Adding PAND to Radical Gastrectomy Does Not Improve Survival in Gastric Cancer

Radical gastrectomy with extended (D2) removal of regional lymph nodes is the standard treatment for patients with potentially curable gastric cancer in Japan. However, adding para-aortic nodal dissection (PAND) to standard gastrectomy with D2 lymphadenectomy did not improve survival, report Japanese researchers in the July 31 issue of the New England Journal of Medicine. Patients with gastric cancer deemed curable were randomly assigned to undergo gastrectomy plus either extensive removal of regional lymph nodes or PAND. In both groups, overall 5-year survival rate was approximately 70% and recurrence-free survival rate was about 62%. The addition of PAND did not appear to offer a survival benefit or to reduce the rate of cancer recurrence in the lymph nodes.

The clinical value of systematic PAND in addition to D2 gastrectomy in curable gastric cancer has been controversial. "It used to be quite common in Japan, especially in specialist centers, such as the National Cancer Center in Tokyo," said lead author Mitsuru Sasako, MD, PhD, a professor of surgery at Hyogo College of Medicine, in Nishinomiya, Japan. "It may have even been performed more frequently than the standard D2. But now we don't perform D2 plus PAND for prophylactic purposes."

The most notable aspect of this study is the high survival rate for a disease that is generally associated with an extremely poor prognosis, write, in an accompanying editorial, David Forman, PhD, professor of cancer epidemiology at the University of Leeds, United Kingdom, and Paola Pisani, senior scientist in the Cancer Epidemiology Unit at the University of Oxford, United Kingdom.

"Most centers outside Japan would struggle to obtain survival rates this high, even after careful selection of patients for curative surgery," they write. "These results reinforce the recognition that Japanese teams have been at the forefront of the development of surgical procedures for the treatment of gastric cancer."

Despite Global Decline, Rates in Japan Remain Elevated

Even though the incidence is declining, gastric cancer remains the second leading cause of cancer death worldwide, and about 60% of new cases occur in eastern Asia. Gastric cancer is the most common cancer in Japan, with more than 100,000 new cases diagnosed every year.

The high incidence of gastric cancer in Japan cannot be easily explained. A high rate of bacterial infection with Helicobacter pylori and a high intake of salty foods are believed to be the 2 major reasons for the rate of gastric cancer in Japan, explained Dr. Sasako.

Although H. pylori infection is now generally regarded as the primary cause of gastric cancer that does not involve the gastroesophageal junction, it is also recognized that cofactors must play a role in the progression to premalignant lesions and cancer after infection-related gastritis, the editorialists write. "In many populations, despite a high burden of infection, gastric cancer develops in only a small proportion of infected people, and there is geographic variation in the risk of gastric cancer that cannot be explained by the relative prevalence of infection."

D2 Standard Treatment

The researchers note that in advanced gastric cancer, the incidence of microscopic metastases in the para-aortic region is 10% to 30% and, because the 5-year overall survival rate of patients with para-aortic nodal metastases can be as high as 20% after systematic dissection, surgeons in Japan have been performing extensive procedures for stage T2b, T3, and T4 gastric cancers for more than 2 decades.

To date, there have not been any large prospective studies that examined the survival benefit of PAND. Dr. Sasako and colleagues conducted this study to determine whether the addition of systematic PAND to standard gastrectomy with D2 lymphadenectomy improves survival in patients with curable disease. Their interim analysis of the data did not show any differences in rates of short-term major complications or in-hospital deaths; in this report, they present their final results.

Survival Rates Similar, PAND Increases Surgical Risks

A cohort of 523 patients was randomly assigned to D2 lymphadenectomy alone (263 patients) or D2 lymphadenectomy plus PAND (260 patients) between July 1995 and April 2001. At follow-up, mortality and disease recurrence rates were similar between the 2 groups. At a median follow-up of 5.6 years, 96 patients who underwent D2 lymphadenectomy alone had died; at a median follow-up of 5.7 years, 95 patients who underwent D2 lymphadenectomy plus PAND had died.

The rates of disease recurrence were also similar: 100 patients for D2 lymphadenectomy alone vs 98 patients for D2 lymphadenectomy plus PAND.

The 5-year overall survival rate was 69.2% for D2 lymphadenectomy alone, compared with 70.3% for D2 lymphadenectomy plus PAND. The hazard ratio for death was 1.03, and after adjustment for standard variables, including age, sex, body mass index, tumor location, tumor size, Borrmann macroscopic type, clinical T stage, and clinical N stage, the hazard ratio remained essentially the same.

The rates of 5-year recurrence-free survival were also similar between the 2 groups: 62.6% for D2 lymphadenectomy alone vs 61.7% for D2 lymphadenectomy plus PAND.

Although there were no significant differences in the rates of major surgery-related complications between the 2 groups, the rate of minor complications, including ileus, lymphorrhea, left pleural effusion, and severe diarrhea, were significantly higher with D2 lymphadenectomy plus PAND (20.0% vs 9.1%). In addition, the median operation time was 63 minutes longer and the median blood loss was 230 mL greater with D2 lymphadenectomy plus PAND. Operative mortality was 0.8% in both groups.

"For many solid tumors, good local control and systemic therapy are essential," Dr. Sasako told Medscape Oncology. "In the case of gastric cancer, local control can be achieved with either radiotherapy or accurate D2 lymphadenectomy."

It should be noted, Dr. Sasako pointed out, that that the treatment of gastric cancer based on accurate lymphadenectomy of regional nodes can produce excellent results. "I don't think that D2 dissection is as common in the US as it is in Japan," he said, "But it seems that D2 lymphadenectomy and total gastrectomy can be performed by experienced surgical oncologists in high gastric cancer volume hospitals with minimal mortality and short hospitalizations. Adding PAND does not influence outcome."

One limitation of this study, the authors write, is that the incidence of metastases in the para-aortic nodes (8.5%) was lower than they had expected. However, D2 lymphadenectomy plus PAND in node-positive patients resulted in poorer survival rates than D2 lymphadenectomy alone. It is unlikely, therefore, that D2 lymphadenectomy plus PAND would have resulted in better survival rates if more patients with para-aortic node metastases had participated in the study.

The researchers have disclosed no relevant financial relationships.

This study was supported in part by grants-in-aid for cancer research and for the Second Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor, and Welfare of Japan.

N Engl J Med. 2008;359:453-452.

Reviewed by Ramaz Mitaishvili, MD

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