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Gastric Cancer

Table of Contents
1 Disease Overview
2 Symptoms and diagnosis
3 Treatment Modalities
4 Pivotal Trials
        4.1 HER-2 Positive
        4.2 Metastatic
        4.3 Targeted Therapy
        4.4 Pancreatic Cancer
        4.5 Colorectal Cancer

Disease Overview

    The incidence of gastric cancer correlates with socioeconomic status and is clearly dependent on environmental factors. The worldwide incidence of gastric cancer has declined; however, there is an increase in more proximal and gastroesophageal cancers. In Canada, there are approximately 3300 cases of gastric cancer (2100 men and 1200 women), and 2100 will die from gastric cancer (1300 men and 790 women).

Risk Factors and Prevention

    Risk factors identified for gastric cancer include the following:

  • Obesity
  • Elevated body mass index with increased incidence of GERD
  • Increased calorie consumption
  • Nutritional factors, such as high salt and nitrate intake, a diet low in vitamins A and C, the consumption of large amounts of smoked or cured foods, lack of refrigerated foods, and poor-quality drinking water
  • Occupational exposure to rubber and coal
  • Cigarette smoking
  • H. pylori infection, Epstein-Barr virus, radiation exposure, and prior gastric surgery for benign ulcer disease
  • Genetic factors: Type A blood, pernicious anemia, family history of gastric cancer, hereditary nonpolyposis colon cancer (HNPCC), and Li-Fraumeni syndrome

History, Symptoms and Signs

    The most common symptoms for gastric cancers are bleeding, hematemesis, upper abdominal pain, anorexia, and dyspepsia. The first clinical symptoms often are a result of metastatic spread inside the peritoneal cavity, resulting in the formation of ascites and abdominal pain.

Diagnosis and Tumour Assessment

    The disease is most often diagnosed by upper endoscopy and direct biopsy or, less commonly, by CT. It is important that a biopsy be performed for samples from any gastric ulcer, because it is difficult to distinguish benign from malignant ulcers endoscopically.

    Staging includes chest x-ray, chest CT scans, and abdominal imaging to rule out metastasis and to determine surgical resectability. PET scans are not (yet) recommended as standard diagnostic procedure in view of limited sensitivity but can be helpful to determine the resectability of gastric cancers in select cases. The role of EUS is less clear in gastric cancer than in esophageal and gastroesophageal junction cancers.

Prognosis

Treatment Modalities

    The only potentially curative treatment approach for patients with gastric cancer is surgical resection. Controversy persists regarding the best operation for gastric cancer, with data from Japanese studies suggesting a better result using a more aggressive, extensive dissection.

Early-Stage Disease

    Patients with operable gastric cancer have a reasonable chance of being cured with surgery alone. Surgery cures 75% - 80% of patients with early-stage node-negative disease. However, for patients with stage III disease, the reported 5-year survival rates are 25% or less. Randomized trials have demonstrated a benefit for adjuvant chemoradiotherapy, as well as for preoperative and postoperative chemotherapy and adjuvant chemotherapy without radiation for stage I to III gastric cancer, resulting in competing standards of care.

Adjuvant chemotherapy

    Recent meta-analysis of 17 trials with 3,838 patients confirmed that adjuvant chemotherapy without radiation after gastric cancer resection was associated with a significant survival benefit, with an HR of 0.82 (95% CI [0.79, 0.90]; p<0.001).

    Pre-operative chemotherapy with the ECF (epirubicin, cisplatin and 5-flourouracil) ECX (xeloda) regimen administered before and after surgery for resectable gastric cancer also has shown a significant overall survival benefit compared with surgery alone (Cunningham D., N Engl J Med 2006).

    Cunningham et al ASCO 2015 OE05 locally advanced gastric cancer Cisplatin and 5FU every 3 weeks for two weeks vs epirubicn, cisplatin and capecitabine (ECX) every 3 weeks for 4 cycles. Resectability was slightly higher in ECX but overall survival no difference 39% vs 42%.

    Advanced disease is treated according to HER2 status on biopsy.

Metastatic Gastric Cancer HER2 Negative

    The medical treatment of metastatic cancer of the stomach is primarily palliative and confers a moderate effect on overall survival. Combination chemotherapy regimens have become more widely used for advanced disease, with some evidence to support benefit.

    Multiple agents are active, including fluoropyrimidines (5-FU, capecitabine), anthracyclines, platinum agents, taxanes (paclitaxel and docetaxel), irinotecan, and others. Combination regimens are associated with higher response rates and, according to one meta-analysis, also are associated with increased overall survival when compared with single-agent therapies. Combinations including cisplatin and 5-FU in various schedules were long considered the standard of care, with epirubicin commonly added to form a triple drug regimen. The combination of epirubicin/oxaliplatin/capecitabine (EOX) was found to be less toxic and at least as active.

    Median survival times in the ECF (control arm), ECX, EOF, and EOX groups were 9.9 months, 9.9 months, 9.3 months, and 11.2 months, respectively; survival rates at 1 year were 37.7%, 40.8%, 40.4%, and 46.8%, respectively. In a secondary analysis, overall survival was longer with EOX than with ECF, with an HR for death of 0.80 in the EOX group (95% CI [0.66, 0.97]; p= 0.02).

