Neoadjuvant and Adjuvant Therapy for Gastric Cancer

MANAGEMENT OF NONMETASTATIC DISEASE

CASE CONTINUED

The patient undergoes EGD, which reveals a large ulcerated, partially circumferential mass measuring approximately 4 cm. The mass extends from the gastric body to the cardia. Biopsy of the mass reveals poorly differentiated adenocarcinoma as well as H. pylori–associated gastritis. He is given antibiotic therapy and undergoes complete work-up of his newly diagnosed gastric adenocarcinoma. CT of the chest/abdomen/pelvis demonstrates a large gastric mass with gastrohepatic and distal perigastric adenopathy, compatible with locally advance primary gastric cancer. There is no evidence of distant metastasis. PET scan shows a large hypermetabolic mass in the stomach body and increased FDG activity in 3 small nodes along the lesser gastric curvature and in 1 node in the gastrohepatic region. EUS reveals a malignant gastric tumor in the body of the stomach, which is staged as T3, and a few malignant-appearing lymph nodes in the perigastric region. Fine-needle aspiration of the perigastric lymph node is performed and the sample obtained is positive for malignant cells. Diagnostic laparoscopy with peritoneal washings is performed and cytology is negative for malignant cells. The patient is staged as clinical stage IIB (T3N1M0).

• How should this patient with newly diagnosed, locally advanced, resectable gastric cancer be managed?

SURGERY

Surgical resection for localized gastric cancer is the mainstay of treatment with curative intent. Only very early stage (Tis or T1a) tumors can be considered for endoscopic mucosal resection. Regarding surgical resection, distal gastric cancers are typically treated with subtotal gastrectomy because there is no survival difference between subtotal and total gastrectomy.^24,25 Moreover, subtotal gastrectomy is associated with better nutritional status and quality of life. For proximal tumors, total gastrectomy is preferred as subtotal gastrectomy has been associated with a higher incidence of reflux esophagitis and anastomotic stenosis.²⁶ In terms of surgical approach, multiple studies have shown that a laparoscopic approach has a lower complication rate and similar outcomes in terms of cancer recurrence and long-term survival when compared to open gastrectomy.^27–29 Thus, a laparoscopic approach is often used in academic centers with highly experienced surgeons.

The extent of lymph node dissection remains a topic of debate. A D1 dissection involves the removal of perigastric lymph nodes. A D2 dissection is a D1 dissection plus the removal of lymph nodes along the left gastric artery, common hepatic artery, celiac artery, splenic hilum, and splenic artery. D2 lymphadenectomy has become the standard of care in Eastern countries where gastric cancer is more prevalent, such as Japan and Korea.³⁰ In Western countries, including the United States, less extensive lymphadenectomies are performed. Both randomized clinical trials and meta-analyses have failed to demonstrate an overall survival advantage of D2 dissection over D1 dissection.^31,32 A Dutch trial by Bonenkamp et al involving 711 patients, one of the largest randomized trials of D1 and D2 lymphadenectomy, showed that D2 patients had a higher operative mortality rate than D1 patients (10% versus 4%, P = 0.004) and experienced more complications (43% versus 25%, P < 0.001).³³ In a 15-year follow-up of this study, patients who had a D2 resection had lower locoregional recurrence and gastric-cancer–related death rates compared to those who had a D1 resection; however, D2 resection was associated with a significantly higher operative mortality and complication rate compared to D1.³⁴ In addition, a 2015 Cochrane meta-analysis has demonstrated improved disease-specific survival (DSS) with D2 dissection (hazard ratio [HR] 0.81 [95% confidence interval {CI} 0.71 to 0.92]).³⁵ Currently, the National Comprehensive Cancer Network (NCCN) recommends a D1 or a modified D2 gastrectomy with at least 15 lymph nodes removed for examination, with D2 lymphadenectomies only to be performed at experienced centers.²³

SYSTEMIC CHEMOTHERAPY

Locally advanced gastric cancer (T3-T4 or node positive) requires systemic chemotherapy in addition to surgery, as this intervention improves the 5-year overall survival by 10% to 15%.³⁶ Systemic therapy should also be considered in patients with T2N0 disease with high-risk features: poorly differentiated or high-grade cancer; lymphovascular invasion; neural invasion; age younger than 50 years; and patients who did not undergo D2 dissection.²³ Currently, there is no global consensus on the best treatment approach. In the United States, where a less aggressive lymph-node dissection is performed, adjuvant chemoradiotherapy after surgery is more commonly seen. In Europe, perioperative (preoperative and postoperative) chemotherapy is the standard treatment. In Japan, adjuvant chemotherapy after D2 lymphadenectomy is the standard of care.³⁷ These regional preferences are largely due to randomized clinical trials that have shown benefit for each approach. The landmark trials are discussed in the following sections and are summarized in Table 2.