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Gastrointestinal Cancer
Lymphadenectomy for Gastric Adenocarcinoma: Should West Meet East?
SAM S. YOON,a HAN-KWANG YANGb Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; bDepartment of Surgery, Seoul National University Hospital, Seoul University College of Medicine, Seoul, South Korea
Key Words. Gastric cancer Surgery Lymphadenectomy Outcomes Review Disclosures: Sam S. Yoon: None; Han-Kwang Yang: None. Section editors Richard M. Goldberg, Patrick G. Johnston, and Peter J. ODwyer have disclosed no financial relationships relevant to the content of this article. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias.
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LEARNING OBJECTIVES
After completing this course, the reader will be able to: 1. Calculate the lymph node drainage patterns of gastric adenocarcinoma based on the location of the tumor. 2. Differentiate and explain the extent of lymphadenectomies performed in different countries. 3. Analyze the risks and benefits of performing more extensive lymphadenectomies for gastric adenocarcinoma.
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This article is available for continuing medical education credit at CME.TheOncologist.com.

ABSTRACT
The extent of lymphadenectomy that should be performed for gastric adenocarcinoma has been a topic of persistent debate. In countries such as Japan and Korea, where the incidence of gastric adenocarcinoma is high, more extensive (e.g., D2) lymphadenectomies are routinely performed, usually by experienced surgeons with low morbidity and mortality. In western countries such as the U.S., where the incidence of gastric adenocarcinoma is tenfold lower, the performance of more extensive lymphadenectomies is generally limited to specialized centers, and quite possibly the majority of patients are treated at nonreferral centers with less than a D1 lymphadenectomy. There is little disagreement among gastric cancer experts that the minimum lymphadenectomy that should be performed for gastric adenocarcinoma should be at least a D1 lymphadenectomy. Two large, prospective randomized trials performed in the United Kingdom and the Netherlands failed to demonstrate a survival benefit of D2 over D1 lymphadenectomy, but these trials have been criticized for high surgical morbidity and mortality rates in the D2 group. More recent studies have demonstrated that western surgeons can be trained to perform D2 lymphadenectomies on western patients with low morbidity and mortality. Retrospective analyses and one prospective, randomized trial suggest that there may be some benefits to more extensive lymphadenectomies when performed safely, but this assertion requires further validation. This article provides an update on the current literature regarding the extent of lymphadenectomy for gastric adenocarcinoma. The Oncologist 2009;14:871 882

Correspondence: Sam S. Yoon, M.D., Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Yawkey 7B-7926, 55 Fruit Street, Boston, MA 02114, USA. Telephone: 617-726-4241; Fax: 617-724-895; e-mail: syoon@ partners.org Received April 6, 2009; accepted for publication August 6, 2009; first published online in The Oncologist Express on September 8, 2009. AlphaMed Press 1083-7159/2009/$30.00/0 doi: 10.1634/theoncologist.2009-0070

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INTRODUCTION
Gastric cancer is one of the leading worldwide causes of cancer death, with about 803,000 deaths each year [1]. The incidence of gastric adenocarcinoma varies tremendously throughout the world, with the highest incidence occurring in South Korea at 66.572.5 per 100,000 males and 19.5 30.4 per 100,000 females [2]. The incidence of gastric cancer in the U.S. is only one tenth that of South Korea. The estimated number of new gastric cancer cases in the U.S. in 2008 was 21,500, and the estimated number of deaths was 10,880 [3]. Gastric adenocarcinoma frequently metastasizes to regional lymph nodes. For T1 lesions invading the submucosa, lymph node involvement is found in about 19% of patients [4]. For T2 lesions (invading the muscularis propria or submucosa), the lymph node metastasis rate increases to 50%. There is also significant evidence that some patients with lymph node metastases beyond the immediate perigastric lymph nodes can be cured with surgical resection alone [5]. Whether this group of patients represents a significant percentage of patients with resectable gastric cancer is a matter of debate, and thus the optimal extent of lymphadenectomy for adenocarcinoma of the stomach continues to be controversial. There are significant differences in the extent of lymphadenectomy performed by surgeons in different countries. To broadly generalize, surgeons in Japan and Korea routinely perform more extensive lymphadenectomies (D2 lymphadenectomy or greater) whereas most surgeons in the U.S. and many other western countries perform more limited lymphadenectomies (D1 lymphadenectomy or less). Two large, prospective randomized trials performed in The Netherlands and the United Kingdom found no survival benefit for D2 over D1 lymphadenectomy [6, 7]. However, there were significant problems with these studies, including a high morbidity and mortality rate in the D2 group, which was associated with inadequate surgical training, and with the frequent performance of a distal pancreatectomy and splenectomy in the D2 group, which is now considered unnecessary [8, 9]. Several studies since these randomized trials have suggested that more extensive lymphadenectomies may be beneficial in certain patients with gastric adenocarcinoma. These studies have demonstrated that: (a) D2 lymphadenectomies can be performed in specialized western centers without distal pancreatectomy or splenectomy and with low morbidity and mortality [1, 10, 11], (b) there may be a survival benefit for D2 lymphadenectomy if performed with low morbidity and mortality [12], and (c) there may be a

