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© 2003 American Society for Clinical Oncology
Improving Treatment Outcome for Gastric Cancer: The Role of Surgery and Adjuvant Therapy
From the Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands. Address reprint requests to Cornelis van de Velde, MD, PhD, Department of Surgery, K6-R, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, the Netherlands; e-mail: c.j.h.van_de_velde{at}lumc.nl.
ALTHOUGH ITS incidence is declining in Western Europe,1 gastric cancer remains the second most common cause of cancer death worldwide.2 Gastric cancer patients are at risk for locoregional failure after surgical treatment, which is accountable for poor survival.3 Although it is beyond dispute that curative treatment remains primarily surgical, the best multimodality treatment, resulting in optimal local control and survival, is still a matter of controversy.4 In this brief report, we highlight the debate that has centered on the extent of lymph node dissection and the role of adjuvant therapy. Reported survival rates for gastric cancer patients have always been consistently higher in Japan than in the West. Japanese investigators ascribe this difference largely to a wider lymph node clearance in their patients compared with that of Western patients. This has led to establishment of the D2 dissection as the standard procedure in Japan, merely based on retrospective reports.5 However, available randomized prospective trials investigating the benefits of D2 compared to D1 dissection have failed to support extended lymph node dissection. The Medical Research Council initiated a multicenter randomized controlled trial and concluded that the classical Japanese D2 resection did not offer any survival advantage over D1 surgery (5-year survival rates, 33% and 35%, respectively).6 Moreover, there was notably increased postoperative morbidity (28% for D1 and 46% for D2) and mortality (6.5% for D1 and 13% for D2) in patients who underwent extended lymph node dissection.7 These results are in line with those of the large-scale trial from the Dutch Gastric Cancer Group that addressed the same question. Morbidity and mortality were 25% and 4% in the D1 group and 43% and 10% in the D2 group, respectively,8 and there was no significant survival difference after a median follow-up of 5 years.9 However, after a median follow-up of 11 years, a noteworthy benefit of D2 dissection is currently observed in N2-positive patients, in that 20% of these patients are still alive (unpublished data). Tools are lacking, however, to identify this subgroup of patients before surgery, which hinders tailored surgical treatment. Based on these randomized trials, one would be inclined to dismiss extended lymph node dissection, at least in the Western patient population. However, the substantial mortality rates in the D2 arm of both trials possibly masked a benefit that might have arisen from extended surgery. Pancreaticosplenectomy was considered compulsory at the start of the Dutch trial8 and was performed in as many as 30% of patients assigned to D2 dissection. Multivariate analysis indicated that splenectomy contributed to hospital death (hazard ratio [HR], 2.16) and overall complications (HR, 2.13) whereas pancreaticosplenectomy carried a major risk for surgical complications (HR, 3.34). Indeed, recent reports have shown that extended lymph node dissection can be performed safely with preservation of the spleen and pancreatic tail, not only in Japanese but also in Western patients: in a recently presented Italian prospective trial10 comparing D1 dissection with D2 dissection in 162 patients, morbidity and mortality were 16.3% and 0%, respectively, in D2 patients, indicating it is possible to achieve results comparable with those of Japanese centers, provided that surgery is centralized in specialized centers. These figures are in concordance with the phase I/II trial that preceded this randomized trial.11 This finding stresses the importance of surgical expertise and skill, which has been previously identified as a risk factor for postoperative mortality in gastric cancer patients.12 Within this surgical context, the question arises as to what role adjuvant therapy plays in the management of gastric cancer. Several meta-analyses have been performed studying the role of postoperative chemotherapy. One early meta-analysis concluded that postoperative chemotherapy did not improve survival,13 whereas more recent meta-analyses that included trials investigating the efficacy of novel agents showed a marginal survival benefit from combined treatment.14–16 The question remains, however, of to what extent adjuvant treatment can contribute to local control and survival when combined with optimal surgery. So far, surgery within Western trials has either been insufficient17,18 or accompanied by considerable morbidity and mortality.6,9 In Japan, where surgery may be regarded as adequate, considering the low morbidity and mortality and excellent local control, postoperative chemotherapy has shown to be of limited value so far. This might be due to an insufficient acting mechanism of applied chemotherapeutics, a delayed initiation of chemotherapy due to slow recovery after surgery, a sample size in Japanese trials too small to detect clinically relevant differences, or a combination of these. Deliberating on the aforementioned, there is a clear need for well-designed prospective trials investigating the efficacy of effective chemotherapeutic regimes in combination with quality controlled surgery, in which postoperative morbidity and mortality are reduced through centralized surgical treatment. Initiating such trials may contribute to a step forward in the treatment of gastric cancer patients.
