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© 2003 American Society for Clinical Oncology
The Gastric Cancer Treatment ControversyDepartment of Surgery Leiden University Medical Center Leiden, the Netherlands GASTRIC CANCER is still a major problem. It is the most frequent cause of cancer-related deaths worldwide, although its incidence has steadily declined during the last decades in Western countries. Although screening programs are active in Japan, gastric cancer is often diagnosed at an advanced stage in areas outside of Japan. In operable gastric cancer, both the extent of surgery and the value of adjuvant treatment remain subject to considerable international controversy. Surgery is the cornerstone in the treatment of gastric cancer. In Japan, a D2 lymph node dissection is the standard surgical procedure because of its acceptable safety profile and superior treatment outcome.1 This extended lymph node dissection was also performed in a randomized trial2 that compared the role of postoperative adjuvant therapy with mitomycin, fluorouracil (FU), and cytarabine followed by oral FU to surgery alone in serosa-negative gastric cancer. In fact, 98% of the patients underwent a D2 or greater lymph node dissection with just one postoperative death in the surgery-only arm. The total recurrence rate at 69 months was almost double in the surgery-alone group (13.8% v 7.1%), indicating a possible role for chemotherapy in the prevention of recurrence. This difference, however, was not statistically significant. Local control was remarkable: only two patients in the surgery-alone arm and none in the combined-treatment arm developed a local recurrence. This excellent local control is probably due to extended surgery and the patient population in this trial. Chemotherapy did not lead to a significant difference in overall survival compared with surgery alone (with 5-year survival rates of 91.2% and 86.1%, respectively) or in relapse-free survival compared with surgery alone (with 5-year survival rates of 88.8% and 83.7%, respectively). Noteworthy is the excellent treatment outcome after surgery alone, which is much better than that expected by the investigators, considering their study design. The trial was designed to detect a 15% absolute difference in 5-year survival. In comparison with a similar percentage increase for early breast cancer, polychemotherapy administered to early breast cancer patients older than 50 years of age showed a 10-year survival benefit of 2% to 3%.3 To accomplish an increase in 5-year survival rate from 70% to 85% in gastric cancer patients in this trial therefore seems rather optimistic, especially if patients are diagnosed at a relatively early stage (serosa-negative, T2). That the results of this underpowered trial did not reach statistical significance is therefore not surprising. Although a D2 dissection is the generally accepted surgical procedure in Japan, the debate about the benefits of D1 versus D2 lymph node dissection is still ongoing. Convinced of the benefits of a D2 resection, Japanese investigators have always been reluctant to conduct a trial comparing D2 with D1 dissection. In Europe, however, two large randomized controlled trials were performed that addressed this issue. The British Medical Research Council Trial4 could not detect a difference in survival, with 5-year survival rates of 35% for D1 and 33% for D2 dissection. Moreover, postoperative morbidity (28% for D1 and 46% for D2) and mortality (6.5% for D1 and 13% for D2) were increased. Another large-scale randomized trail, conducted by the Dutch Gastric Cancer Group,5 proved no benefit from D2 lymphadenectomy in either survival or in local relapse rates. This latter trial included surgical quality control that required surgeons to be trained in the technique of D2 node dissection by a Japanese surgeon.6 Additional quality-control measures were taken to guarantee the intended technical difference between D1 and D2 resection. Nevertheless, contamination (dissection of lymph nodes outside the indicated area) and noncompliance (incomplete lymph node dissection) were observed and acknowledged as possible confounders of treatment outcome.7 After postoperative deaths were excluded, patients that underwent a curative (R0) resection had a cumulative risk of relapse of 43% after a D1 dissection and 37% after a D2 dissection (95% confidence limit = -2.4%, +14.4%). However, morbidity and mortality were 25% and 4% in the D1 group and 43% and 10% in the D2 group, respectively.8 Splenectomy was performed in 11% of the D1 patients and in 37% of the D2 patients, with resection of the spleen as a major risk for hospital death (hazard ratio, 2.16) and overall complications (hazard ratio, 2.13), whereas pancreatosplenectomy (30% in the D2 group and 2.6% in the D1 group) increased the risk for surgical complications (hazard ratio, 3.34). The operative mortality caused by splenectomy in both European trials could have reduced the chance of detecting a marginal benefit from D2 dissection. Multivariate analysis has shown that splenectomy has a deleterious effect on 5-year survival probability.9 Taken together, both randomized trials failed to demonstrate an advantage for the extended D2 procedure. However, a recent randomized surgical trial of 153 patients with gastric cancer that compared D1 to D2 dissection showed that extended lymph node dissection could be performed with low morbidity (9.4% and 16.3%, respectively; P < .1) and mortality (1.3% and 0%, respectively) in experienced centers.10 Another prospective randomized trial by Wu et al11 of 220 eligible patients comparing D1 with D2 or D3 dissection showed equal morbidity (7%) and no mortality in both treatment groups. If all of these findings are considered, a so-called over D1 lymphadenectomy (ie, a D1 dissection and retrieval of at least 20 to 25 nodes) might be recommended on the basis of the finding that the probability of accurate assessment of the lymph node status increases with the number of nodes resected, with a plateau reached at 20 to 25 nodes.12 This recommendation adheres to the principle that lymph nodes are regarded as indicators rather than governors of disease, which indicates that lymphadenectomy serves as a staging tool rather than exerting a therapeutic effect.13 The controversy involving D1 versus D2 lymph node dissection might be settled by the introduction of the over D1 dissection, omitting splenectomy and distal pancreatectomy. The roles of adjuvant and neoadjuvant therapy also have been debated for a long time. Gastric cancer is a disease in which locoregional control is difficult to obtain. Gunderson and Sosin14 showed that relapse in gastric cancer patients after initial curative surgery consisted of local recurrence or regional lymph node metastasis in 87.8% of the patients. This high risk of local recurrence prompted some investigators to study the combination of radiotherapy and chemotherapy. The results of the United States Intergroup study by the Southwest Oncology Group, which indicated a significant overall survival benefit (36 v 27 months in the surgery-alone group) after postoperative chemoradiation, have lead to standardization of this regimen in the United States.15 During the trial, much attention was paid to quality assurance for radiotherapy, reflected in the fact that 35% of the treatment plans were found to contain major or minor deviations from the protocol and could be corrected before the start of radiotherapy. There was, however, criticism of the adequacy of the surgical procedure: Although a D2 lymph node dissection was recommended in the protocol, this procedure was only performed in 10% of the patients and 54% of the patients did not have a formal clearance of the N1 tier of regional lymph nodes. This noncompliance clearly undermined survival16 and led to a high relapse rate of 64% after a median follow-up of 5 years in the surgery-only arm. Although trial results should be compared with care, the difference is considerable when compared with the Dutch trial, in which only 44% of patients in the D1 arm developed a local recurrence after a median follow-up of 6 years. It is clear that the extent and quality of surgery affects the value of adjuvant treatment. In a considerable part of Europe, surgery alone is the standard of care, with increasing emphasis on surgical quality assurance. Although a meta-analysis17 of randomized trials to evaluate the effect of adjuvant treatment concluded that postoperative chemotherapy could not be considered as standard adjuvant treatment, many patients in Japan and in southern Europe routinely receive postoperative chemotherapy. Yet another meta-analysis by Earle and Maroun18 of 13 trials showed a small but significant survival benefit for patients receiving postoperative chemotherapy. There was an absolute risk reduction from 65% to 61% in relapse-free survival after postoperative chemotherapy, indicating that 25 patients need to be treated to prevent one death. In Japan, seven early trials conducted before 1975 used various adjuvant chemotherapy regimens with a comparison to a surgery-alone arm. After 1975, the surgery-alone control arm suddenly disappeared in Japanese multi-institutional trials, without a definite reason. Therefore, 14 trials between 1975 and 1988 were conducted without a surgery-alone arm. Four trials were performed to compare different regimes of chemotherapy, two trials compared dose-intensity of a chemotherapy regimen, and eight trials were designed to test the effect of adding an immunotherapeutic agent to the chemotherapy. Mitomycin, which was also investigated by Nashimoto et al,2 was almost always used as a cytotoxic agent in combination regimens. Local recurrence, in this trial, occurred in only two patients in the surgery-alone arm, which means that locoregional control was well achieved by extensive surgery in this group of patients. In the Southwest Oncology Group trial, in which patients had more advanced disease than in this study, local relapse occurred in 29% and regional relapse occurred in as many as 72% of the patients after surgery alone. Chemoradiation improved local and regional relapse to 19% and 65%, respectively, possibly indicating that the role for adjuvant treatment was partly compensation for inadequate surgery. In the present Japanese study, however, the chemotherapy regimen did not improve treatment outcome. The question remains, however, whether novel and effective chemotherapeutic agents have a role in combination with optimal surgery to further increase locoregional control and survival. Large randomized trials with enough power to detect clinically relevant differences are necessary to answer this question. Neoadjuvant treatment seems an attractive option in patients with gastric cancer. It has the potential of downstaging the disease, and possibly enabling curative resection and increased compliance of systemic therapy in patients who often have prolonged