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From the Roswell Park Cancer Institute, Buffalo, New York.
Correspondence: Address correspondence to: Harold O. Douglass, MD, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263; Fax: 716-845-3434; E-mail: Harold.douglass{at}roswellpark.org
Why do reports from large volume single institutions continue to demonstrate low operative mortalities, short hospital stays, and prolonged patient survivals for patients with gastric cancer treated by D2 lymphadenectomy when randomized trials show no survival advantage and increased operative mortality with this procedure? Should gastric cancer resections be added to the growing list of procedures with reduced mortality and improved survivorship when performed in high-volume institutions?
Although not a randomized trial, the report by Dr. Sierra and colleagues from the University of Navarra in Paploma, Spain, adds credence to the concept that D2 resections can be performed safely and provide enhanced survival when performed in high-volume hospitals by a small group of experienced surgeons.1,2 The D2 dissection that they performed included total gastrectomy and splenectomy but did not require resection of the tail of the pancreas as performed in the Dutch and British randomized trials.3,4 Instead, lymph nodes along the splenic artery (station 11 in the Japanese classification) were usually dissected away from surrounding tissues to be included with the resected specimen. Pancreatic fistulas did occur in three of the eight D2 patients who required pancreatic resection. This suggests that, in the randomized trials, the pancreatic resection, rather than the splenectomy and the D2 lymphadenectomy, was the major cause of the excess operative mortality in the D2 group.3,4
In this nonrandomized comparison, how comparable were the two groups of patients? Could patient characteristics explain the better survival in the D2 group? Patients in the D2 group were younger and had fewer comorbidities (ASA I index in 82% of D2 patients vs. 52% of the D1 group) and were treated by total gastrectomy (100% of D2 vs. 44% of D1 patients) and adjuvant radiotherapy (47% of D2 vs. 27% of D1 patients). On the other hand, patients treated by D1 resection were less likely to have lymph node metastases (45% of D1 patients were stage N0 vs. 37% of the D2 group) and M1 disease (13% of D1 vs. 20% of D2 patients). Thus, survival benefit of D2 dissection could only be explained from these characteristics if total gastrectomy vastly improved survival, which it does not.
On average, more than twice as many lymph nodes were removed by D2 resections as compared with D1 (31 vs. 14 lymph nodes, respectively). The authors evaluated the fraction of lymph nodes containing metastases divided by the total number of lymph nodes removed (nodal index), noting that this fraction was 20% or less in 34% of patients in the D2 group but was only 17% among D1 patients. Patients with a nodal index of 20% or less had a significantly prolonged survival compared with the group of gastric cancer patients as a whole, whether treated by D1 or D2 resection. Although increased survival of more advanced stage patients in a series of D2 resections has been attributed to stage migration, there is no question that the D2 dissection allows long-term survival of some patients with metastases in second echelon lymph nodes who would otherwise be expected to have local recurrence if only a D1 resection had been performed. In our experience nearly one third of patients with metastases in second echelon lymph nodes survived more than 5 years.5
The significance of the number of positive metastatic lymph nodes in gastric cancer patients has been repeatedly emphasized and was the basis of the change in the 1997 International Union Against Cancer and American Joint Committee on Cancer gastric cancer staging systems. For accurate staging in this system, at least 16 lymph nodes must be subjected to histopathologic study. This goal is difficult to attain with D1 resection. Takagane and colleagues emphasized that the ratio of the numbers of lymph nodes containing metastases to the total number of lymph nodes examined was highly prognostic.6 Subsequently, Inoue demonstrated that this ratio-based classification of lymph nodes was prognostically more accurate than the total number of positive lymph nodes.7
Although a median survival of 37 months defines the Sierra report as "early", most patients with recurrent gastric cancer develop that recurrence within 18 months, and median survival with disease adds approximately another 6 months. Thus, it is likely that at the time when minimum follow-up exceeds 5 years, the survival patterns of patients treated by D2 and D1 resections may diverge still further.
Finally, what was the role of adjuvant treatment with radiotherapy (given to 47% of the D2 group vs. 27% of D1 patients) and chemotherapy (administered to 33% of D1 patients vs. 28% of the D2 group)? Obviously, radiotherapy was well tolerated after total gastrectomy and D2 lymphadenectomy. With estimated overall 5-year survivals of almost 51% of D2 patients and 41% of D1 patients with stages II, III, and IV gastric cancer, how much did adjuvant therapy add? Unfortunately, Dr. Sierra did not provide the data to determine whether there was any evidence that adjuvant therapy impacted on survival. The large intergroup controlled gastric cancer chemoradiation trials showed an approximately 20% survival advantage in survival in the group of patients receiving chemoradiation versus those who did not.8 Since only 10% of patients entered into that trial were treated by D2 lymphadenectomy, this difference was not related to surgical intervention. In the intergroup study, adjuvant therapy had no impact on distant metastases (occurring in 15% of the surgery-only group and 14% of the chemoradiotherapy group). The impact of chemoradiotherapy was confined to control of local and regional relapse (67% recurrence in the surgery-only group vs. 33% in patients who received chemoradiotherapy). Since most of the benefit of chemoradiation occurred in the surgical field, and most of these sites would be removed by total gastrectomy and D2 lymphadenectomy, the question of how much benefit can be expected from adjuvant chemoradiation after a thorough surgical oncologic procedure for gastric cancer must be raised. Not to be overlooked is the 41% 5-year survival of D1 patients and 51% survival of D2 patients with stages II, III, and IV gastric cancer at the University of Navarra versus the less than 30% survival of the surgery-only patients entered into the intergroup study.
What have we learned from Dr. Sierra and colleagues? A D2 lymphadenectomy and total gastrectomy can be performed by experienced surgical oncologists in high gastric cancer volume hospitals with minimal mortality and short hospitalizations, providing a significantly enhanced duration of survival. Whether a D2 operation for gastric cancer can replace 4500 centigray of radiotherapy and 4 months of chemotherapy is still to be determined. If it can, the cost-benefit ratio would strongly shift to favor surgery.
Received for publication January 21, 2003. Accepted for publication February 10, 2003.
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