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Results demonstrate ‘ongoing need for improvement’ in gastric cancer treatment
Controversy about the required radicality of surgery in the curative treatment of gastric cancer has lessened in recent years.
There is now a nearly global consensus that D2 lymphadenectomy represents the optimal surgery for gastric cancer. Supportive data from Western trials include the 15-year update of the Dutch D1 vs D2 gastrectomy trial — which indicated a significant survival benefit for D2 gastrectomy — and retrospective analyses of surgical databases in the United States, which indicated a survival benefit for retrieval of 15 or more lymph nodes during gastrectomy vs less than 15 nodes.
The adequacy of surgery performed in adjuvant therapy clinical trials is critical to interpreting the relative role of chemotherapy and radiotherapy. Although the first positive adjuvant therapy trial for gastric cancer in the West came from U.S. INT Trial 116 — which indicated a survival benefit for postoperative 5-fluorouracil (5-FU), folinic acid, and radiotherapy — the adequacy of surgery on this trial has called into question the universal application of this approach.
David H. Ilson
Only 10% of patients on this trial had a D2 lymphadenectomy. The high 29% rate of local tumor recurrence on the surgery arm, and the benefit of adjuvant chemoradiotherapy limited only to reducing local recurrence, suggest that adjuvant therapy was only making up for inadequate surgery.
In contrast to INT 116, rates of local recurrence were 3.2% on the D2 gastrectomy surgery arms of the Japanese ACT-GS Trial and 8.5% on the Korean CLASSIC trial. On the British MAGIC Trial, in which 40% had D2 resection, local recurrence occurred in 20%. Chemotherapy alone, without radiotherapy, has now been clearly validated as a successful adjuvant therapy in gastric cancer. This includes both perioperative chemotherapy, as given on the MAGIC trial, and adjuvant chemotherapy post-D2 resection, as given on the Japanese and Korean trials.
Datta and colleagues now report in the journal Cancer results of a contemporary evaluation of lymph node staging (LNS) of gastric cancer in the United States in the era of application of adjuvant and neoadjuvant therapies.
The current study evaluated a cohort of more than 22,000 patients with gastric cancer undergoing curative surgical resection from 1998 to 2011 identified through the National Cancer Database.
The survival analyses were limited to 9,139 patients treated through 2006. Using the criterion of 15 or more nodes as adequate nodal retrieval, 61.2% of patients had inadequate LNS. Inadequate LNS increased the risk for death (HR=1.33; P<.001) and a survival detriment was observed for patients with stage I, II and III disease, with the greatest negative impact on survival observed with stage II disease.
Utilization of preoperative chemotherapy was uncommon at only 14.3%, and 36% received surgery followed by adjuvant therapy, representing only 43.3% of patients who were eligible for adjuvant treatment. Delivery of any adjuvant therapy, either pre-surgery (HR=0.66; P=.02) or post-surgery (HR=.65; P<.001), translated into a significant survival improvement.
Results from this retrospective study reinforce the need for adequate LNS in the curative surgical management of gastric cancer, and they support added survival benefits for the application of adjuvant therapy. The fairly high rate of failure to achieve adequate LNS and the less than 50% rate of application of adjuvant therapy indicate an ongoing need for improvement in delivery of therapy for gastric cancer in the United States, and emphasizes the need for patients to be treated at centers of excellence, which typically treat a higher volume of patients with rare diseases.
The optimal adjuvant therapy remains to be established by ongoing clinical trials. Current acceptable adjuvant therapy options include postoperative 5-FU and radiotherapy in patients undergoing less than a D1 resection, adjuvant chemotherapy alone after D2 resection, and the use of pre- and postoperative chemotherapy in high-risk patients with endoscopic ultrasound clinically staged T3 or node-positive disease.
The role of postoperative radiotherapy will be better defined by ongoing clinical trials, including the Dutch CRITICS trial [NCT00407186] — evaluating perioperative chemotherapy with or without the addition of postoperative radiotherapy — and the Korean ARTIST 2 trial, in which patients with high-risk, node-positive disease will be randomly assigned post-gastrectomy to adjuvant chemotherapy with or without postoperative radiotherapy.
The greatest promise for the future is the study of driver biologic pathways in gastric cancer, which in recent Western and Eastern patient series have identified ERBB2, EGFR, FGF and MET as commonly amplified in genomic analyses. All of these pathways are currently the focus of new drug investigation in advanced disease.
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For more information:
David H. Ilson, MD, PhD, is a medical oncologist with Memorial Sloan Kettering Cancer Center’s Gastrointestinal Oncology Service, a professor of medicine at Weill Cornell Medical College and HemOnc Today’s gastrointestinal cancers section editor. He can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: ilsond@mskcc.org.