ITT analysis and had less than 1% loss to follow-up (Appendix 3). One published literature meta-analysis was identified (44) that included most of the items deemed necessary by AMSTAR for a well-conducted meta-analysis except a list of excluded studies and an assessment of the quality of the included studies (Appendix 4).

# (b) Outcomes
One Phase III RCT comparing postoperative CRT vs. postoperative chemotherapy was identified (28). Initially, the chemotherapy regimen consisted of docetaxel and cisplatin. However, the cisplatin was subsequently changed to carboplatin, owing to high rates of nausea and vomiting. The arms did not differ significantly with respect to median and 3-year OS or median and 3-year PFS. This was not surprising as the trial did not meet its accrual target and was, therefore, underpowered to detect a survival difference. The most common grade 3 and 4 toxicities reported, other than alopecia, were non-febrile neutropenia, febrile neutropenia, and diarrhea. However, the difference between the two arms was not statistically significant for any of these toxicities.
One meta-analysis of RCTs of postoperative CRT was identified (44). Five RCTs were included, three of which compared postoperative CRT vs. surgery alone, and two of which compared postoperative CRT vs. postoperative chemotherapy. Meta-analysis of the five trials indicated no significant benefit for postoperative chemoradiotherapy over control in 3-year mortality (OR, 0.79; 95% CI, 0.59 to 1.05; p=0.10); however, a meta-analysis of three trials that provided 5-year mortality data indicated a significant benefit for postoperative CRT over surgery (OR, 0.45; 95% CI, 0.32 to 0.64; p<.00001). No significant statistical heterogeneity between trials was reported. Fiorica et al. (44) report that 52% of patients did not complete the CRT protocol as planned. Grades 3 and 4 hematologic and gastrointestinal toxicities as well as mucositis were significantly greater in the CRT arms compared to controls in this meta-analysis.
Two secondary analyses of the SWOG/Intergroup trial (49) were identified that also reported updated survival data (47,48). The results from Hundahl (47) are consistent with earlier data reported in Section 2B of this report. Updated results indicated a median survival of 36 months for patients who received postoperative CRT (5-FU/leucovorin vs. 27 months for patients who underwent surgery alone (p=0.003). Relapse-free survival was 30 vs. 19 months (p<0.001), respectively. Further updates of the SWOG/Intergroup trial were presented at ASCO in 2009 (48). The abstract based on 10 years of follow-up demonstrated continued benefit for the chemoradiotherapy group for both survival (HR, 0.76; p=0.004) and DFS (HR, 0.66; p<0.001). The presentation of this abstract was based on 11 years of follow-up and demonstrated similar results for both OS (HR, 0.76; 95% CI, 0.63 to 0.92; p=0.005) and DFS (HR, 0.66; 95% CI, 0.55 to 0.80; p<0.001).
The original publication on the SWOG/Intergroup trial (49) reported that 33% and 54% of patients in the CRT arm had Grade 3 or higher hematologic and gastrointestinal toxicities, respectively.

# Preoperative or Perioperative Chemotherapy (a) Study/Trial Quality and Design
Two of the four RCTs identified were terminated early for poor accrual before reaching target (29,32). Neither of these trials reported whether their analyses were intention-to-treat (ITT). Both the Cunningham (30) and Boige (31) trials achieved their accrual targets, and both conducted ITT analyses. Only Hartgrink (29) reported on the loss to follow-up, which was 0% (Appendix 3).
Two published literature meta-analyses were identified comparing preoperative chemotherapy to surgery alone. Neither of these meta-analyses scored well on the AMSTAR instrument, likely owing to the fact that they were only available in abstract form (Appendix 4).

