10.1245/ASO.2006.07.015
Annals of Surgical Oncology 13:659-667 (2006)
© 2006 Society of Surgical Oncology
Comparison of Surgical Results of D2 Versus D3 Gastrectomy (Para-Aortic Lymph Node Dissection) for Advanced Gastric Carcinoma: A Multi-Institutional Study
Chikara Kunisaki, MD, PhD1,
Hirotoshi Akiyama, MD, PhD1,
Masato Nomura, MD, PhD1,
Goro Matsuda, MD, PhD1,
Yuichi Otsuka, MD, PhD1,
Hidetaka Ono, MD, PhD1,
Yutaka Nagahori, MD, PhD2,
Hideo Hosoi, MD, PhD2,
Masazumi Takahashi, MD, PhD3,
Fumihiko Kito, MD, PhD3 and
Hiroshi Shimada, MD, PhD1
1 Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, 3–9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
2 Department of Surgery, Yokosuka Kyosai Hospital, 1–16 Yonegahamadori, Yokosuka 238-0011, Japan
3 Department of Surgery, Yokohama Municipal Hospital, 56 Okazawa-cho, Hodogaya-ku, Yokohama 240-0062, Japan
Correspondence: Address correspondence and reprint requests to: Chikara Kunisaki, MD, PhD; E-mail: s0714{at}med.yokohama-cu.ac.jp
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ABSTRACT
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Background: Curative gastrectomy is a promising approach for the treatment of gastric cancer; however, the optimal extent of lymph node dissection for advanced cancer remains controversial. The aim of this multi-institutional study was to evaluate the feasibility of D3 gastrectomy (para-aortic lymph node dissection) for advanced gastric cancer. The surgical results of D2 and D3 gastrectomy (para-aortic lymph node dissection) were retrospectively compared.
Methods: A series of 580 advanced gastric cancer patients were registered between 1992 and 2000. Of these, 430 underwent D2 gastrectomy and 150 underwent D3 gastrectomy. Survival time, prognostic factors, postoperative morbidity/mortality, and pattern of recurrence were compared.
Results: There was no significant difference in survival time between D2 and D3 patients. However, the survival times of D3 patients with tumor diameters measuring 50 to 100 mm or with pN1 disease were significantly longer than those of the corresponding D2 patients. Analysis of the survival of patients with tumor diameters measuring 50 to 100 mm revealed that D3 gastrectomy conferred a survival advantage only to patients with pN2 disease. The incidence of lymphatic recurrence was lower in D3 patients with 50- to 100-mm tumors than in the corresponding D2 patients.
Conclusions: D3 gastrectomy might be beneficial in patients with advanced pN2 gastric cancer within the group with tumors measuring 50 to 100 mm. A randomized controlled trial of patients with 50- to 100-mm tumors should be performed to test the validity of this preliminary result.
Key Words: Advanced gastric cancer • D2 gastrectomy • D3 gastrectomy • Para-aortic lymph node dissection
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INTRODUCTION
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Despite the high frequency of gastric cancer worldwide, the optimal surgical dissection area remains controversial. In general, surgery is the most promising treatment for both early and advanced gastric cancer. In Japan, most surgeons consider D2 gastrectomy to be the standard and optimal surgical procedure for patients with advanced gastric cancer.1 However, randomized controlled trials in Europe indicated that D2 gastrectomy did not improve survival compared with D1 gastrectomy.2,3 These studies concluded that the higher postoperative morbidity and mortality in patients with D2 gastrectomy offset its long-term effect on survival. However, after a trial in Dutch patients,3 it was claimed that incorrect indications for pancreaticosplenectomy had been adopted and that the management of patients was inadequate.4 Japanese surgeons do not accept that mortality—even after pancreaticosplenectomy—offsets the surgical benefits, because they rarely encounter life-threatening complications after gastrectomy; postoperative mortality in Japan is reported to be only 1% to 2%.5
Superextended para-aortic lymph node dissection (D3 gastrectomy) has been used in many Japanese institutions with the aim of eliminating metastatic lymph nodes, not only in the first and second tiers, but also in the third tier (around the upper abdominal aorta).6–8 We reported previously that results from a single institute showed that D3 gastrectomy provides a survival benefit compared with D2 gastrectomy in patients with advanced gastric cancers measuring 50 to 100 mm or classified as pN1.9 Although there was a high incidence of postoperative morbidity (such as pancreatic fistula) after pancreaticosplenectomy, the mortality rate was extremely low (.67%). To thoroughly evaluate the clinical significance of D3 gastrectomy for advanced gastric cancer, we compared the results of surgery in patients who had undergone D2 and D3 gastrectomy from several institutions.
