Summary of Literature Review
In 2013, it was estimated that approximately 21,600 new cases of gastric cancer would occur in the United States, with an estimated 10,990 deaths from the disease. Although 2000–2009 data demonstrated that gastric cancer is among the top four cancers with the largest annual decline in death rates in the United States, it remains the second leading cause of death worldwide, with an annual estimated 989,600 new cases; the highest incidences are in Eastern Asia, Europe, and South America. Although surgery remains the mainstay of management in gastric cancer, due to the high rate of locoregional and distant relapse, curative treatment generally requires a multimodality approach. Outcomes data from the Surveillance, Epidemiology, and End Results (SEER) program demonstrate an overall 5-year survival of approximately 30%, largely due to the fact that most patients present with locally advanced disease. Although the 5-year survival for patients with localized disease at diagnosis is 62.3%, patients with lymph node–positive disease (27.7%) or metastatic disease (3.7%) have a much worse prognosis.
Previously, the classification of gastric carcinomas included tumors arising at the gastroesophageal junction (GEJ) or tumors originating in the stomach at 5 cm or less from and crossing the GEJ. However, the seventh edition of the American Joint Committee on Cancer (AJCC) staging system defines gastric carcinomas as either tumors arising in the distal stomach or those originating in the proximal 5 cm of the stomach, but not crossing the GEJ. This revision is mainly due to the prognostic implication of inappropriately including GEJ tumors in gastric tumor staging, since the outcomes for GEJ tumors after resection differ from the outcomes for gastric cancers.
Histologic tumor type can correlate with prognosis. The diffuse type/signet cell histology correlates with poorer outcomes, with a predilection for intraperitoneal metastases when compared with the intestinal type.[6,7] Disease location also has a prognostic implication, and generally, outcomes are worse for proximal tumors of the cardia compared with distal gastric lesions.[8,9] Distal gastric tumors are more common in Asia and tend to have a more favorable 5-year overall survival rate of up to 60%, compared with gastric cardia tumors, which are more common in the United States, with 5-year overall survival rates of approximately 20%.[9,10] Although this difference in outcome may be due to genetic variations between the two populations, it may also be associated with the presence of widespread screening programs in countries such as Japan, which permit earlier detection of gastric cancer. In addition, it is believed that the superior outcomes in Asia may be due to an increased utilization of more comprehensive yet potentially morbid D2 lymph node dissections, which remove additional lymph node basins, as compared with D1 nodal dissections, which only evaluate the perigastric nodal regions. Although several studies have shown no survival advantage for a D2 resection, a recent study demonstrated a significant benefit in cancer specific–survival in long-term follow-up.[12-14]
Surgical resection is an essential component of the management of gastric cancer and may involve various approaches, including endoscopic mucosal resection for early-stage disease (Tis, T1a) and minimally invasive laparoscopic resection or open gastrectomy for more advanced disease. Minimally invasive approaches are becoming increasingly popular due to technological advances and the publication of data from randomized studies, which have demonstrated equivalent outcomes for laparoscopic procedures compared with open techniques.[15,16] Commonly, a total gastrectomy is utilized for proximal or middle-third lesions, and a partial gastrectomy is recommended for lesions in the distal third of the stomach. The goal of resection is to obtain a negative margin (R0) resection, since a microscopically positive (R1) resection is associated with a worse prognosis; typically, a wide resection margin (4 to 6 cm) around the primary gastric cancer is desired for potentially curative surgery. Due to the propensity for mucosal spread, “simple” or “close” gross negative margins are not sufficient. Given the significant disease-specific survival benefit with a more comprehensive nodal resection, a D2 nodal dissection with a minimum of 15 lymph nodes is preferred in large-volume centers.[14,17] The number of involved nodes reflects the burden of disease, and AJCC stage group survival estimates are thought to be best represented when at least 15 nodes are examined. However, the concept of lymph node ratio, described as the ratio of positive lymph nodes to total number of retrieved lymph nodes, has been recently proposed as a more accurate indicator of lymph node metastasis. Based on several studies, use of lymph node ratio offers an independent prognostic factor that can reduce the influence of the extent of lymphadenectomy.
