Correspondence

Surgery for Gastric Cancer

N Engl J Med 1999; 341:538-539August 12, 1999

Article

To the Editor:

The results of the randomized trial comparing extended (D2) and limited (D1) lymph-node dissection for gastric cancer, reported by Bonenkamp et al. (March 25 issue),1 should be interpreted with caution. Patients in the D2 group had a higher in-hospital death rate than those in the D1 group. It has already been suggested that the learning curve and protocol design (removal of the pancreatic tail in patients with a proximal tumor who were undergoing a D2 dissection) account for the difference.2 The high percentage of in-hospital deaths in the D2 group might have introduced a bias in the estimate of long-term survival. The excess early mortality in the D2 group may explain, at least in part, the small difference in the survival rate between the two groups at five years. Using data from Table 2 of the report by Bonenkamp et al., we estimated the risk of death for patients in each group: the relative risk was 1.04 (95 percent confidence interval, 0.9 to 1.2) for the patients in the D1 group as compared with those in the D2 group when in-hospital deaths were included; when these deaths were excluded, it was 1.11 (95 percent confidence interval, 1.0 to 1.3). These calculations suggest that the inclusion of in-hospital deaths biased the difference toward the null hypothesis.

The high rate of protocol deviations also might have reduced the ability to detect differences between the two treatments. The authors acknowledged this problem in an interim report3 but gave no information about the number and sites of dissected nodes.

The conclusions of the paper that D2 dissection is unsafe and does not improve long-term survival are debatable, because they may have a negative influence on Western surgeons who treat this curable disease. Indeed, extended lymphadenectomy can be safely and effectively performed by Western surgeons.4,5 The introduction of techniques that preserve the pancreas has reduced postoperative complications.6 The argument that differences in survival might reflect stage migration is contradicted by the persistent differences when overall survival curves are compared, regardless of staging.5

Fabio Pacelli, M.D.
Antonio Sgadari, M.D.
G.B. Doglietto, M.D.
Catholic University School of Medicine, 00168 Rome, Italy

6 References

1. 1

   Bonenkamp JJ, Hermans J, Sasako M, van de Velde CJH. Extended lymph-node dissection for gastric cancer. N Engl J Med 1999;340:908-914
   Full Text | Web of Science | Medline

2. 2

   Sue-Ling HM, Johnston D. D1 versus D2 dissection for gastric cancer. Lancet 1995;345:1515-1516
   CrossRef | Web of Science | Medline

3. 3

   Bunt AM, Hermans J, Boon MC, et al. Evaluation of the extent of lymphadenectomy in a randomized trial of Western- versus Japanese-type surgery in gastric cancer. J Clin Oncol 1994;12:417-422
   Web of Science | Medline

4. 4

   Siewert JR, Bottcher K, Stein HJ, Roder JD. Relevant prognostic factors in gastric cancer: ten-year results of the German Gastric Cancer Study. Ann Surg 1998;228:449-461
   CrossRef | Web of Science | Medline

5. 5

   Pacelli F, Doglietto GB, Bellantone R, Alfieri S, Sgadari A, Crucitti F. Extensive versus limited lymph node dissection for gastric cancer: a comparative study of 320 patients. Br J Surg 1993;80:1153-1156
   CrossRef | Web of Science | Medline

6. 6

   Pacelli F, Doglietto GB, Alfieri S, et al. Avoiding pancreatic necrosis following pancreas-preserving D3 lymphadenectomy for gastric cancer. Br J Surg 1998;85:125-126
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: The comment of Pacelli and colleagues that insufficient experience and incorrect indications for pancreaticosplenectomy accounted for the relatively high rate of in-hospital deaths among the patients in the D2 group in our trial has already been answered: D2 dissection remains an independent risk factor for in-hospital death in a multivariate Cox regression.1

Pacelli et al. further suggest that the inclusion of in-hospital deaths biased the results with respect to the long-term survival in favor of D1 dissection. Apart from being methodologically incorrect in excluding the in-hospital deaths from an analysis of survival, they have made a miscalculation in their estimate of the relative risks. Cox regression analysis of the data in Table 2 of our report, along with the data on individual patients, reveals that the long-term relative risk of death, including in-hospital deaths, is 1.00 (95 percent confidence interval, 0.82 to 1.21); when in-hospital deaths are excluded, the relative risk is 1.11 (95 percent confidence interval, 0.91 to 1.37). In our report we also provided data for the risk of relapse for patients who had R0 resections (i.e., those who had no microscopical evidence of remaining disease) but did not die in the hospital. For this cohort, we showed Kaplan–Meier curves for the risk of relapse and survival (Figure 2 of our report), again supporting our conclusions.

Finally, Pacelli and colleagues suggest that protocol deviations might have reduced differences in the survival rate by diminishing the distinction between D1 and D2 dissections. However, we stated explicitly in the Discussion section of our article, on the basis of the meticulously collected information on lymph nodes in our trial, that the surgeons conformed well to the protocol. Detailed information on compliance with the protocol has been provided in earlier reports.2,3

Our conclusion — that we found no support for the routine use in the Netherlands of D2 lymph-node dissection in patients with gastric cancer — is based on the results of a large, randomized trial. Further support for this conclusion can be found in the results of the British Medical Research Council trial.4 This evidence cannot be invalidated by referring to single-center, nonrandomized studies demonstrating a lower in-hospital death rate with D2 dissection.

J.J. Bonenkamp, M.D., Ph.D.
Leiden University Medical Center, 2300 RC Leiden, the Netherlands

Mitsuru Sasako, M.D.
National Cancer Center Hospital, Tokyo 104-0045, Japan

Cornelis van de Velde, M.D., Ph.D.
Leiden University Medical Center, 2300 RC Leiden, the Netherlands

4 References

1. 1

   Sasako M. Risk factors for surgical treatment in the Dutch Gastric Cancer Trial. Br J Surg 1997;84:1567-1571
   CrossRef | Web of Science | Medline

2. 2

   Bunt AM, Hermans J, Boon MC, et al. Evaluation of the extent of lymphadenectomy in a randomized trial of Western- versus Japanese-type surgery in gastric cancer. J Clin Oncol 1994;12:417-422
   Web of Science | Medline

3. 3

   Bonenkamp JJ, Hermans J, Sasako M, van de Velde CJH. Quality control of lymph node dissection in the Dutch randomized trial of D1 and D2 dissection for gastric cancer. Gastric Cancer (in press).
   

4. 4

   Cuschieri A, Weeden S, Fielding J, et al. Patient survival after D1 and D2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Br J Cancer 1999;79:1522-1530
   CrossRef | Web of Science | Medline