survival benefit if lymph node stations that are predicted to have metastatic disease preoperatively are removed [13, 14]. This article examines important historical trials and contemporary studies regarding lymphadenectomy for gastric adenocarcinoma. Regional differences in the extent of lymphadenectomy are reviewed. Hypothetical advantages of more extensive lymphadenectomies are discussed followed by an analysis of the available studies supporting or disclaiming these potential advantages. Barriers to the performance of more extended lymphadenectomies in western countries are also examined, followed by a discussion of how these barriers may be overcome.

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NODAL STATION AND LYMPHADENECTOMY DEFINITIONS

Prior to a discussion of lymph node dissections for gastric adenocarcinoma, one must define the terms to be used. The lymph node stations surrounding the stomach have been precisely defined by the Japanese Research Society for Gastric Cancer (JRSGC) [15] (Fig. 1, Table 1). The JRSGC defines four levels of lymph node stations, N1N4. The designation of N1N4 nodes varies according to the site of the primary tumor (i.e., upper, middle, or lower third of the stomach). The D level of lymphadenectomy (formerly known as the R level of lymphadenectomy) is based on the JRSGC definitions of lymph node station level [16]. A D1 lymphadenectomy is defined as removal of all N1 level nodes, and a D2 dissection is defined as removal of all N1 and N2 level nodes. Table 2 shows the lymph node stations that should be removed for a D1 and D2 lymphadenectomy (based on the location of the primary tumor) as recommended by the Japanese Gastric Cancer Association.

REGIONAL DIFFERENCES IN LYMPHADENECTOMY FOR GASTRIC ADENOCARCINOMA

As noted earlier, South Korea has the highest incidence of gastric adenocarcinoma in the world. Despite the high incidence of gastric adenocarcinoma in Korea, patients are often referred to tertiary care centers for treatment. Two thirds of all gastric cancer surgeries in South Korea are performed at 16 high-volume institutions, which perform at least 200 gastric cancer surgeries per year. Thus, gastric cancer surgeons at high-volume institutions in Korea gain tremendous experience in the surgical management of gastric cancer. The minimum lymphadenectomy performed by Korean surgeons for gastric adenocarcinoma is generally a D2 lymphadenectomy. Despite performing extensive lymphadenectomies, the morbidity and mortality rates are quite

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Figure 1. Locations of lymph node stations. Adapted from Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma2nd English editionresponse assessment of chemotherapy and radiotherapy for gastric carcinoma: Clinical criteria. Gastric Cancer 2001;4:1 8, with permission.

low. For example, Seoul National University Hospital, which performs almost 1,000 gastric cancer operations per year, recently reported a morbidity rate of 18% and mortality rate of 0.5% [17]. Japanese patients with gastric cancer are also frequently treated at high-volume institutions with low complication rates. In a prospective, randomized trial from 24 Japanese institutions of D2 versus extended paraaortic lymphadenectomy, the morbidity rate was 20.9% 28.1%, and the mortality rate was 0.8% [18]. Unlike in Korea and Japan, the majority of gastric cancer surgeries in the U.S. are performed at nonreferral centers, and thus a high-volume institution in the U.S. has been reported in some studies to be centers with only 1520 or more cases per year [19, 20]. Birkmeyer et al. [19] reviewed a database of Medicare patients and found that hospitals that performed 20 gastrectomies per year had significantly lower mortality rates, yet 80% of patients

were operated on at centers that performed 20 gastrectomies per year. Given that most U.S. general surgeons see few gastric cancer patients, these surgeons likely err on the side of more limited lymphadenectomies in order to avoid excess morbidity and mortality. The American College of Surgeons performed a survey study in 1993 of 18,000 patients treated at 700 institutions [21]. Of the 77% of patients that underwent gastric resection, perigastric lymph nodes were resected in 50% of patients. The overall survival rate in resected patients at 5 years was 19%, and the first site of recurrence was local or regional in 41% of patients that recurred. In the Intergroup 0116 trial, in which patients were randomized after gastric cancer surgery to no further therapy or chemoradiation, 50% of patients enrolled received less than a D1 lymphadenectomy [22, 23]. Most gastric cancer experts in both the east and west would agree that a D1 lymphadenectomy is the minimum lymph-

