Summary of Gastric Cancer

Epidemiology & Etiology:

• Aspirin and other nonsteroidal anti-inflammatory agent use has been associated with a lower risk for cancer of the gastroesophageal junction and other gastrointestinal tumors.41
• Cigarette smoking, H. pylori infection, Epstein-Barr virus, radiation exposure, and prior gastric surgery for benign ulcer disease also have been implicated as risk factors.

Diagnosis:

• 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.48
• The role of EUS is less clear in gastric cancer than in esophageal and gastroesophageal junction cancers.

Treatment:

• D2 lymphadenectomy was associated with lower locoregional recurrence (12% vs. 22%) and gastric cancer–related death rates (37% vs. 48%) than D1 surgery.51 Although D2 dissection was associated with increased operative morbidity, these data suggest that D2 lymphadenectomy should be considered surgical standard of care.
• Early stage disease:
• A randomized phase III trial was presented in which adjuvant chemotherapy was combined with radiation therapy.53 Patients with stages I to III gastroesophageal or gastric cancers were randomly assigned to either surgery alone or surgery followed by bolus 5-FU/LV-based chemotherapy (Mayo Clinic regimen) with sandwiched chemoradiotherapy (45 Gy) with bolus 5-FU/LV as a radiosensitizer. The results showed an approximate 20% improvement in survival for the group receiving the combined-modality therapy. The median overall survival in the surgery-only group was 27 months compared with 36 months in the chemoradiotherapy group. The HR for relapse was 1.52 (95% CI 1.23, 1.86; p < 0.001). The study has been criticized for the very low rate of D1 (or D2) lymph node dissection. In fact, less than 50% of patients underwent a D1 resection, which was mandated per protocol. In addition, only the rate of local recurrence, not the rate of distant metastasis, was reduced in the adjuvant chemoradiotherapy group, suggesting that the adjuvant therapy could have mainly compensated for inferior surgery. On the other hand, the survival benefit observed with postoperative therapy was maintained in all (preplanned) subgroup analyses. Although these trial results were met with skepticism elsewhere, they established a new standard of care for patients with this disease in the United States.
• Perioperative chemotherapy with the ECF regimen administered before and after surgery for resectable gastric cancer also has shown a significant overall survival benefit compared with surgery alone
• in the MAGIC trial. It is of note that only about 55% of patients in the perioperative chemotherapy group actually received post-resection therapy, which suggests that the main therapy component responsible for the improved outcome was the preoperative treatment phase.
• 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 a HR of 0.82
• Based on the aforementioned trials and meta-analyses, three different approaches toward the management of early-stage gastric cancer are considered standard of care and are used with varying frequency based on regional preferences:
• Postoperative chemoradiotherapy (United States).
• Pre- and postoperative chemotherapy (United Kingdom).
• Adjuvant chemotherapy alone after D2 resection (Asia).
• Advanced disease:  
• Combination regimens are associated with higher response rates and, according to a meta-analysis, also are associated with increased overall survival when compared with single-agent therapies.61.  
• Combinations including cisplatin and fluorouracil in various schedules were long considered the standard of care, with epirubicin commonly added to form a triple-drug regimen that was pioneered mainly in the United Kingdom.62
• large randomized phase III trial including 1,002 patients tried to improve the ECF regimen by substituting oral capecitabine (X) for continuous-infusion fluorouracil and by using the non-nephrotoxic compound oxaliplatin (O) instead of cisplatin (C).64 The combination of epirubicin, oxaliplatin, and capecitabine (EOX) was found to be less toxic and at least as active as the ECF combination, with all efficacy parameters trending toward superiority. 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 a HR for death of 0.80 in the EOX group (95% CI 0.66, 0.97; p = 0.02). PFS and RR did not differ significantly between the regimens.
• Although these two trials investigated triplet combinations, the value of an anthracycline or taxane component in the treatment of advanced gastric cancer has repeatedly been questioned; thus, a fluoropyrimidine/platinum chemotherapy doublet is still considered standard of care by most experts.65
• 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
• Based on these trial data, a combination regimen with a platinum agent (cisplatin or oxaliplatin) plus fluoropyrimidine as a backbone, with or without the addition of epirubicin or docetaxel, can be considered first-line standard of care in the palliative treatment of advanced gastric cancer. Irinotecan has clearly demonstrated activity and could be integrated in a sequential treatment approach.
• Based on the preclinical observations that about 20% of gastric cancers (and about 30% of gastroesophageal adenocarcinomas) overexpress HER2,67. The phase III ToGA trial investigated whether the addition of trastuzumab to standard chemotherapy would extend survival in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction.37. The addition of trastuzumab to cisplatin/fluoropyrimidine increased median overall survival from 11.1 months to 13.8 months.
• The ToGA trial was the first phase III trial to demonstrate a survival advantage with the addition of a biologic agent, trastuzumab, to standard chemotherapy in advanced gastric cancer.
• Two phase III trials of lapatinib, an oral HER2/EGFR kinase inhibitor, added to chemotherapy in first- (LOGIC) and second-line (TYTAN) failed to meet their primary endpoints.68,69
• The consistently negative data from these two large phase III trials confirm that there is no role for the use of EGFR monoclonal antibodies in advanced gastroesophageal adenocarcinoma.
• In the first phase III trial, bevacizumab failed to demonstrate an overall survival benefit when added to cisplatin/fluoropyrimidine (mainly capecitabine) in patients with gastroesophageal junction and gastric adenocarcinomas.34
• A second set of trials investigated ramucirumab, a VEGFR2 monoclonal antibody, in the second-line setting of advanced gastroesophageal cancer. The REGARD trial randomly assigned 472 patients after first-line fluoropyrimidine/platinum therapy in a 2:1 fashion to single-agent ramucirumab or placebo.36 Median overall survival was 5.2 months for the ramucirumab arm and 3.8 months for the placebo arm. Aside from a higher rate of hypertension, no relevant differences were seen in recorded side effects between ramucirumab and placebo.
• The RAINBOW study addressed these concerns by randomly assigning 665 patients with advanced gastroesophageal cancer after first-line therapy with a platinum-fluoropyrimidine combination to weekly paclitaxel with or without ramucirumab.71 The study met its primary endpoint of overall survival with an HR of 0.81 and a median difference of 2.2 months (9.6 vs. 7.4 months, p = 0.017). Progression-free survival and response rates were also improved in favor of the paclitaxel-ramucirumab combination.
• Three randomized trials of chemotherapy compared with best supportive care clearly demonstrated an improvement in overall survival with the use of second-line chemotherapy with either irinotecan or a taxane after failure of first-line fluoropyrimidine/platinum therapy.72-74