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PATIENTS AND METHODS
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A series of 580 patients with primary advanced gastric adenocarcinoma that was histologically confirmed as having a depth of invasion deeper than the subserosa and who underwent potentially curative gastrectomy were enrolled onto this study between April 1992 and March 2000 in the Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Japan, and its associated institutions. Although D2 gastrectomy is regarded as a standard procedure for advanced gastric cancer in Japan, few previous reports have considered the efficacy of D3 gastrectomy for advanced gastric cancer in cases for which the tumor invades beyond the subserosa (T2-SS).10,11 We therefore used D3 gastrectomy with curative intent for patients with T2-SS or deeper primary gastric adenocarcinoma, all of whom gave informed consent and had no critical comorbid disease (that is, no abnormal findings in electrocardiograms, a 24-hour creatinine clearance of 
70 mL/min, forced expiratory volume in 1 second 70%, vital capacity 80%, and indocyanine green (ICG)15 x 10%). Patients with incurable determinants, such as macroscopic peritoneal metastasis, positive peritoneal lavage cytology, and hematogenous metastasis during operation, were excluded from the study group. There were no other exclusion criteria relating to clinicopathologic factors (such as age, macroscopic appearance, or tumor diameter).
Experienced surgeons took part in this study after sufficient training in D3 gastrectomy at the Department of Gastroenterological Surgery, Yokohama City University. Of the 580 patients, 430 underwent D2 gastrectomy (D2 patients), and 150 underwent D3 gastrectomy. D3 gastrectomy was mainly used in the Department of Gastroenterological Surgery, Yokohama City University. This study was neither randomized nor controlled.
Preoperative imaging studies to determine the location of the tumor, its macroscopic appearance and diameter, depth of invasion, lymph node metastasis, and distant metastasis were routinely performed after an upper gastrointestinal barium meal, an endoscopic examination, abdominal ultrasonography, and computed tomography.
The Japanese Gastric Cancer Association has approved standardized lymph node dissections (standard D2 gastrectomy) for gastric cancer.1 In this study, D2 gastrectomy was performed in accordance with the Japanese Classification of Gastric Carcinoma12: distal gastrectomy was performed principally for tumors located in the lower third of the stomach; distal or total gastrectomy was selected for tumors in the middle third, depending on the direction of tumor invasion; and total gastrectomy was used for tumors in the upper third of the stomach or those occupying the entire stomach. An additional pancreaticosplenectomy was routinely performed in patients with tumors extending into the upper third of the stomach, with the aim of eradicating the lymph nodes at the splenic hilum and along the distal splenic artery.