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Table 1. Regional lymph nodes of the stomach Number Description 1 2 3 4 sa sb d 5 6 7 8 a p 9 10 11 p d 12 a b p 13 14 v a 15 16 a1 a2 b1 Right paracardial Left paracardial Lesser curvature Greater curvature Along short gastric vessels Along left gastroepiploic vessels Along right gastroepiploic vessels Suprapyloric Infrapyloric Along left gastric artery Along common hepatic artery Anterosuperior group Posterior group Around celiac artery Splenic hilum Along splenic artery Along proximal splenic artery Along distal splenic artery Hepatoduodenal ligament Along hepatic artery Along bile duct Along portal vein Posterior surface of pancreatic head Along superior mesenteric vessels Along superior mesenteric vein Along superior mesenteric artery Along middle colic vessels Aortic hiatus Abdominal aorta (from upper margin of celiac trunk to lower margin left renal vein) Abdominal aorta (from lower margin left renal vein to upper margin inferior mesenteric artery) Abdominal aorta (from upper margin inferior mesenteric artery to aortic bifurcation) On anterior surface of pancreatic head Along inferior margin of pancreas Infradiaphragmatic In esophageal hiatus of diaphragm Paraesophageal in lower thorax Supradiaphragmatic Posterior mediastinal

Table 2. Extent of lymphadenectomy Location D1 dissection D2 dissection LMU LD/L LM, M, ML MU, UM U 16 3, 4d, 5, 6 1, 3, 4sb, 4d, 5, 6 16 1, 2, 3, 4sa, 4sb 7, 8a, 9, 10, 11p, 11d, 12a, 14v 1, 7, 8a, 9, 11p, 12a, 14v 7, 8a, 9, 11p, 12a 7, 8a, 9, 10, 11p, 11d, 12a 4d, 7, 8a, 9, 10, 11p, 11d
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When the tumor involves only one of the three portions of the stomach, this is expressed by U, M, or L. If the lesions involves more than one of the three portions of the stomach, this is expressed by listing the primarily involved portion first followed by the less involved portion(s). Abbreviations: D, duodenum; L, lower; M, middle; U, upper. Adapted from Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma2nd English editionresponse assessment of chemotherapy and radiotherapy for gastric carcinoma: Clinical criteria. Gastric Cancer 2001;4:1 8.

b2 17 18 19 20 110 111 112

Despite the performance of less extensive lymphadenectomies in the U.S., surgical morbidity and mortality rates for gastric adenocarcinoma are generally much higher in the U.S. than in South Korea and Japan. A recent analysis of the Nationwide Inpatient Sample from 1998 2003 of 50,000 patents with gastric cancer found that the overall mortality rate following gastric surgery was 6% [25]. Single-institution series have reported morbidity rates following gastrectomy of up to 40% [26]. Certain factors in Japanese and Korean patients, such as less advanced gastric cancer and fewer comorbidities such as cardiovascular disease and obesity, allow for lower morbidity and mortality rates, but almost certainly the surgical expertise and better perioperative care that comes with a higher volume play a significant role. Thus, in order for western surgeons to consider performing more extended lymphadenectomies with low morbidity and mortality, volume at referral centers needs to be increased and some additional surgical training is likely needed. The learning curve for training general surgeons for D2 lymphadenectomy has been estimated to be at least 23 cases [27]. Following adequate training, D2 lymphadenectomies can be performed by western surgeons on western patients with low morbidity and mortality rates similar to high-volume centers in the east [10, 11].

POTENTIAL BENEFITS OF MORE EXTENSIVE LYMPHADENECTOMIES

adenectomy that should be performed for gastric adenocarcinoma beyond an early T1 lesion [24]. Lymphadenectomy for cancer can serve three primary purposes: staging of disease, prevention of locoregional recur-

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rence, and improvement in overall survival. There is little doubt that more extensive lymphadenectomies for gastric adenocarcinoma lead to better staging of disease. The 2002 Sixth Edition of the American Joint Committee on Cancer Staging Manual for gastric adenocarcinoma recommends that at least 15 lymph nodes be examined for correct assessment of the N category [28]. An analysis of 6,000 gastric cancer patients treated at 691 U.S. hospitals found that 40% of patients undergoing surgical resection had the requisite 15 lymph nodes examined [29]. Using the Surveillance, Epidemiology, and End Results database, Coburn et al. [30] found that only 29% of 10,807 resected gastric cancer patients had 15 lymph nodes examined. In a study from the United Kingdom analyzing 18 hospitals, only 31% of the 699 surgical resections resulted in 15 lymph nodes analyzed [31]. Thus, many western patients are understaged following surgical resection of their gastric cancers because of inadequate lymph node sampling. Significant variability in the extent of lymphadenectomy and number of lymph nodes examined pathologically leads to difficulty in comparing the outcomes of patients from different regions based on stage of disease as well as stage migration. It is difficult to be confident that a tumor is truly node negative when 10 lymph nodes are examined [32, 33], and N1 tumors can be upstaged to N2 or even N3 tumors as more lymph nodes are harvested [33, 34]. Furthermore, it is impossible to be categorized as N3 if 15 lymph nodes are harvested. Several studies have demonstrated that examination of even more than 15 lymph nodes improves the ability to predict prognosis in patients with gastric adenocarcinoma [33, 35]. Shen et al. [35] found that increasing the total lymph nodes examined to 30 improved the accuracy of staging for patients with T3 disease. Several authors have found that the ratio of involved lymph nodes to resected lymph nodes may be a better predictor of prognosis than the absolute number of positive lymph nodes. In one study of 9,058 patients who underwent resection for gastric cancer, the ratio of involved lymph nodes to resected lymph nodes was a more precise predictor of prognosis than the absolute number of positive lymph nodes [36]. Similar findings were reported by the German Gastric Cancer Study [37] and the Italian Research Group for Gastric Cancer [38]. Thus, there is little debate that more extensive lymphadenectomies improve staging for patients with gastric adenocarcinoma. One must also recognize that, even if a surgeon performs an extensive lymphadenectomy, the pathologist is usually the one who finds and examines the dissected lymph nodes. Thus, a coordinated effort is required between the surgeon and pathologist if more extensive lymphadenectomies are to result in better staging of patients. In

