# Background
The recognized risks factors for gastric cancer include male gender, older age, chronic inflammation (e.g.: Helicobacter pylori infection, intestinal metaplasia, pernicious anemia), cigarette smoking, obesity, and certain hereditary conditions (e.g. familial adenomatous polyposis).
Prognosis depends upon the stage at diagnosis; that is, prognosis is better with less penetration of tumour into the stomach wall, fewer involved regional lymph nodes, and no evidence of metastatic disease.
A multidisciplinary team is required to define and provide the optimal care for a patient with gastric carcinoma. It should be composed of thoracic and general surgeons, gastroenterologists, and oncologists.
Early involvement of a dietician is recommended to complete a nutritional assessment and to optimize the patient's nutritional status.
This guideline was developed to outline the management recommendations for adult patients with gastric cancer. 
Guideline Questions

# Target Population
Adult (18 years of age) patients with a confirmed or suspected diagnosis of gastric cancer.

# Recommendations
Suggested Diagnostic Work-Up i. A complete endoscopic and radiologic evaluation is required to allow the multidisciplinary team to define the optimal management plan. ii. Esophagogastroduodenoscopy helps to distinguish between a gastric cancer that extends into esophagus and an esophageal cancer that extends into stomach. It also obtains a biopsy of the intraluminal mass to confirm the histologic diagnosis.
iii. CT scan of the thorax abdomen, and pelvis should be performed at baseline and should be repeated prior to surgery if patients receive neoadjuvant therapy. iv. For gastric cancer patients, a PET CT can be considered for locally advanced cancers (for example node positive). PET CT may have limited utility in mucinous or diffuse tumours and does not replace a laparoscopic assessment for peritoneal disease. 40 v. If no metastases are seen on baseline imaging, a laparoscopic evaluation for peritoneal metastasis should be considered prior to surgical resection. Laparoscopic evaluation can alter management in up to 44% of cases. 1 vi. Bone scans can be done for patients suspected of having bone metastases, CT head or MRI for patients suspected of having brain metastases. vii. For patients on palliative systemic treatment, CT chest, abdomen, pelvis should be done every 2-3 months. viii. Individualized discussion regarding imaging after definitive chemoRT or after surgical resection for non-metastatic patients. ix. Perioperative chemotherapy should be considered for curative intent cases. Surgical resection should be with oncologic principles. A minimum D1 resection by an experienced surgeon with a goal of 16 or more lymph nodes examined should be performed.
x. Mismatch repair (MMR) or microsatellite instability (MSI) testing should be considered for curative intent cases. Retrospective analyses, and an individual patient meta-analysis of 1156 patients from 4 randomized trials (MAGIC, CLASSIC, ARTIST, and ITACA-S), identified 121 (7.8%) patients that were MSI high. MSI-high patients had better 5 year DFS (71.8 vs 52.3%, HR 1.88, 95% CI 1.28-2.76, p<0.01) and OS (77.5 vs 59.3%, HR 1.78, 95% CI 1.17-2.73, p 0.008), and did not seem to benefit from chemotherapy with 5 year DFS 70 vs 77% HR, 1.27; 95% CI, 0.53 to 3.04), and the 5-year OS was 75% versus 83% (HR, 1.50; 95% CI, 0.55 to 4.12). 2 MMR status may influence decisions regarding adjuvant and neoadjuvant chemotherapy for gastric cancer. Currently, the preferred neoadjuvant regimen is FLOT. A retrospective review of 101 patients, including 5 MSI-H patients treated with FLOT, demonstrated a relatively poor histological response to neoadjuvant therapy but a significantly superior overall survival for MSI-H versus MSS tumors. 3 Given the limited data available using the FLOT regimen, the applicability of using MSI testing is less clear.
xi. Early involvement with a registered dietician, experienced with gastric cancer is recommended to support the unique nutritional needs of this patient population, particularly in the setting of surgery and/or significant >10% weight loss.

# Stage Information:

# Note:
Tumors involving the esophagogastric junction (EGJ) with the tumor epicenter no more than 2 cm into the proximal stomach are staged as esophageal rather than gastric cancers (refer to esophageal cancer guideline). In contrast, EGJ tumors with their epicenter located more than 2 cm into the proximal stomach are staged as stomach cancers. As described above N3a-3b As described above M0 Absent Stage IV Tany As described above N1-3 As described above M1 Present - A tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. In this case, the tumor is classified as T3. If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be classified as T4. The adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum. *Intramural extension to the duodenum or esophagus is not considered invasion of an adjacent structure, but is classified using the depth of the greatest invasion in any of these sites.

