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Originally published as JCO Early Release 10.1200/JCO.2004.02.995 on June 15 2004 © 2004 American Society of Clinical Oncology.
Lymphadenectomy for Gastric CancerDepartment of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Perhaps the greatest criticism of reports from Japan and other Asian countries demonstrating significant benefits and modest morbidity from extended lymph node dissection for gastric cancer has been the retrospective nature of the data. Despite enormous numbers of patients afflicted with gastric cancer in Japan, these retrospective reports have often been considered suspect by many Western surgeons because of a lack of prospective randomized studies. These suspicions will be challenged with the first report of the Japan Clinical Oncology Group (JCOG) study of lymphadenectomy in this issue of the Journal of Clinical Oncology.1 Although some questions may yet persist as to the applicability and rationale for extended lymphadenectomy for gastric cancer, Sano et al are to be commended for completing this ambitious trial of D2 lymph node dissection compared with a more extensive lymphadenectomy. A D1 lymphadenectomy includes only those nodes adjacent to the stomach; a D2 dissection also removes the nodes around the branches of the celiac axis. The JCOG trial randomly assigned patients at surgery, after confirming the ability to perform a curative resection (R0) to either a D2 dissection or to a more radical node dissection that included the nodal tissue along the aorta. This study built on lessons learned by Professor Sasako (one of the major collaborators of this study) from his significant involvement in the Dutch randomized trial of D1 dissection compared to D2 dissection.2,3 The JCOG study was conducted at 24 centers, each of which entered an average of more than 20 patients; this compares with the Dutch trial, in which 80 centers averaged fewer than 10 entries each. In addition, surgeons in this study had to have personally performed more than 100 gastric resections or be at an institution with a specialized unit where more than 80 gastric resections were performed annually. There are relatively few surgeons in the United States who would have been able to participate in this study. To put this level of experience into perspective, we conducted a recent review of all patients who underwent a gastric resection for cancer at a hospital in the state of Texas during a 3-year period. We found that the median annual number of resections per institution was only two, and only two hospitals in the entire state performed more than 15 gastric resections per year. Neither would have met the criteria for participation in the JCOG study. Not surprisingly, our review found that operative mortality was significantly lower at the higher volume centers. When the operative survival rates of the JCOG study are compared with large population-based studies of US patients, where the operative mortality for gastrectomy approximates 9%, the mortality rate presented here of less than 1% seems remarkable.4 There are, however, likely to be significant differences in the patient populations. Virtually all of the patients in this study were considered to be potentially curative after a rigorous intraoperative evaluation that included negative peritoneal cytology. Patients who undergo a palliative resection are much more likely to suffer postoperative morbidity and mortality than those undergoing a potentially curative resection. However, one must also consider the experience at major US centers such as Memorial Sloan-Kettering, where D2 dissection is routinely used, with a reported operative mortality rate of 3.6% in 865 patients undergoing an R0 resection.5 At The University of Texas M.D. Anderson Cancer Center, where spleen-preserving D2 dissection is performed, the mortality rate was 1.7% in 175 patients treated on eight prospective trials of neoadjuvant therapy. These rates, although not quite as low as the rates reported in the current JCOG study, are well below those seen in both the Dutch and Medical Research Council trials, as well as the large US national database surveys.2,6 Another important factor seen in this report is the pathologic evaluation of the specimen. Patients who had the "limited" procedure (D2) had an average of 54 nodes evaluated. This is compared with the experience in the United States, where, in the retrospective study by Wanebo et al,4 more than one third of patients had no nodes reported in the pathologic specimen. Though surgery was not part of the protocol in the Intergroup 0116 trial, which demonstrated a significant survival advantage with adjuvant chemoradiotherapy therapy, it was found that more than half of the patients entered were considered to have had a D0 dissection (less than a D1 dissection).7 Although there are relatively few surgeons in the United States who perform a D2 dissection, it is very difficult—if not impossible—to remove a stomach without taking some nodes with the specimen. This raises serious questions as to the thoroughness of pathologic evaluations of resected gastric specimens in this country. Why is the mortality rate so low in the JCOG study? The authors identify some possible explanations. First, patients had to be considered very fit for a major operation. The median age for all patients was only 61 years, and no patient was older than 75 years. It is unclear as to whether all patients were required to undergo a stress EKG or only those patients in whom some clinical suspicion for cardiac disease was raised. Second, surgeons and their centers were highly experienced in performing the procedures. While Birkmeyer et al8,9 did not specifically look at gastrectomy in their studies