Japan and Korea, following the en bloc dissection of the stomach and lymph nodes, the surgeon dissects out the individual nodal stations from the surgical specimen, allowing the pathologist to examine and report the number of positive and negative lymph nodes for each nodal station. At Massachusetts General Hospital, where one author has been routinely been performing D2 lymphadenectomies, the institution of a protocol of dissecting out the individual nodal stations from the resected surgical specimen has increased the average number of lymph nodes examined per specimen from 35 to 42. There is some indirect evidence that more extensive lymphadenectomies result in lower rates of locoregional recurrence. Locoregional recurrence after potentially curative surgery for gastric adenocarcinoma can be quite high. In a 1982 series from the University of Minnesota, 107 patients with gastric adenocarcinoma underwent second-look laparotomy, and 80% had a recurrence [39]. Of these recurrences, 88% were locoregional, 54% were peritoneal, and 29% were distant. More recently, in the U.S. Intergroup 0116 trial, 177 of 275 patients (64%) in the surgery-only group developed recurrent disease [22]. In terms of the site of first relapse, 29% had local recurrence, 72% had regional recurrence, and only 18% had distant recurrence. Rates of locoregional recurrence are generally lower in reports from both western and Asian institutions that perform more extensive lymphadenectomies. In a series of 367 patients with recurrent gastric adenocarcinoma from Memorial SloanKettering Cancer Center over 15 years, 81% of patients had a D2 or greater lymphadenectomy, and the median number of lymph nodes removed was 22 [40]. Of patients who recurred, locoregional recurrence was the initial and only site of recurrence in 26% of patients and was a component of initial recurrence in 54% of patients. Yoo et al. [41] examined 508 patients who developed recurrent disease after curative gastrectomy at Yonsei University in South Korea. Nineteen percent of patients had locoregional recurrence only as the first site of recurrence, and 32.5% of patients had locoregional recurrence combined with peritoneal or distant recurrence as the initial site of recurrent disease. In the patients with only locoregional disease as the site of first recurrence, the anastamosis was the most common location of recurrence, followed by the lymph nodes. In a Japanese prospective randomized trial of adjuvant S-1 chemotherapy, 188 (35.5%) of 530 patients treated with surgery suffered a recurrence [42]. The site of first recurrence in those 188 patients was local in 7.9% and in lymph nodes in 24.5%. The effect of more extensive lymphadenectomies on overall survival for gastric cancer is still quite controversial. The majority of gastric surgeons in Korea and Japan

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believe that more extensive lymphadenectomies improve overall survival and refuse to perform a prospective, randomized trial. There are several retrospective studies demonstrating that more extensive lymphadenectomies are correlated with longer survival. A study of 4,789 patients at Seoul National University Hospital found that, for patients with stage IIIB disease, those who had 35 lymph nodes examined had better survival than those who had 20 nodes examined [43]. The German Gastric Carcinoma Study Group found, in an analysis of 1,654 patients, that those patients who underwent a radical lymphadenectomy ( 25 lymph nodes) had a significantly higher survival rate than patients who had a standard lymph node dissection for stage II or stage IIIA tumors [37, 44]. Similarly, investigators in a single Turkish institution study of 301 patients found that D2 dissection was associated with a more favorable prognosis for stage II and IIIA tumors [45]. Karpeh et al. [46] found, in a study of 1,038 patients at Memorial Sloan-Kettering Cancer Center, that the median survival time for N1, N2, and N3 disease was significantly longer when 15 lymph nodes were examined. Undoubtedly, these retrospective studies suffer from the confounding issue of stage migration. Dissecting out additional lymph nodes will result in patients often being upstaged, which makes future comparisons regarding therapeutic benefit invalid. Two large, prospective randomized trials in western countries have failed to identify a survival advantage for D2 over D1 lymphadenectomy [6, 7]. However, these two largest trials had fairly high morbidity (43% 46%) and mortality (10%13%) rates for D2 lymphadenectomy. In those trials, the distal pancreas and spleen were often resected during dissection of station 10 and 11 nodes. Of note, in the Dutch trial, if patients with hospital mortality are excluded, patient with N2 disease had a significant survival advantage when treated with a D2 lymphadenectomy [5]. Several studies have now demonstrated that D2 lymphadenectomies can be performed without the need for distal pancreatectomy [47] or splenectomy [8, 9]. Furthermore, a recent randomized trial in Taiwan demonstrated an overall survival advantage of more extensive lymphadenectomy over D1 lymphadenectomy, with overall 5-year survival rates of 59.5% and 53.6%, respectively (p .041) [12]. There was low morbidity and no mortality in the more extensive lymphadenectomy group, supporting the notion that more extensive lymphadenectomy can improve overall survival if done with low morbidity and mortality. However, the applicability of that trial to western patients has been called into question [48].