# Goals of Therapy
To render the patient free of disease, delay or prevent recurrence, and to improve or prolong survival. In patients that cannot be rendered disease free, prolong survival, palliate symptoms and maximize quality of life.

# Treatment Recommendations
Consider treatment on a clinical trial, if available.
See the Treatment Flow Chart found here:  Stage Ia i. Perform surgical resection with oncologic principles (minimum D1 resection by an experienced surgeon with a goal of 16 or more lymph nodes). ii. No adjuvant local or systemic therapy is indicated.
Stage Ib-IIIc i. Surgery should be performed with oncologic principles (minimum D1 resection by an experienced surgeon with a goal of 16 or more lymph nodes examined).
Peri-operative chemotherapy should be considered in patients with clinical T2 or node positive disease prior to surgical resection (see below).
Peri-Operative Chemotherapy: 11 Note: According to the CRITICS trial, in patients who have received pre-operative chemotherapy, there is no evidence to suggest that further intensification of post-operative treatment with chemoradiation has any benefit. 4 Preferred FLOT was shown to be superior to ECF/ECX in preliminary reports from the FLOT4-AIO phase III trial in terms of median overall survival (50 months vs. 35 months, HR:0.77, p=0.012), and progressionfree survival (30 months vs 18 months, HR:0.75, p=0.004), and should therefore be considered standard of care. 12  i. Prophylactic GCSF should be considered for patients undergoing FLOT, as grade 3/4 neutropenia occurs at a higher rate than ECF/ECX.

# Alternative Protocols (ECX/ECF/MAGIC): for patients not eligible for FLOT
i. When compared to surgery alone in patients with good performance status (ECOG 1) and T2-4N0-3M0 adenocarcinoma of the distal third of the esophagus, gastro-esophageal junction, or stomach, peri-operative chemotherapy improves the five-year progression-free (HR 0.66, CI95% 0.53-0.81, p < 0.001) and overall survival (from 23.0% to 36.3%, HR 0.74, CI95% 0.59-0.93, p = 0.008). 14  ii. Similarly, peri-operative Cisplatin + Fluorouracil the five-year disease-free survival (34% versus 19%, HR 0.65, CI95% 0.48-0.89, p = 0.003), overall survival (38% versus 24%, HR 0.69, CI95% 0.50-0.95, p = 0.02), and rate of curative resection (84% versus 73%, p = 0.04). 15 iii. These regimens require placement of a central venous catheter (CVC), peripherally inserted central catheter (PICC line), or port. iv. For patients who decline a central line, based on extrapolation from the ST03 trial, 16 ECX would be a reasonable option. Consideration should be made to substitute infusional 5-Fluorouracil for the capecitabine component in patients with impaired gastric acid production (eg. post gastrectomy, proton pump inhibitor)

# For patients not suitable for peri-operative chemotherapy:
In patients who have not had pre-operative chemotherapy, treatment options include adjuvant chemoradiation or chemotherapy. The decision between the two approaches benefits from multidisciplinary discussion.(see below).
Adjuvant Chemoradiation: 5 i.Leucovorin followed by 5-Fluororuacil combined with radiotherapy. 6  Improves five-year relapse-free survival from 22% to 40% (HR 1.51, CI95% 1.25-1.83, p < 0.001) and five-year overall survival from 26% to 40% (HR 1.32, CI95% 1.10-1.60, p = 0.0046) when compared with surgery alone. Stage IV (First Line) i. Palliative maneuvers to maintain and/or improve quality of life are indicated (e.g.: stent placement or radiotherapy to relieve dysphagia, pain, obstruction, or bleeding). ii. Palliative chemotherapy regimens 17,18 are generally continued as long as tumour shrinkage or stability is confirmed, as long as the side effects remain manageable, as long as the patient wishes to continue, and as long as the treatment remains medically reasonable. iii. Consider an early referral to palliative care . iv. In those patients with unresectable disease, consider early referral to dietician and psychosocial oncology. 45

# HER2 Normal: Preferred Oxaliplatin/fluoropyrimidine or FOLFIRI 
i. A network meta-analysis of systemic therapy for advanced gastric cancer demonstrated that anthracycline triplet chemotherapy and docetaxel, cisplatin, fluorouracil (5FU) triplets showed no benefit over fluoropyrimidine (FP: 5-fluorouracil (5FU) or capecitabine) doublets for overall survival (OS) or progression-free survival (PFS), and increased toxicity was noted. 19 ii. A fluoropyrimidine doublet containing oxaliplatin or irinotecan significantly improved overall survival compared with a fluoropyrimidine plus cisplatin (for a fluoropyrimidine plus irinotecan, the HR for death was 0.85, 95% CI 0.71-0.99; for a fluoropyrimidine plus oxaliplatin, the HR was 0.83, 95% CI 0.71-0.98). The cisplatin-fluoropyrimidine doublet was also associated with more grade 3 or 4 toxicity.