The authors indicated no potential conflicts of interest.
K.C.M.P. is a European Organization for the Research and Treatment of Cancer Medical Research Fellow.
1. Ekstrom AM, et al: Decreasing incidence of both major histologic subtypes of gastric adenocarcinoma: A population-based study in Sweden. Br J Cancer 83:391–396, 2000[CrossRef][Medline] 2. Parkin DM, Pisani P, Ferlay J: Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer 80:827–841, 1999[CrossRef][Medline] 3. Gunderson LL, Sosin H: Adenocarcinoma of the stomach: Areas of failure in a re-operation series (second or symptomatic look) clinicopathologic correlation and implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 8:1–11, 1982
4. van de Velde CJ, Peeters KC: The gastric cancer treatment controversy. J Clin Oncol 21:2234–2236, 2003 5. Maruyama K, Sasako M, Kinoshita T, et al: Should systematic lymph node dissection be recommended for gastric cancer? Eur J Cancer 34:1480–1489, 1998 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. Cuschieri A, Fayers P, Fielding J, et al: Postoperative morbidity and mortality after D1 and D2 resections for gastric cancer: Preliminary results of the MRC randomised controlled surgical trial—The Surgical Cooperative Group. Lancet 347:995–999, 1996[CrossRef][Medline] 8. 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]
9. 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 10. Degiuli M: Morbidity and mortality after D1 and D2 gastrectomy for cancer: Preliminary results of the Italian Gastric Cancer Study Group (IGCSG) randomised surgical trial. Presented at the Fifth International Gastric Cancer Congress, Rome, Italy, May 4–7, 2003
11. Degiuli M, et al: Morbidity and mortality after D2 gastrectomy for gastric cancer: Results of the Italian Gastric Cancer Study Group prospective multicenter surgical study. J Clin Oncol 16:1490–1493, 1998 12. Bottcher K, Siewert JR, Roder JD, et al: Risk of surgical therapy of stomach cancer in Germany. Results of the German 1992 Stomach Cancer Study. German Stomach Cancer Study Group (’92). Chirurg 65:298–306, 1994[Medline]
13. Hermans J, Bonenkamp JJ, Boon MC, et al: Adjuvant therapy after curative resection for gastric cancer: Meta-analysis of randomized trials. J Clin Oncol 11:1441–1447, 1993 14. Earle CC, Maroun JA: Adjuvant chemotherapy after curative resection for gastric cancer in non-Asian patients: Revisiting a meta-analysis of randomised trials. Eur J Cancer 35:1059–1064, 1999
15. Mari E, et al: Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: A meta-analysis of published randomised trials—A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’Apparato Digerente). Ann Oncol 11:837–843, 2000 16. Panzini I, et al: Adjuvant chemotherapy in gastric cancer: A meta-analysis of randomized trials and a comparison with previous meta-analyses. Tumori 88:21–27, 2002[Medline]
17. Macdonald JS, 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 18. Hundahl SA, Macdonald JS, Benedetti J, et al: Surgical treatment variation in a prospective, randomized trial of chemoradiotherapy in gastric cancer: The effect of undertreatment. Ann Surg Oncol 9:278–286, 2002[CrossRef][Medline] Submitted August 5, 2003; accepted August 5, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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