EXTENT OF LYMPHADENECTOMY AND ADJUVANT THERAPY

A common problem with prior clinical trials of adjuvant therapies for gastric adenocarcinoma in western countries has been the lack of standardization in surgical technique, including lymphadenectomy. The Intergroup 0116 trial was the first prospective, randomized trial to demonstrate a survival benefit of chemoradiation over surgery alone. Given that 54% of patients received less than a D1 lymphadenectomy, only 10% of patients received a D2 lymphadenectomy, and the chemoradiation appeared to primarily reduce logoregional recurrence, some have argued that the chemoradiation likely improved survival by making up for inadequate surgery [49]. Of note, an observational study from Samsung Medical Center (Seoul, Korea), of 990 patients who underwent surgical resection along with D2 lymphadenectomy, found that the median survival time was significantly longer in the 544 patients who received chemoradiation than in the 446 patients who received no adjuvant therapy [50]. Two prospective randomized trials, one from Europe and one from Japan, have shown survival benefits for neoadjuvant or adjuvant chemotherapy without radiation therapy [41, 51]. The majority of patients in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial received at least a D1 lymphadenectomy, and the majority of patients in the Japanese trial received a D2 lymphadenectomy, supporting the notion that chemotherapy alone can improve survival in gastric cancer patients. The ChemoRadiotherapy after Induction Chemotherapy in Cancer of the Stomach (CRITICS) multicenter trial is currently comparing MAGIC-style perioperative chemotherapy with preoperative chemotherapy followed by postoperative chemoradiation. Given that all these trials have different criteria regarding a major component of treatment, namely, the extent of lymphadenectomy, decisions regarding adjuvant treatment can be difficult. Patients receiving less extensive lymphadenectomies likely have higher locoregional recurrence rates, and oncologists may be more inclined to give 5-fluorouracil (FU)-based chemoradiation as opposed to multidrug chemotherapy alone. For patients receiving more extensive lymphadenectomies, staging is more accurate, and oncologists may be more inclined to treat with multidrug chemotherapy, especially for patients with more advanced disease. Greater standardization of the extent of lymphadenectomy in future adjuvant trials may help in better establishing standards of care. In Korea, Taiwan, and China, there is currently a multi-institutional randomized trial of adjuvant oxaliplatin and capecitabine or observation for stage II and III gastric cancer that has nearly completed

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its 1,024 patient accrual goal. A D2 lymphadenectomy is required for that trial, and survival results are pending.

SPLEEN, PANCREAS, AND D2 LYMPHADENECTOMIES

Tumors of the upper and middle stomach are known to metastasize to the splenic artery (station 11) and splenic hilar (station 10) lymph nodes, and distal pancreatectomy and splenectomy were historically routinely performed to clear these nodal stations [52]. Pancreatic fistula rates were high, thus significantly increasing the morbidity of the D2 lymphadenectomy procedure. Maruyama et al. [47] described a pancreas-preserving D2 lymphadenectomy that resected the spleen and splenic artery along with the station 10 and 11 lymph nodes. A retrospective study from Japan of nearly 400 patients found that there was no survival benefit in patients undergoing total gastrectomy combined with distal pancreatectomy and splenectomy over patients undergoing total gastrectomy with splenectomy only [53]. Distal pancreatectomy is now generally considered to be unwarranted in the routine performance of a D2 lymphadenectomy until there is direct extension of the tumor. A retrospective Japanese study of 224 patients with proximal gastric cancer found no survival benefit in patients who received pancreaticosplenectomy or splenectomy over pancreas and spleen preservation, but morbidity was significantly greater in the pancreaticosplenectomy group [54]. As shown in Table 3, Sasako et al. [55] estimated the benefit of dissecting the station 10 and 11 lymph nodes for a proximal gastric cancer at 5.6%. Hartgrink et al. [56] analyzed the patients in the Dutch Gastric Cancer Trial who had lymph node metastases at stations 10 and 11. Of the 18 patients with station 10 metastases, the 11-year survival rate was 11%. Of the 24 patients with station 11 metastases, the 11-year survival rate was 8%. The authors concluded that the relevance of the dissection of these nodes has to be questioned as the survival benefit is small and morbidity and hospital mortality are significantly increased. Although most expert gastric cancer surgeons no longer resect the distal pancreas as part of a D2 lymphadenectomy unless there is direct tumor extension, the resection of the spleen continues to be controversial. Two prospective randomized trials of total gastrectomy and lymphadenectomy with or without splenectomy have been performed in Chile and South Korea [57, 58]. Both studies found no difference in overall survival, and the Chilean study found a significantly higher rate of infectious complications in the splenectomy group. However, the number of patients in these studies was 187207, and thus the power of these studies to determine a modest improvement in survival for splenectomy is limited. A multicenter randomized trial to evaluate