# FOLFOX/CAPOX
Four phase III trials have compared oxaliplatin to cisplatin based regimens (including ECF) suggesting similar efficacy. A meta-analysis of the REAL-2 trial and two randomized phase II trials - Nivolumab is Health Canada approved, but not funded in Alberta for this indication.
Subsequent lines of therapy comparing oxaliplatin to cisplatin based regimens demonstrated that oxaliplatin was associated with significant improvements in PFS (HR 0.88, 95% CI 0.80-0.98) and overall survival (HR for death 0.88, 95% CI 0.78-0.99), and with less neutropenia, anemia, alopecia, and thromboembolic events, but with more neurotoxicity and diarrhea.  FOLFIRI i. Suitable first or second line regimen for patients with an ECOG of 0-2: Irinotecan (180 mg/m2 IV over ninety minutes) and Leucovorin (400 mg/m2 IV over two hours) followed by 5-Fluorouracil (2400 mg/m2 as 46 hour infusion) every 2 weeks.
ii. FOLFIRI followed by ECX was compared to the reverse sequence in the first line setting of metastatic GE junction/gastric adenocarcinoma. 25 The dosing and duration of Capecitabine in the ECX arm (oral Capecitabine 1g/m2 twice per day from day 2 to day 15 every 3 weeks) was different than in the REAL-2 trial.
iii. FOLFIRI followed by ECX was superior to the reverse strategy for the primary endpoint of time to treatment failure (5.08 months versus 4.24 months, HR 0.77, CI95% 0.63-0.83, p = 0.008), however, OS (9.5 months versus 9.7 months; p=0.95) and PFS (5.3 months versus 5.8 months; p=0.96) were similar between the two sequences. iv. Patients who received first line ECX had higher rates of grade 3/4 toxicities, especially hematological ones.

# Nivolumab with FOLFOX/CAPOX CPS5
i. In the ATTRACTION-4 study 41 patients in Japan, Korea or Taiwan were randomized to nivolumab or placebo with chemotherapy (SOX or CapeOx). In this study with dual primary endpoints, the nivolumab + chemotherapy patients had improved progression free survival (median PFS 10.45 months versus 8.34 months with chemotherapy alone (HR: 0.68, 95%CI: 0.51-0.90, p<0.001).
However, there was no improvement in overall survival.
ii. The Checkmate 649 study 42 study was an international trial (including poppulations from Asia, North America and the rest of the world) which randomized patients to nivolumab with chemotherapy (Nivolumab + XELOX or Nivolumab + FOLFOX) or chemotherapy alone (XELOX or FOLFOX). This study demonstrated a statistically significant improvement in overall survival in patients with the addition of nivolumab in the PD-L1 CPS5 (median OS 14.4 months versus 11.1 months in the chemotherapy alone arm; HR: 0.71, 95%CI: 0.59-0.86, p<0.001). Furthermore, OS benefit was also seen in the secondary endpoints analyzing patients with PD-L1 CPS1 as well as in all randomized patients. Similarly, benefits were seen in PFS, overall responses and duration of response in the patients receiving nivolumab  .

# Pembrolizumab i.
In the phase III KEYNOTE-062 trial, 763 patients with previously untreated advanced gastric or GE junction adenocarcinoma patients with a CPS > 1 were randomized to pembrolizumab, chemotherapy (cisplatin plus a fluoropyrimidine) or combined therapy. Pembrolizumab was non-inferior to chemotherapy alone for overall survival. In an exploratory analysis of patients with a CPS > 10, there was a clinically meaningful improvement in median overall survival with pembrolizumab compared to chemotherapy alone (17.4 vs 10.8 months, HR 0.69, 95% CI 0.49-0.97). Pembrolizumab is not currently funded.
ii. At this time, the addition of pembrolizumab to chemotherapy has not demonstrated sufficient improvement in outcomes to justify the associated toxicities. 43 Palliative ii. Oxaliplatin is the preferred platinum as it reduces the risk of death (HR 0.88, CI95% 0.78-0.99, p = 0.04), progression (HR 0.88, CI95% 0.80-0.98, p = 0.02), and thromboembolism. 23,27 HER2 Positive: i. HER2 over-expression can be demonstrated in 16% of gastric cancers. The addition of Trastuzumab to Cisplatin plus either Capecitabine or 5-Fluorouracil was associated with a superior progression-free (6.7 months versus 5.5 months, HR 0.71, CI95% 0.59-0.85, p = 0.0002) and overall survival (13.8 months versus 11.1 months, HR 0.74, CI95% 0.60-0.91, p = 0.0046). 28 In a preplanned exploratory analysis, the subset of patients with high-level HER2 expression (immunohistochemistry scores (IHC) of 2+ with FISH positivity or IHC3+) achieved a median overall survival of 16.0 months.  In the updated survival analysis, the median overall survival for the addition of trastuzumab was 13.1 months as compared to 11.7 months for the chemotherapy alone arm (HR 0.80, CI95% 0.67-0.91). In the updated pre-planned analysis, only the patients in the IHC3+ subgroup showed a statistically significant survival benefit (18.0 months vs 13.2 months, HR 0.66 (CI95% 0.50-0.87)). 