morbidity after surgery. Ongoing trials will determine whether neoadjuvant chemotherapy has a role in gastric cancer. The MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial, initiated by the Medical Research Council in the United Kingdom, is investigating the role of pre- and postoperative epirubicin, cisplatin, and FU chemotherapy in combination with surgery compared with surgery alone, and the first results are eagerly awaited. New treatment regimens that are based on novel cytotoxic agents (such as paclitaxel and irinotecan) and biologic agents (such as antiangiogenics and epidermal growth factor receptor monoclonal antibody) might also gain a place in the treatment of gastric cancer in the future. The limited benefit from adjuvant therapy in many trials to date might have been due to a residual tumor burden after surgery that was too high, a delayed initiation of chemotherapy, a sample size that was too small, insufficient activity mechanism of current chemotherapeutics, or any combination of these factors. Within Europe, the need for a well-designed prospective randomized trial is acknowledged by the European Organization for Research and Treatment of Cancer in the study of irinotecan with infusional FU plus leucovorin in combination with radiotherapy after surgery for resectable gastric cancer compared with surgery alone. Patients will be treated in specialized centers to ensure optimal surgery, using an over D1 resection without splenectomy and preservation of the pancreatic tail, thus minimizing postoperative morbidity and mortality. There will be mandatory extensive quality assurance of surgery and radiotherapy and close cooperation with pathology. In this way, the role of adjuvant treatment in combination with optimal surgery can be established. Tools such as sentinel lymph node biopsy are currently being developed to identify patients with a high risk of lymph node metastases, which could influence the extent of surgery. Genomic profiling of gastric adenocarcinomas using microarray analysis of chromosomal copy number changes also seems to be a promising development, enabling more tailored treatment.19 Until the use of these tools is validated, we must rely solely on the evidence for large groups of patients originating from quality-controlled trials. REFERENCES 1. Maruyama K, Sasako M, Kinoshita T, et al. Should systematic lymph node dissection be recommended for gastric cancer? Eur J Cancer 34:1480–1490, 1998[CrossRef][Medline]
2. Nashimoto A, Nakajima T, Furukawa H, et al: Randomized Trial of Adjuvant Chemotherapy With Mitomycin, Fluorouracil and Cytosine Arabinoside Followed by Oral Fluorouracil in Serosa Negative Gastric Cancer: Japan Clinical Oncology Group 9206-1. J Clin Oncol 21:2282–2287, 2003 3. Polychemotherapy for early breast cancer: An overview of the randomized trials—Early Breast Cancer Trialists’ Collaborative Group. Lancet 352:930–942, 1998[CrossRef][Medline] 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—Surgical Co-Operative Group. Br J Cancer 79:1522–1530, 1999.[CrossRef][Medline]
5. 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
6. Sasako M, Maruyama K, Kinoshita T, et al. Quality control of surgical technique in a multicenter, prospective, randomized, controlled study on the surgical treatment of gastric cancer. Jpn J Clin Oncol 22:41–48, 1992 7. Bunt TM, Bonenkamp HJ, Hermans J, et al. Factors influencing noncompliance and contamination in a randomized trial of "Western" (r1) versus "Japanese" (r2) type surgery in gastric cancer. Cancer 73:1544–1551, 1994[CrossRef][Medline] 8. Bonenkamp JJ, Songun I, Hermans J, et al. Randomized comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients. Lancet 345:745–748, 1995[CrossRef][Medline] 9. Bozzetti F, Marubini E, Bonfanti G, et al. Subtotal versus total gastrectomy for gastric cancer: Five-year survival rates in a multicenter randomized Italian trial— Italian Gastrointestinal Tumor Study Group. Ann Surg 230:170–178, 1999[CrossRef][Medline] 10. Deguili M, Sasako M, Garino M, et al. Outcome of D1 and D2 gastrectomy for gastric cancer: Preliminary results of the Italian Gastric Cancer Study Group (IGCSG) randomized controlled surgical trial. Presented at the XXXIII World Congress Int Coll Surg, Taipei, Taiwan, October 27–November 1, 2002 11. Wu CW. Preliminary results of gastric cancer surgery trials in a single institute. Presented at the XXXIII World Congress Int Coll Surg, Taipei, Taiwan, October 27–November 1, 2002 12. Bozzetti F. Principles of surgical radicality in the treatment of gastric cancer. Surg Oncol Clin N Am 10:833–854, 2001[Medline]
13. Cady B. Lymph node metastases: Indicators, but not governors of survival. Arch Surg 119:1067–1072, 1984 14. 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[Medline]
15. 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
16. 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
17. 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 18. Earle CC, Maroun JA. Adjuvant chemotherapy after curative resection for gastric cancer in non-Asian patients: Revisiting a meta-analysis of randomized trials. Eur J Cancer 35:1059–1064, 1999[CrossRef][Medline] 19. Weiss MM, Kuipers EJ, Postma C, et al. Genomic profiling of gastric cancer predicts lymph node status and survival. Oncogene 22:1872–1879, 2003[CrossRef][Medline]
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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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