Table 3. Estimated benefit from lymph node dissection at each nodal station, according to tumor location (%) Lower Middle Upper Entire Station third third third stomach 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16
a b

1.6b 0.0c 17.3a 14.5a 3.9a 21.3a 8.2b 7.5b 3.9b 0.0c 1.0c 2.7c 0.0c 2.1c 2.4d

7.9a 0.9b 26.3a 13.0a 0.8a 3.9a 10.5b 4.6b 5.2b 4.0b 1.3b 0.5c 0.0c 0.0c 0.0d

12.0a 5.1a 17.1a 3.0a 0.0b 0.4b 5.3b 2.0b 3.3b 3.8b 1.8b 0.0c 0.0c 0.0c 0.0d

3.7a 1.5a 11.7a 10.1a 2.7a 7.0a 8.2b 5.9b 3.8b 1.6b 0.8b 0.0c 0.0c 0.0c 2.9d

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First level (N1). Second level (N2). c Third level (N3). d Fourth level (N4).

the role of splenectomy for proximal gastric cancers is currently under way in Japan [59]. Taking lymph node stations beyond those incorporated in a D2 lymphadenectomy (D2 lymphadenectomy) likely does not improve survival, given that disease at such distant nodal stations is unlikely to be cured by surgical therapy alone. Based on data from the National Cancer Center (NCC) in Japan, the station 13 lymph nodes posterior to the head of the pancreas are rarely involved, and their involvement predicts a 5-year survival rate close to 0% [52]. Adding dissection of station 16 para-aortic nodes to a D2 lymphadenectomy was studied in a multicenter, prospective randomized trial in Japan. In that study, 523 patients were randomized to D2 lymphadenectomy or D2 lymphadenectomy plus additional para-aortic lymph node dissection (D2 ) [18]. The surgical morbidity rate was slightly higher in the D2 group (28.1% versus 24.5%), but the mortality rate was only 0.8% in both groups. The 5-year overall survival rate was 69%70% in both groups [60]. Thus, performing lymphadenectomies beyond a D2 lymphadenectomy is not warranted.

CAN WESTERN SURGEONS PERFORM MORE EXTENSIVE LYMPHADENECTOMIES SAFELY?

Dr. Maurizio Degiuli and colleagues in Turin, Italy, approached the issue of western surgeons performing more

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Table 4. Incidence of lymph node metastasis and 5-year survival rates of those having nodal metastasis in each station, according to tumor location Lower third Middle third Upper third Entire stomach Station 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 Incidence 6.2 7.1 40.9 34.2 10.5 46.3 23.4 24.5 12.8 3.8 6.7 9.0 8.3 14.6 13.1 5-yr survival 25.0 0.0 42.2 42.3 37.5 46.0 34.9 30.6 30.4 0.0 15.4 29.6 0.0 14.3 18.2 Incidence 15.0 3.4 44.8 26.8 2.4 14.6 22.6 11.0 11.0 11.9 6.3 1.6 0.0 8.7 7.4 5-yr survival 52.6 25.0 58.7 48.4 33.3 26.8 46.5 41.5 47.5 33.3 21.4 33.3 0.0 0.0 0.0 Incidence 38.0 22.0 45.1 14.5 3.0 6.8 26.9 10.2 16.0 17.4 16.1 2.5 2.5 10.0 12.1 5-yr survival 31.7 23.2 37.9 20.5 0.0 6.3 19.7 20.0 20.5 21.6 11.4 0.0 0.0 0.0 0.0 Incidence 32.7 18.2 66.0 53.1 14.2 37.7 44.4 30.6 18.5 21.6 20.6 4.4 5.6 4.5 26.5 5-yr survival 11.3 8.0 17.8 19.0 18.8 18.7 18.5 19.2 20.7 7.4 3.7 0.0 0.0 0.0 11.1