of operative mortality and volume, it is clear that critical determinants of surgical mortality for major operations are the surgical volume of both the surgeon and the institution. Third, surgeons in the JCOG trial, though frequently employing splenectomy (in 36.5% of all patients) to effect a complete node dissection, assiduously avoided pancreatectomy, (in 4.2% of all patients) unless absolutely necessary. The Dutch and Medical Research Council studies both found pancreatectomy to be significantly associated with an increased risk of operative mortality. What are not addressed in this study are other risk factors likely to be very different between Asian and Western patients. We do not know what the ranges (and averages) were for body mass index in this study, but it would be safe to assume that they would be significantly less than most American patients. With numerous reports in the lay press citing the increasing obesity of the population in the US, the impact on surgical morbidity and mortality should not be underestimated. Risks of both hypertension and diabetes are significantly increased in the obese patient and both of these are known to increase the risks of major surgical procedures. In addition, operations in these patients are more difficult, and it is at least this surgeon's observation that the risk of blood loss during resection sufficient to require a blood transfusion is increased in the obese patient. In this study, there was a significantly increased risk of needing a blood transfusion when the more extensive resection was performed. If there is any negative impact on long-term survival from blood transfusions, as has been debated in the literature, it may obscure any benefit of the more extended procedure and may become a point of academic discussion.10,11 Nonetheless, it will be most interesting to see whether the more extensive resection has an impact on survival; we will need to wait another 2 or more years for that information. Intuitively, leaving positive nodes behind assures the patient's demise secondary to recurrence of disease, and the potential survival impact of removing various nodal areas can be calculated by knowing the likelihood of involvement of those areas.12 However, it remains unclear as to how extensive any nodal dissection must be to optimize the benefit to the patient. For most solid malignancies, nodal dissection is considered principally a staging procedure. Whether extensive node dissection is a therapeutic or a staging endeavor, the JCOG trial will have a chance to answer this question, at least partially, because the toxicity of the intervention was so low. If highly effective adjuvant systemic therapies are available, such as for breast cancer, the benefit of a more extensive dissection may ultimately become more limited. Given the many differences between Japan and Western countries in incidence, surgical experience, and patient populations, it is unlikely that the final results of this study will have a significant immediate impact on surgical practices in the United States. Nevertheless, the results could impact how studies, such as the Intergroup 0116 trial, are interpreted. We may need to reconsider whether chemoradiotherapy is taking the place of a more extensive surgical procedure (possibly at a much higher cost), or if its benefit would also be extended to a more aggressive operation. Regardless of the eventual results of the JCOG study on our understanding of the impact of the more extensive nodal dissection on survival, it will serve as a landmark in the Japanese surgical experience, and I await JCOG's next surgical study with great anticipation. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
1. Sano T, Sasako M, Yamamoto S, et al: Gastric cancer surgery: Results of morbidity and mortality of a prospective randomized controlled trial (JCOG 9501) comparing D2 and extended para-aortic lymphadenectomy. J Clin Oncol 22:2767-2773, 2004 2. Bonenkamp JJ, Songun I, Hermans J, et al: Randomised comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients. Lancet 345:745-748, 1995[CrossRef][Medline]
3. Bonenkamp JJ, Hermans J, Sasako M, et al: Extended lymph-node dissection for gastric cancer. Dutch Gastric Cancer Group. N Engl J Med 340:908-914, 1999 4. Wanebo HJ, Kennedy BJ, Winchester DP, et al: Gastric carcinoma: Does lymph node dissection alter survival? J Am Coll Surg 183:616-624, 1996[Medline] 5. Martin RC 2nd, Jaques DP, Brennan MF, et al: Extended local resection for advanced gastric cancer: Increased survival versus increased morbidity. Ann Surg 236:159-165, 2002[CrossRef][Medline] 6. 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. Surgical Co-operative Group. Br J Cancer 79:1522-1530, 1999[CrossRef][Medline]
7. Macdonald JS, Smalley SR, Benedetti J, et al: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345:725-730, 2001
8. Birkmeyer JD, Siewers AE, Finlayson EV, et al: Hospital volume and surgical mortality in the United States. N Engl J Med 346:1128-1137, 2002
9. Birkmeyer JD, Stukel TA, Siewers AE, et al: Surgeon volume and operative mortality in the United States. N Engl J Med 349:2117-2127, 2003
10. Hyung WJ, Noh SH, Shin DW, et al: Adverse effects of perioperative transfusion on patients with stage III and IV gastric cancer. Ann Surg Oncol 9:5-12, 2002 11. Bortul M, Calligaris L, Roseano M, et al: Blood transfusions and results after curative resection for gastric cancer. Suppl Tumori 2:S27-S30, 2003[Medline] 12. Sasako M, McCulloch P, Kinoshita T, et al: New method to evaluate the therapeutic value of lymph node dissection for gastric cancer. Br J Surg 82:346-351, 1995[Medline] Related Editorial
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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