    A third phase III trial compared cisplatin plus 5-FU with irinotecan plus 5-FU in 333 patients with advanced gastric cancer. No difference in outcome measures (response rate, progression-free, and overall survival) could be found, but the non-cisplatin, irinotecan-based regimen was found to be less toxic and, thus, could be an alternative for patients who are not considered candidates for a platinum-based treatment regimen. Ramucirumab as a single agent (vs. best supportive care) and in combination with paclitaxel (vs. paclitaxel alone) has been shown to improve survival as second-line therapy in advanced gastroesophageal cancers (Fuchs CS, Lancet 2013; Wilke H, J Clin Oncol 2013).

Metastatic Gastric (20%) and GE Junction (30%) Adenocarcinoma HER2 Positive

    The first targeted agent with documented efficacy in advanced gastric and gastroesophageal junction cancer was trastuzumab, the humanized monoclonal antibody against HER2. Of 3,807 tumours from patients with gastric cancer who were tested, 810 (22.1%) were positive for HER2 overexpression using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis. Eventually, 584 patients were randomly assigned to receive a fluoropyrimidine (800 mg/m2 of 5-FU daily on days 1 through 5 or 1,000 mg/m2 of capecitabine twice daily on days 1 through 14 based on physician choice) plus 80 mg/m2 of cisplatin on day 1 with or without trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) on day 1. Cycles were repeated every 3 weeks for six cycles, and trastuzumab was subsequently continued every 3 weeks until disease progression.

    The addition of trastuzumab to cisplatin/fluoropyrimidine increased median overall survival from 11.1 months to 13.8 months (HR 0.74, 95% CI [0.60, 0.91]; p = 0.0046) and progression-free survival (6.7 months vs. 5.5 months; p = 0.0002) and overall response rate (47.3% vs. 34.5%; p = 0.0017) were also improved in the trastuzumab arm. There were no significant differences in the toxicity between the two treatment arms. Asymptomatic decrease in ejection fraction occurred in 4.6% and 1.1% in the trastuzumab and chemotherapy-alone arms, respectively.

    Two recent randomized trials of chemotherapy versus best supportive care clearly demonstrated improvement in overall survival with the use of second-line chemotherapy with either irinotecan or taxane after failure of first-line fluoropyrimidine/platinum therapy.

    Further phase III trials are investigating the role of other EGFR/HER2 inhibitors such as TDM1,lapatinib, cetuximab, and panitumumab in gastric cancer.

    In contrast to these positive results for trastuzumab in HER2-overexpressing gastric cancers, bevacizumab failed to demonstrate an overall survival benefit when added to cisplatin/fluoropyrimidine (mainly capecitabine) in patients with gastroesophageal junction and gastric adenocarcinomas.

    Radiation therapy can be effective for metastatic disease (e.g., metastasis to bony structures for symptomatic control) and perhaps for unresectable, bleeding tumours in conjunction with chemotherapy, but it is rarely used to treat primary advanced unresectable gastric cancer.


Pivotal Trials

HER-2 Positive

Bang YJ, et al. ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–697.

Metastatic

Fuchs CS, et al. Ramucirumabmonotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet.2014; 383(9911):31-9.

Hecht JR, et al. Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): The TRIO-013/LOGiC Trial.J ClinOncol. 2013; (suppl): abstr LBA4001.

Lordick F, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial.Lancet Oncol.2013; 14(6):490-9.

Targeted Therapy

Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012; 30(28):3499-506.

Pancreatic Cancer

Fukutomi A, et al. JASPAC 01: Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 for patients with resected pancreatic cancer . J ClinOncol. 2013;31(suppl):abstr 4008.

Von Hoff DD, et al. Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine.N Engl J Med. 2013; 369:1691-1703.

Colorectal Cancer

Cunningham D, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial.Lancet Oncol.2013; 14(11): 1077-85.

Douillard JY, et al. Panitumumab–FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013; 369(11):1023-34.

Falcone A, et al. FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group.J ClinOncol. 2013; (suppl): abstr 3505.

Domingo E, et al. Evaluation of PIK3CA Mutation As a Predictor of Benefit From Nonsteroidal Anti-Inflammatory Drug Therapy in Colorectal Cancer. J ClinOncol. 2013; 31(34):4297-305.

James RD, et al. Mitomycin or cisplatinchemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial.Lancet Oncol. 2013; 14(6): 516-24.

Koopman M, et al. Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC): The phase III CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG).J ClinOncol.2013; (suppl): abstr 3502.

Liao X, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival.N Engl J Med. 2012; 367(17):1596-606.

Nishihara R, et al. Long-term colorectal-cancer incidence and mortality after lower endoscopy.N Engl J Med. 2013; 369(12):1095-105.

Shaukat A, et al. Long-term mortality after screening for colorectal cancer.N Engl J Med. 2013; 369(12):1106-14.


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