# (b) Outcomes
Two meta-analyses were identified that compared preoperative chemotherapy vs. surgery alone (42,43). Both of these meta-analyses were only available in abstract form, providing only a limited amount of methodological information, and for this reason will not be discussed further. No meta-analyses were identified that compared perioperative chemotherapy vs. surgery alone. Four RCT reports, comparing preoperative or perioperative chemotherapy vs. surgery alone, have been published since 2002 (29-32) (Table 4, Table 5). One of the reports (29) presents long-term results of the Dutch trial by Songun et al. (50) included in Section 2B of this report. This trial was stopped after accrual of 59 of a planned 450 patients, owing to the slow recruitment and poor interim results. No benefit for preoperative fluorouracil-doxorubicin-methotrexate (FAMTX) over surgery alone could be demonstrated. Another trial compared preoperative chemotherapy with folinic acid and cisplatin followed by surgery to surgery alone in patients with locally advanced adenocarcinoma of the stomach and cardia. This trial was stopped early owing to poor accrual. Only 144 of an expected 360 patients (40%) were accrued during more than four years of the study. No survival benefit for the addition of preoperative chemotherapy was demonstrated (32). The Federation Nationale des Centres de Lutte Contre le Cancer (FNLCC) ACCORD07 (31) trial of 224 patients comparing preoperative 5-FU/cisplatin vs. surgery alone in resectable gastric and lower esophageal cancer is available only in abstract form. A significant improvement in OS and DFS with preoperative 5-FU/cisplatin was reported (Table 5).
The MAGIC trial reported by Cunningham et al. in 2006 (30) is the largest trial incorporating preoperative therapy to date and the only randomized trial with a perioperative approach. A total of 503 patients were randomized to preoperative and postoperative ECF or surgery alone. Patients with adenocarcinoma of the stomach or lower third of the esophagus who had stage II or higher (M0) disease or locally advanced inoperable disease were included. It should be noted that only 68% of patients underwent curative surgery, while the remaining patients had palliative surgery, no surgery, or surgery of unknown intent. Of the patients assigned to perioperative ECF, 41.6% completed all six cycles of chemotherapy, and 49.5% of patients who completed preoperative ECF also completed postoperative therapy. A significant benefit for perioperative ECF was reported for OS and PFS (Table 5). Although results for patients with gastric and GEJ tumours were not reported separately from results for tumours of the lower esophagus, no heterogeneity of treatment effect according to disease site was demonstrated (interaction p=0.25).
Overall, preoperative and perioperative chemotherapy approaches resulted in greater hematologic toxicities as well as nausea and vomiting compared to surgery alone (Table 5).  

# Preoperative Radiotherapy (a) Study/Trial Quality and Design
One RCT was identified (33), but it provided very little information with respect to methodological quality (Appendix 3). Three meta-analyses were identified (44)(45)(46) 46) study scored poorly as it was only available in abstract form (Appendix 4).

# (b) Outcomes
Three published literature meta-analyses of trials comparing preoperative radiotherapy vs. surgery alone were identified in the updated literature search (44)(45)(46), as well as a full publication of a trial by Skoropad et al included in abstract form in the original systematic review (Section 2B) (33). The Skoropad trial ( 33) is included in the Fiorica et al. (44) meta-analysis and will not be discussed separately.
The meta-analysis by Fiorica et al. (44) included four RCTs of preoperative radiotherapy vs. surgery alone, one of which combined preoperative radiotherapy with local hyperthermia. Results indicated a significant survival benefit for preoperative radiotherapy at both three years (OR, 0.57; 95% CI, 0.43 to 0.76; p=0.0001) and five years (OR, 0.62; 95% CI, 0.46 to 0.84; p<0.00001), and no significant statistical heterogeneity between trials was demonstrated. All patients in the studies of this meta-analysis were able to complete the preoperative radiation without dose reductions.
The meta-analysis by Valentini et al. (45) included studies of preoperative, postoperative, and intraoperative radiation as well as radiation combined with chemotherapy all combined into one analysis. Because of this clinical heterogeneity, this meta-analysis will not be discussed further. The meta-analysis by Lu et al. (46) was only available in abstract form, and because only a limited amount of methodological information was provided, it will not be discussed further.

# Ongoing Trials
The NCI database of ongoing clinical trials (/) was searched on April 7, 2010. Twelve relevant phase III trials were identified and are described in Table 6. 
Many trials and meta-analyses of trials have investigated the value of neoadjuvant and adjuvant treatment in gastric cancer. These efforts have produced conflicting results. The Gastrointestinal DSG decided that an update of EBS #2-14, which was first developed in 2000 and updated in 2003, was justified, given the availability of new evidence that could change the recommendations made in the last version of this guidance document.

# Postoperative Chemotherapy
The IPD meta-analysis by the GASTRIC group (41) demonstrated that there is a modest but significant survival advantage for postoperative chemotherapy, based on the 17 trials for which they could get IPD. This conclusion was maintained when a sensitivity analysis, which added in summary statistics for another 11 trials, was carried out.

# Postoperative Radiation
No trials solely comparing postoperative radiation therapy to surgery alone were identified in the updated literature search.

