Cancer of the Stomach

Summary of Key Points

• Epidemiology and Pathology

• In the United States, it was predicted that there would be 28,000 patients diagnosed with gastric cancer in 2017, with an estimated 10,960 deaths.

• In the United States, the site of origin is shifting as more proximal lesions are diagnosed.

• Biological Characteristics

• Prognostic factors relate to tumor extent and include nodal involvement and extension beyond the gastric wall.

• Chronic infection with Helicobacter pylori and environmental and dietary factors increase the risk for gastric cancer. As such, it is more much common in East Asia and developing countries than in the United States and Western Europe. There is ongoing controversy as to whether there are biological differences between gastric cancer in the East versus West.

• Recent efforts by The Cancer Genome Atlas and the Asian Cancer Research Group have identified specific molecular subtypes of gastric cancer. These have helped for the first time to establish a framework for research stratification and for the evaluation of targeted therapies.

• Staging Evaluation

• Staging should always include endoscopy with biopsy, ultrasonography (determine degree of direct tumor extensions), and computed tomography of the chest, abdomen, and pelvis.

• Laparoscopy (to rule out peritoneal seeding or early liver metastases) and positron emission tomography are important tests that complete baseline staging and may help to identify patients with metastatic disease who do not benefit from surgery.

• Primary Therapy

• Surgical resection is the primary therapy of resectable gastric and Siewert type III gastroesophageal junction (GEJ) tumors.

• Cure rates of 80% or higher are achieved only with early lesions (patients with nodes negative, confined to mucosa or submucosa), which are uncommon in the United States.

• A role for an extended D2 lymph node dissection has not been clearly demonstrated in randomized trials compared with a standard D1 dissection, in part because of significant morbidity and mortality related to the more extensive surgery. Long-term follow-up does suggest a potential benefit for D2 dissection, which should be considered if it can be performed safely in an experienced center.

• Surgery alone is appropriate for patients with T1-2N0 tumors.

• Adjuvant Therapy

• Perioperative chemotherapy and surgery improves outcomes versus surgery alone and is the standard in the United States and Western Europe for T3–4N _any or T _any N+ tumors. Chemotherapy consists of a fluoropyrimidine/platinum doublet, and the benefit of adding an anthracycline appears to be marginal. The optimal duration of chemotherapy is not known, just as the optimal sequence (pre- or perioperative) has not been fully determined.

• Adjuvant chemoradiation is an option for patients who have undergone initial surgery for a locally advanced tumor, especially if they have undergone a D0/D1 nodal dissection. Chemoradiation should not be administered postoperatively in a standard fashion to patients who have received preoperative chemotherapy.

• Adjuvant chemotherapy for a locally advanced tumor after initial surgery with D2 resection with a fluoropyrimidine with or without a platinum drug also has a clearly demonstrated benefit based on Asian studies. There may also be a benefit to adding adjuvant chemoradiation to chemotherapy in such patients if they have lymph node positivity and intestinal histology.

• Palliation

• Palliative resection of gastric component of disease may be indicated for significant symptoms from the primary tumor.

• Phase III trials demonstrate improved quality and duration of life with palliative chemotherapy versus supportive care.

• Treatment of Metastatic Disease

• Multiple-drug chemotherapy regimens have response rates of 30% to 50% and are associated with progression-free survival of 4 to 6 months and overall survival of 9 to 12 months.

• A fluoropyrimidine/platinum doublet is considered the standard combination globally. Although an anthracycline is routinely added to this doublet in the United Kingdom, there are no data to support a benefit. On the other hand, there is a benefit to adding docetaxel to the doublet but at the expense of significant toxicity.

• There are now randomized data showing a benefit for second- and third-line chemotherapy in gastric cancer.

• The addition of trastuzumab to first-line chemotherapy improves outcomes in patients with HER2 -positive disease.

• Ramucirumab, an antibody against vascular endothelial growth factor receptor-2, has activity in the second-line setting as monotherapy or when combined with paclitaxel chemotherapy.

• The evaluation of immune checkpoint inhibitors is of intense interest. At this time, one phase III study in East Asian patients reveals modest but very notable activity in chemorefractory patients for nivolumab, an antibody against programmed death-1.

• Algorithm

• Surgical resection is the primary therapy of resectable gastric and Siewert type III GEJ tumors.

• There is a benefit for D2 lymph node dissection, provided it can be performed by an experienced surgeon in a high-volume center.

• In addition to surgery, the two options are perioperative chemotherapy versus upfront surgery and adjuvant treatment.

• In terms of perioperative chemotherapy regimens, the FLOT regimen (docetaxel, infusional 5-fluorouracil, leucovorin, and oxaliplatin) has now emerged as a new standard of care.

• The two adjuvant strategies are either chemotherapy or chemoradiation. We favor chemotherapy with a fluoropyrimidine/platinum doublet for 6 months, given the increased toxicity of chemoradiation.

• For patients who undergo initial surgery and have intestinal-type tumors with lymph node positivity, consideration can be given to adjuvant systemic chemotherapy with a fluoropyrimidine/platinum doublet and chemoradiation with a fluoropyrimidine.

• Chemotherapy is the mainstay of treatment for recurrent or metastatic disease, in which response rates and duration of response are modest for most patients. The standard doublet consists of a fluoropyrimidine and platinum drug. Adding docetaxel to this doublet slightly improves outcomes in patients with adenocarcinomas but at the expense of significant additional toxicity.

• The addition of trastuzumab to first-line chemotherapy for HER2- positive adenocarcinomas incrementally improves outcomes. Similarly, ramucirumab with or without paclitaxel in the second-line setting is a validated strategy for adenocarcinomas.

• There are now phase III studies showing benefit for a taxane and irinotecan in the second- and third-line settings.

• The evaluation of immune checkpoint inhibitors against the programmed death 1 (PD-1)/PD-L1 axis reveals a modest but notable benefit in the metastatic setting and is of high priority.

• Although conceptually attractive, there are no data that show a clear benefit for intraperitoneal chemotherapy either in addition to standard treatments in the curative setting or as palliative therapy for patients with peritoneal carcinomatosis.

• There may also be a role for palliative surgical resection or radiation (with or without chemotherapy) under specific circumstances.