In an autopsy-based series used to examine patterns of relapse, 80% to 93% of patients showed locoregional relapse after resection, with 49% demonstrating distant relapse. Considering the high local and distant relapse rates with surgery alone, multiple studies have focused on efforts to improve outcomes with adjuvant treatment. Although initial studies did not seem to indicate a benefit to adjuvant chemotherapy over surgery alone for resectable stage II/III gastric cancer, two large randomized Asian trials (Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer [ACTS-GC] and the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer [CLASSIC] trial) demonstrated a significant survival benefit with postoperative chemotherapy after D2 resection.[19,20] Although the benefit of postoperative chemotherapy has been questioned in patients treated with D1 gastrectomy in Western countries, the recent Global Advanced/Adjuvant Stomach Tumor Research International Collaboration (GASTRIC) meta-analysis of 17 worldwide randomized trials of postoperative chemotherapy vs surgery alone demonstrated a significant improvement in both overall survival and disease-free survival, as well as a significant improvement in median survival (4.9 years with surgery alone vs 7.8 years with the use of adjuvant fluorouracil [5-FU]–based chemotherapy).
Studies have investigated the role of preoperative chemotherapy in gastric cancer. The Medical Research Council (MRC) Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial was a phase III design that randomized 503 patients with locally advanced, resectable adenocarcinoma of the stomach (74%), GEJ (14%), or distal esophagus (12%) to perioperative chemotherapy (epirubicin, cisplatin, and 5-FU [ECF]) vs surgery alone. Although none of the patients in the chemotherapy group demonstrated a pathologic complete response, the 5-year overall survival rate was significantly improved with perioperative chemotherapy (36%) compared with surgery alone (23%), with no difference in postoperative morbidity between the two groups. However, the relative contribution of preoperative and postoperative chemotherapy in the study is unclear, since only 42% of patients assigned to perioperative chemotherapy completed protocol therapy and 34% of patients completing preoperative chemotherapy and surgery did not receive postoperative chemotherapy. A smaller phase III trial including 224 patients with esophageal (13%), GEJ (62%), or gastric (25%) cancer noted a benefit in R0 resection rate and disease-free and overall survival using a perioperative platinum/fluorinated pyrimidine combination (see Variant 1).
The European Organisation for Research and Treatment of Cancer (EORTC) conducted a study comparing preoperative chemotherapy (cisplatin and 5-FU) followed by surgery vs surgery alone. The results showed a significant improvement in the R0 resection rate (82% vs 67%) and a 7.1% rate of pathologic complete response, but failed to demonstrate an overall survival benefit. The discrepancy in outcomes of the MAGIC and the EORTC studies may be attributed to differences between the two studies, including earlier-stage disease, higher statistical power, and postoperative chemotherapy in the MAGIC trial. In addition, patients in the EORTC trial were possibly more accurately staged with endoscopic ultrasound (EUS), whereas the MAGIC trial did not routinely utilize EUS-based staging.
Many studies have examined the role of radiation therapy (RT), both in the preoperative and postoperative setting, in efforts to achieve a benefit over surgery alone. Of these, a randomized controlled trial by the British Stomach Cancer Group examined the benefit of postoperative RT or postoperative chemotherapy compared with surgery alone. Although there was a significant reduction in locoregional recurrence with postoperative RT (10% with RT vs 27% with surgery alone), there was no benefit in survival with either adjuvant treatment. The role of preoperative RT was evaluated in a large randomized trial from China that found that its addition to surgery vs surgery alone led to a significant improvement in overall survival (30% vs 20%), with benefits in local recurrence (39% vs 52%), reduction in regional nodal metastases, and tumor downstaging, as well as a higher resection rate (89.5% vs 79%).
A recent meta-analysis of nine trials was conducted to examine the benefit of RT (postoperative, preoperative, or intraoperative) compared with surgery alone or surgery and chemotherapy. Results indicated a significant benefit in 5-year overall survival (relative risk, 1.39 by intent-to-treat analysis) with the addition of preoperative RT. Of note, the meta-analysis included trials utilizing preoperative RT both alone and in combination with chemotherapy, making it difficult to distinguish the relative benefit of preoperative RT alone in this setting. The Quality Research in Radiation Oncology (QRRO) patterns of care survey noted that 19% of patients receiving RT as a component of treatment for stage IB–IV (nonmetastatic) gastric cancer did so in the preoperative setting.
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