# Contraindications to platinum/fluoropyrimidine or FOLFIRI
In patients who have a contraindication to a platinum/fluoropyrimidine combination, or FOLFIRI, the following regimen may be considered as an alternative but it does not have the same degree of survival benefit: a. ELF 29 Stage IV (Second Line) Combination Systemic Therapy: i. In patients with a preserved performance status, modest benefits have been achieved with secondline chemotherapy. For patients who are fit enough, combination systemic therapy should be considered. Options include: a. Paclitaxel + Ramucirumab 1. Compared to Paclitaxel alone, in patients with ECOG 0-1 the addition of Ramucirumab significantly improved overall survival (7.6 months versus 9.6 months, HR 0.807, CI95% 0.678-0.962, p = 0.017) 30  2. Similar time to deterioration in performance status was reported in the paclitaxel arm and the paclitaxel plus ramucirumab arm (p=0.0941) according to QLQ-C30 scales. EQ-5D scores were comparable between treatment arms, stable during treatment, and worsened at discontinuation. 25,31 b. FOLFIRI as above can be considered in the second line setting, after a fluoropyrimide/platinum combination. 25 It is unclear as to whether the addition of 5-fluouracil to irinotecan confers additional benefit and consideration can be single agent irinotecan (see below). c. A fluoropyrimidine/platinum combination such as FOLFOX or CAPOX can be considered in the second line setting after FOLFIRI. 25 While combinations like ECX, EOX, ECF or EOF have more direct evidence in this setting, it is reasonable to omit the anthracycline in the second line setting due to the added toxicities and lack of increased efficacy observed in the first line setting. 19,25  a. This improved overall survival when compared to best supportive care (5.2 versus 3.8 months, multivariable HR 0.774, CI95% 0.605-0.991, p = 0.042) with no difference in quality of life scores at 6 weeks. 36 Patients enrolled in the study had an ECOG 0-1 and Ramucirumab was also associated with a delay to median time to deterioration of performance status. Ramicirumab is not currently funded for single agent use. In patients with an ECOG 0-1 who had received 2 or more lines of systemic therapy, TAS-102 demonstrated an improvement in median overall survival to 5.7 months from 3.6 months, compared to placebo (HR 0.69, CI95% 0.56-0.85, p = 0.00029, two-sided p=0.00058). 37 c. Higher rates of grade 3 or higher were observed with TAS-102 in terms of neutropenia (n=114, 35=4%) and anemia (n=64, 19%), while with placebo abdominal pain (n=15, 9%) and general deterioration of physical health (n=15, 9%) were more common. No differences were seen in quality of life between patients treated with TAS-102 and placebo.  ii. Nivolumab  a. The ATTRACTION-2 44 study randomized patients with advanced gastric or GEJ cancer who were refractory or intolerant to two or more previous lines of chemotherapy and naive to PD-1 therapy or other pharmacotherapies for the regulation of T-cells to randomly receive nivolumab or placebo. Median overall survival was improved in the nivolumab group as compared to the placebo group (5.26 months versus 4.14 months, HR 0.63, 95%CI: 0.51-0.78, p<0.001). b. Nivolumab is not currently available on the Alberta CancerCare Drug Benefit List for this indication c. At this time, the Alberta GI Tumour Group does not support the routine use of nivolumab in this setting. At this point the clinical benefit may not outweigh the associated toxicities.