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extensive lymphadenectomies in western patients in a series of two prospective clinical trials [10]. Dr. Degiuli learned the D2 lymphadenectomy method at the NCC Hospital in Tokyo, Japan, from Dr. Mitsuru Sasako, a wellknown Japanese gastric surgeon. He was also given didactic videos and manuscripts. Dr. Degiuli then organized meetings for 16 surgeons from eight university or general hospitals in northern Italy (Italian Gastric Cancer Study Group). At those meetings, the terminology was explained and indications and technique were agreed upon for the trials. At least one of the two surgeons from each center attended the first 10 procedures of the trial, which were performed at Dr. Degiulis hospital. Dr. Degiuli then attended the first three operations performed at each of the remaining seven centers. Following this advanced training of surgeons in gastric surgery, a phase II trial of D2 lymphadenectomy was instituted. At each institution, all surgeries were performed by the same two attending surgeons. Of the 191 patients enrolled in the study, 106 (55%) were ultimately found to be ineligible, usually as a result of more extensive disease. The mean number of lymph nodes removed was 39 (range, 2293). The overall postoperative morbidity and mortality rates were impressively low, at 20.9% and 3.1%, respectively. Subsequent to this study, the surgeons from the five highest volume centers performed a randomized trial of D1 versus D2 lymphadenectomy [11]. Of 296 patients registered, 134 patients (45%) were ineligible, with

the most common causes of ineligibility being N2 or N3 nodal spread (25.2%), peritoneal disease (19.3%), and T4 disease (18.4%). Of 162 randomized patients, the total morbidity rate was 10.5% in the D1 group and 16.3% in the D2 group. Only one postoperative death occurred, and that patient received a D1 dissection. Survival results are pending. The experience of the Italian Gastric Cancer Study Group clearly demonstrates that, following a period of fairly rigorous training, western surgeons can perform D2 lymphadenectomies on western patients with morbidity and mortality results similar to those of high-volume centers in Korea and Japan.

LOW MARUYAMA INDEX SURGERY

Many centers in Japan and Korea have been performing extended lymphadenectomies for gastric cancer for decades. At the NCC in Japan, gastric cancer surgeons routinely perform D2 or greater lymphadenectomies and meticulously dissect out and label each station of lymph nodes following removal of the surgical specimen. NCC pathologists then examine each nodal station separately and document positive and negative nodes in each nodal station. Using a large database of patients treated with D2 or greater lymphadenectomy, Maruyama et al. [61] calculated the risk for lymph node metastasis in each lymph node station by location of the primary tumor (Table 4). In 1989, the NCC database of 3,843 cases was used to create the Maruyama computer

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program [62]. This program estimates the risk for lymph node metastasis for each lymph node station based on the input of eight variables: sex, age, endoscopic or Bormanns classification, depth of invasion, maximal diameter, location (upper, middle, or lower third), position (lesser or greater curvature, anterior or posterior wall, or circumferential), and World Health Organization histological classification. The Maruyama computer program was later expanded to include 4,302 cases (WinEstimate 2.5) [63]. By matching input variables to this large database of patients, the program gives a percent likelihood of disease in each of the 16 lymph node stations defined by the JRSGC. The accuracy of this program was analyzed in 222 patients treated at the Technical University in Munich, Germany. The accuracies for lymph node stations 1 6, 712, and 1316 were 82%, 89%, and 96%, respectively [64]. Guadagni et al. [65] subsequently analyzed 282 Italian patients with gastric cancer who underwent at least a D2 lymphadenectomy and found the Maruyama program to be 83% accurate for stations 1 6, 82% accurate for stations 712, and 72% accurate for stations 1316. Moreover, if an absolute cutoff point of 0% was used to direct the subsequent harvesting of lymph nodes, only six patients (3.4%) would have had lymph node metastases left undissected. Using the NCC database, Sasako et al. [52] were able to not only determine the incidence of lymph node metastasis in each nodal station based on location but to also determine the 5-year survival rate of patients who had lymph node metastasis to any given station stratified by tumor location (Table 4). Using these data, the estimated benefit from lymph node dissection of each nodal station was calculated stratified by tumor location (Table 3). When one compares the likelihood of involvement of lymph node stations (Table 4) with the nodal stations resected in a D1 versus D2 lymphadenectomy (Table 2), one can see that there is a significant risk of leaving involved lymph nodes undissected when performing a D1 dissection for a tumor in any stomach location. Performing less than a D1 lymphadenectomy leaves even more positive lymph nodes behind. Hundahl et al. [66] went on to define the Maruyama Index (MI) of unresected disease as the sum of the regional nodal disease (stations 112) percentages, as estimated by the Maruyama program, not removed by the surgeon. That study calculated the MI for 553 patients who enrolled in the Intergroup 0116 prospective, randomized trial of 5-FU based chemoradiation versus surgery alone. Only 10% of patients in that study underwent the recommended D2 lymphadenectomy. Thus, the median MI for 553 analyzed patients was 70, and MI proved to be an independent prognostic factor for overall survival (p .005) and recurrence-free survival (p .002). The authors concluded that surgical undertreatment of pa-