# Preoperative Radiation
A published literature meta-analysis by Fiorica et al. (44) included four RCTs of preoperative radiotherapy vs. surgery alone, one of which combined preoperative radiotherapy with local hyperthermia. Results indicated a significant survival benefit for preoperative radiotherapy at both three years (OR, 0.57; 95% CI, 0.43 to 0.76; p=0.0001) and five years (OR, 0.62; 95% CI, 0.46 to 0.84; p<0.00001), and no significant statistical heterogeneity between trials was demonstrated.
A preoperative radiotherapy approach seems to provide a superior outcome with respect to 3-year and 5-year OS. However, this treatment has not been taken up in the North American oncology community. There are four main reasons for this. First, the evidence for preoperative radiation originated predominantly from China and Russia. The generalizability of the results to Canadian/North America practice cannot be assumed. There was significant heterogeneity in the way the preoperative therapy was delivered. The radiotherapy used in three of the four studies used large dose per fraction (20 Gy in 5 fractions) (51,52) although one study did employ a standard 2 Gy dose per fraction (40 Gy in 20 fractions) (53). Similarly, the target volume included for radiotherapy varied across the studies. These differences create challenges toward understanding how to implement these findings into practice. The magnitude of benefit as demonstrated through meta-analysis ( 44) is potentially smaller compared with a postoperative CRT approach (Number Needed to Treat  for RT =10 and for CRT = 6) (44). Finally, the high probability of both local and distant recurrence in gastric cancer has led to a preference towards strategies that incorporated both radiotherapy and chemotherapy.
The preference towards incorporating chemotherapy into adjuvant or neoadjuvant approaches is reflected by the fact that none of the clinical trials currently ongoing evaluate the use of preoperative radiation therapy alone, although the evaluation of preoperative CRT, perioperative chemotherapy, and postoperative CRT approaches continue to be actively pursued.

# Postoperative Chemoradiation
The meta-analysis by Fiorica et al. (44) of RCTs comparing postoperative chemoradiation to surgery alone did demonstrate a significant benefit with respect to 5-year mortality (OR, 0.45; 95% CI, 0.32 to 0.64; p<0.00001), although it is interesting to note that the results for 3-year mortality were not significant. This might be an indication that the 5-year results are spurious, though it is not possible to determine this. It should also be noted that one of the trials included in this meta-analysis is the Macdonald et al. (49) SWOG/Intergroup trial. Updated survival data from this specific trial was identified (47) and indicate superior median survival for patients receiving postoperative chemoradiation over surgery alone (36 vs. 27 months; p=0.003). Similarly, relapse-free survival was superior in the chemoradiation arm (30 vs. 19 months; p<0.001). A further update of SWOG/Intergroup trial demonstrates the robustness of these findings even after 11 years of follow-up for both OS (HR, 0.76; 95% CI, 0.63 to 0.92; p=0.005) and DFS (HR, 0.66; 95% CI, 0.55to 0.80; p<0.001) (48).
In the Macdonald et al. SWOG/Intergroup trial (49), the protocol recommended that a D2 (more extensive) lymph node dissection be performed, but as many of the referrals to the trial occurred postoperatively, this could not be mandated. Upon final analysis, only 10% of patients had a D2 lymph node dissection, 36% had a D1 lymph node dissection, and 54% had a D0 lymph node dissection (i.e., not all of the N1 nodes were removed). The lack of adequate lymph node dissection in over half of the SWOG/Intergroup patients has lead to criticism of the trial, with suggestions that the addition of adjuvant chemoradiation may be compensating for inadequate surgical resection (54,55). However, subsequent trials, in which a D2 lymph node dissection occurred in the majority of patients, have upheld a survival benefit for adjuvant chemoradiation in patients who underwent more aggressive surgery (56). Furthermore, the MAGIC (30) and the S-1 (20) trials had 68% and 100% of patients with a D2 resection, respectively, demonstrating a significant benefit to adjunct chemotherapy, even with cohorts of patients who have had a D2 lymph node dissection.

# Preoperative or Perioperative Chemotherapy
The MAGIC trial (30) was a large trial of over 500 patients comparing perioperative chemotherapy (ECF) to surgery alone. This trial demonstrated significant improvement in 5year OS (HR, 0.75; 95% CI, 0.60 to 0.93; p=0.009) and 5-year PFS (HR, 0.66; 95% CI, 0.53 to 0.81; p<0.001).