# Stage IV (Third or Greater

# Appendix A: Chemotherapy Regimens Regimen Description
Perioperative FLOT 4-cycles prior to surgery, with a further 4 cycles post-surgery. Each cycle lasts 14 days and consists of 5-FU 2600 mg/m2 (24 h) day 1 and leucovorin 200 mg/m2 (2h), day 1 and oxaliplatin 85 mg/m2 (2 h) day 1 and docetaxel 50 mg/m2 (1 h), every 2 weeks. Perioperative ECX/ECF/MAGIC 3-cycles prior to surgery, with a further 3 cycles post-surgery. three-week cycles of Epirubicin 50 mg/m2 and Cisplatin 60 mg/m2 IV on day one plus a continuous IV infusion of 5-Fluorouracil 200 mg/m2/day over twenty-one days. Perioperative Cisplatin + Fluorouracil Six four-week peri-operative cycles of Cisplatin 100 mg/m2 IV on day one plus 5-Fluorouracil 800 mg/m2/day over days one through five days Adjuvant Leucovorin + 5-Fluorouracil + RT Five four-week cycles where Leucovorin (20 mg/m2 IV) followed by 5-Fluorouracil (425 mg/m2 IV) is administered daily on the first five consecutive days of cycles one, four, and five. During cycles two and three, radiotherapy is administered on weekdays for twenty-five fractions (180 cGy per fraction). Leucovorin (20 mg/m2 IV) followed by 5-Fluorouracil (400 mg/m2 IV) is administered daily on the first four and last three days of radiotherapy (see grid below). Adjuvant Leucovorin + 5-Fluorouracil (de Gramont) Nine cycles of Leucovorin 100 mg/m2 IV over 2 hours on days 1-2 and 5-Fluorouracil 400 mg/m2 as bolus followed by daily 22 hour infusion of 600 mg/m2 every 14 days
Six cycles of the Capecitabine 1,000 mg/m2 twice daily on days 1 to 14 and Cisplatin 60 mg/m2 on day 1 every 3 weeks Adjuvant Capecitabine + Oxaliplatin (CLASSIC) Eight cycles of Capecitabine 1,000 mg/m2 twice daily on days 1 to 14 and Oxaliplatin 130 mg/m2 on day 1 every 3 weeks Adjuvant Capecitabine + Cisplatin + RT (ARTIST) Two cycles of Capecitabine/Cisplatin followed by 45-Gy chemoradiation with capecitabine 1,650 mg/m2 per day for 5 weeks, followed by two more cycles of Capecitabine/Cisplatin Nivolumab + SOX (ATTRACTION-4) Nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) Nivolumab + CapeOx (ATTRACTION-4) Nivolumab (360 mg intravenously every 3 weeks) plus CapeOX (capecitabine, 1000 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) Nivolumab + XELOX (Checkmate 649) Nivolumab 360mg IV + XELOX (intravenous oxaliplatin 130 mg/m(2) (day 1) followed by oral capecitabine 1,000 mg/m(2) twice daily (day 1, evening, to day 15, morning)q 3 weekly Nivolumab + FOLFOX (Checkmate 649) Nivolumab 240mg + FOLFOX (oxaliplatin 85 mg/m2 IV infusion on day 1, then leucovorin 400 mg/m2 IV infusion, plus 5-FU 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day for 2 d (total 2400 mg/m2 over 46-48 h) q2 weekly ECX Epirubicin (50 mg/m2 IV over twenty minutes) and Cisplatin (60 mg/m2 IV over one hour) are administered on day one, and Trastuzumab (Initial loading dose 8 mg/kg i.v. infusion on Day 1 of cycle, followed by 6 mg/kg i.v. infusion every 3 weeks until disease progression) added to six three-week cycles of Cisplatin 80 mg/m2 IV on day one plus Capecitabine 1,000 mg/m2 po BID for fourteen days Trastuzumab + Cisplatin + 5-Fluorouracil (ToGA) Trastuzumab (Initial loading dose 8 mg/kg i.v. infusion on Day 1 of cycle, followed by 6 mg/kg i.v. infusion every 3 weeks until disease progression) added to six three-week cycles of Cisplatin 80 mg/m2 IV on day one plus 5-Fluorouracil 800 mg/m2 continuous IV infusion on days one through five 

# Single Agent Nivolumab
Nivolumab (3mg/kg IV q 2 weekly) FOLFIRI Irinotecan (180 mg/m2 IV over 90 minutes) concurrently with folinic acid (400 mg/m2  IV over 120 minutes) followed by fluorouracil (400-500 mg/m2 IV bolus) then fluorouracil (2400-3000 mg/m2 intravenous infusion over 46 hours) FOLFOX FOLFOX (oxaliplatin 85 mg/m2 IV infusion on day 1, then leucovorin 400 mg/m2 IV infusion, plus 5-FU 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day for 2 d (total 2400 mg/m2 over 46-48 h) q2 weekly

# Development and Revision History
This guideline was reviewed and endorsed by the Alberta GI Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, gastroenterologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Tumour Teams, external participants identified by the Working Group Lead, and a knowledge management specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2010. 

# Levels of Evidence