tients in this study clearly undermined survival. Peeters et al. [14] calculated the MI for 648 patients enrolled in the Dutch trial and found the median MI to be 26. MI 5 was found to be an independent predictor of longer overall and recurrence-free survival times on univariate and multivariate analysis. Moreover, a doseresponse relationship was demonstrated, with longer survival times as the MI decreased. The authors concluded that MI was a quantitative yardstick for assessing the adequacy of lymphadenectomy in gastric cancer. Performing less than a D2 lymphadenectomy can result in leaving positive lymph nodes behind. The Maruyama computer program thus allows one to prospectively know with fairly high accuracy which nodal stations have any likelihood of harboring metastatic disease. Retrospective analyses suggest that removal of all nodal stations that are predicted to harbor metastases results in superior survival, but a prospective trial of this approach is needed to confirm any validity.

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BARRIERS TO PERFORMANCE OF MORE EXTENSIVE LYMPHADENECTOMIES IN WESTERN COUNTRIES

Several tertiary referral centers in western countries routinely perform D2 lymphadenectomies for gastric cancer [40], but as noted earlier, lymphadenectomies for gastric cancer in western countries are limited and often do not even reach the D1 threshold. There are several reasons why more extensive lymphadenectomies are not more commonly performed. First and foremost is the lack of a proven benefit in terms of overall survival for D2 over D1 lymphadenectomy based on the Dutch and United Kingdom trials. Unfortunately, many western surgeons have interpreted the results of these trials to mean any lymphadenectomy does not improve overall survival. Certainly some patients with lymph node positive disease are cured by surgical resection alone, and these patients would undoubtedly not have been cured if diseased lymph nodes were left undissected without additional therapy. Another significant obstacle to the performance of more extensive lymphadenectomies is the relative paucity of gastric adenocarcinomas seen at any given institution. In order for more extensive lymphadenectomies to benefit gastric cancer patients, they must be performed without excess morbidity and mortality, and this can be achieved only with adequate surgical training and adequate case volume. Contributing to the lack of highvolume centers for gastric cancer surgery is a significant reluctance of general surgeons to refer gastric cancer patients to tertiary referral centers, given that gastric surgery has historically been the realm of the general surgeon [67]. Finally, there are geographical and language barriers between different countries that make dissemination of information

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and techniques on the surgical treatment of gastric cancer difficult.

SUMMARY
The Dutch and United Kingdom trials of D1 versus D2 lymphadenectomy demonstrated that when D2 lymphadenectomy is performed with excess morbidity and mortality there is no survival benefit over D1 lymphadenectomy. What have we learned since these trials? Many, and perhaps the majority, of patients in the U.S. receive an inadequate lymphadenectomy (i.e., less than a D1 lymphadenectomy). Distal pancreatectomy is not required to perform an adequate D2 lymphadenectomy and likely should be performed only when there is direct tumor invasion. Splenectomy is not required for distal tumors, but the role of splenectomy for mid or proximal tumors is currently being investigated in a prospective, randomized trial in Japan. D2 lymphadenectomy can be taught to western surgeons such that the procedure can be performed on western patients with low morbidity and mortality [10]. When a more extensive lymphadenectomy is performed, there is clearly a benefit in terms of

staging, and possibly in terms of less locoregional recurrence. If D2 lymphadenectomy is performed with low morbidity and mortality, there also may be a benefit in terms of overall survival [12], but this potential benefit needs to be demonstrated by prospective, randomized trials in western patients. D1 lymphadenectomies incorporating only lymph node stations beyond the N1 level that are predicted to harbor metastatic disease by the Maruyama computer program may optimize resection of disease and minimize complications, but this has not been proven. There exist several barriers to the performance of more extensive lymphadenectomies in western countries. Future collaborations and clinical trials will hopefully answer whether west should meet east, east should meet west, or there exists some utopian Shangri-La in between.

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AUTHOR CONTRIBUTIONS
Conception/Design: Sam S. Yoon, Han-Kwang Yang Administrative support: Sam S. Yoon Provision of study materials: Sam S. Yoon, Han-Kwang Yang Collection/assembly of data: Sam S. Yoon, Han-Kwang Yang Data analysis: Sam S. Yoon, Han-Kwang Yang Manuscript writing: Sam S. Yoon, Han-Kwang Yang Final approval of manuscript: Sam S. Yoon, Han-Kwang Yang

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Lymphadenectomy for Gastric Adenocarcinoma: Should West Meet East? Sam S. Yoon and Han-Kwang Yang The Oncologist 2009;14;871-882; originally published online September 8, 2009; DOI: 10.1634/theoncologist.2009-0070 This information is current as of October 13, 2011
Updated Information & Services including high-resolution figures, can be found at: http://theoncologist.alphamedpress.org/content/14/9/871

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