# Considerations for Choice of Therapy
The Macdonald et al. (47)(48)(49) and the Cunningham et al./MAGIC (30) trials have provided strong support for either a postoperative chemotherapy/radiotherapy approach to treatment or a perioperative approach, respectively. Summaries of these protocols are provided in Appendix 6.
The decision to initiate a perioperative chemotherapy approach vs. the postoperative chemoradiation approach should be based on a number of patient and tumour-specific factors and ideally be made preoperatively.
Diagnostic laparoscopy is reasonable to consider prior to initiation of perioperative chemotherapy to determine if there is peritoneal spread of metastatic disease not detected on CT imaging, as this assessment may be less accurate following the administration of chemotherapy. While down-staging is not considered an indication for the MAGIC protocol, a perioperative approach does allow for assessment of biologic response to systemic chemotherapy, which may be important in clinical decision-making for patients with bulky tumours, or radiologically positive lymph nodes. Patients who are undergoing a total gastrectomy, as opposed to a sub-total gastrectomy, may have difficulty with nutrition postoperatively especially when additional therapy is introduced as described in the SWOG/Intergroup clinical trials (49). A feeding tube should be considered for patients undergoing a total gastrectomy with plans for post-operative therapies if there are doubts that the patient will be able to complete postoperative treatment because of poor caloric intake. Some factors can be associated with increased or escalated risk of radiotherapy toxicities specifically. The anastomosis is typically included in the radiotherapy portal. For patients where the esophagogastric anastomosis or planned location is above the carina, the inclusion of this region that is required would predict for excessive lung and cardiac radiotherapy toxicities. The nodal regions and the blind loop post resection are frequently immediately adjacent to the kidneys. For patients with borderline renal function, radiation is expected to be associated with an increased risk of chronic renal impairment. In these patients, consideration for the Cunningham approach (30) using chemotherapy alone should be considered.
Similarly, there are factors that need to be made for the use of perioperative chemotherapy. The presence of cardiac or renal dysfunction would contraindicate the use of epirubicin and cisplatin, respectively.
During the combined modality treatment of radiation and chemotherapy used during the Macdonald (49) protocol, some centres used a low-dose continuous 5-FU infusion or alternatively used oral capecitabine as a radiosensitizer. This would seem to be reasonable from a biologic perspective and is considered acceptable.
Clearly, all patients would benefit from a multidisciplinary care assessment prior to surgery in order to determine the best plan of care for each individual patient. Clinicians must tailor the decision to recommend postoperative CRT according to a patient's nutritional and performance status. Unless obviously contraindicated owing to poor performance status, all patients undergoing gastric surgery with curative intent should be considered for adjuncts to resection.

# TECHNICAL CONSIDERATIONS FOR RADIATION THERAPY
Many technical issues for the provision of radiation therapy have been introduced to refine and enhance the quality of the radiotherapy plan. The target volume is in the upper abdomen targeting the tumour bed and regional nodes, 2 cm beyond the proximal and distal margin of resection.
The extent of regional node irradiation is further modified based on the location of the primary tumour: for example, for T3 lesions in the proximal stomach and the medial left hemidiaphragm was also included. The regional nodes were defined (based on the Japanese Research Society for Gastric Cancer) as perigastric, celiac, local para-aortic, splenic, hepatoduodenal or hepatic portal, and pancreaticodudenal. In addition, for GEJ tumours, the regional nodes included paracardial and para-esophageal lymph node beds but excluded the pancreatic duodenal and splenic nodal beds. The latter were also excluded in antral tumours. Guidelines for more specific tailoring of nodal regions based on tumour location as well as T and N stage are provided in Tepper and Gunderson (57) and a recent guideline for preoperative radiation treatments of the stomach published by the EORTC (58).
Strategies to incorporate internal organ motion into treatment planning allows for further individualization of treatment plans. Respiratory motion can be incorporated through the use of four-dimensional computerized tomography (4-D CT) (59), and gastric volume variation can be reduced through instructions for 'standardized meals' prior to treatment planning and each treatment (60). The use of renal perfusion scans allow for refinement of radiotherapy beam geometry based on risk and organ function.
The use of conformal radiotherapy has generally superseded the techniques described in the original MacDonald study. IMRT techniques may provide further incremental benefit with lower doses to normal structures being achieved, although the optimal way of adopting this continues to be investigated (61,62).
Permissible radiation dose limits for organs at risk (OAR) may affect the expected and observed long-term risks. More conservative parameters than described in the original Macdonald (49) study have been recommended (58) and adopted into clinical practice.
OS in patients with resectable gastric cancer is significantly improved with the use of either postoperative chemoradiation implementing the Macdonald protocol (47-49) or perioperative ECF implementing the MAGIC protocol (30). The choice of which option to utilize should be based on individual patient factors affecting their ability to tolerate either the radiation used in the Macdonald protocol or the epirubicin/cisplatin used in the MAGIC protocol.
If neither of these approaches is appropriate for a given patient, then postoperative chemotherapy is a reasonable alternative. All patients with resectable gastric cancer should undergo a multidisciplinary assessment to determine the best plan of care.

# CONFLICT OF INTEREST
GI DSG members involved in the development of the systematic review and clinical practice guideline were polled for potential conflicts of interest. All authors declared no conflicts of interest.

# JOURNAL REFERENCE
The following systematic review and practice guideline have been published in Gastric Cancer ( The International Gastric Cancer Association and The Japanese Gastric Cancer Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.