D3 gastrectomy was performed as follows. The notation of para-aortic lymph nodes was based on the Japanese Classification of Gastric Carcinoma. First, after the Kocher’s maneuver, the lymph nodes between the level of the inferior margin of the left renal vein and the inferior mesenteric artery were dissected adjacent to the abdominal aorta (No. 16 b1 preaortic lymph nodes and those between the aorta and the inferior vena cava). Second, the lymph nodes between the level of the inferior margin of the left renal vein and the celiac artery were dissected. The splanchnic nerves and the celiac plexus were preserved. The lymph nodes behind these nerves and the plexus were usually exposed by lateral traction of the nerve tissues and then removed (No. 16 a2 preaortic lymph nodes and those between the aorta and the inferior vena cava). Third, gastrectomy was performed, followed by lymph node dissection to the left of the abdominal aorta between the celiac axis and the inferior margin of the left renal vein. In this procedure, the left adrenal gland was partially removed for complete clearance of regional lymph nodes (No. 16 a2 lateral to the aorta). Fourth, we dissected the lymph nodes on the left of the abdominal aorta between the inferior margin of the left renal vein and the inferior mesenteric artery (No. 16 b1 lateral to the aorta). Fifth, and finally, the alimentary tract was reconstructed.
Eight experienced surgeons participated in this study, each of whom had performed more than 200 D2 gastrectomies. These surgeons also performed the D3 gastrectomies after appropriate training in the Department of Gastroenterological Surgery, Yokohama City University, and the quality of the surgery was controlled. In each case, 15 lymph nodes were dissected according to the International Union Against Cancer tumor, node, metastasis classification.13
A follow-up of patients was performed according to our standard protocol (every 8–12 weeks for at least 5 years), which included tumor-marker studies, endoscopic examinations, ultrasonography, computed tomography, and chest radiography. Patients who were suspected of having peritoneal metastases on the basis of the results of a physical examination or the use of imaging modalities underwent an aspiration biopsy for confirmation. The median follow-up was 41.2 ± 33.1 months for all registered patients. A total of 18 patients (3.1%) were lost to follow-up.
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Definition of Postoperative Morbidity and Mortality
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Respiratory complications were defined as conditions for which administration of oxygen was necessary for > 1 week as a result of pneumonia or for which mechanical ventilation was necessary to improve respiratory function. Renal dysfunction was defined as a condition in which serum creatinine was > 3.0 mg/dL or transient hemodialysis was necessary until renal function recovered. Diagnosis of pancreatic fistula was based on an amylase value of 1000 U/L in the discharge from the drain.
Statistical Analysis
Data were analyzed by using SPSS software (SPSS Inc., Chicago, IL). Patient characteristics were compared by using the two-tailed Fisher’s exact test or the 
2 test with Yates’ correction, as appropriate. Quantitative variables were compared by using Student’s t-test and expressed as the median ± SD. The Cox proportional hazards regression model was used to identify prognostic factors. Step-forward regression was used to build a valid statistical model of the association of prognostic factors with disease-specific survival in patients with complete data. Overall and disease-specific survival were calculated by using the Kaplan-Meier estimation and examined by the log-rank test. Probability values were considered statistically significant at the .05 level. The clinicopathologic terminology in this article follows the Japanese Classification of Gastric Carcinoma.12
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RESULTS
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Patient Characteristics
There was no significant difference in clinicopathologic characteristics between D2 and D3 patients, with the exception of lymph node metastases (Table 1
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Operative Variables
The mean operation duration was 224 ± 80 minutes for D2 gastrectomy and 455 ± 120 minutes for D3 gastrectomy. Thus, there was a significant difference in operation times between the two groups (P < .0001). Intraoperative bleeding also differed between D2 and D3 patients (479 ± 302 mL and 865 ± 485 mL, respectively; P < .0001). There was a significant difference in the incidence of blood transfusion between the two groups (15.1% vs. 53.3%; P < .001).
Postoperative Morbidity and Mortality
There was a significant difference in the incidence of respiratory complications (P < .001) and renal dysfunction (P = .0014) between D2 and D3 patients. Hemodialysis was performed in one patient who underwent D2 gastrectomy and in two patients who underwent D3 gastrectomy. All of the patients who required hemodialysis were > 70 years of age. Pancreatic fistulas were observed frequently in both groups, and there was no significant difference between the groups (Table 2). All of the complicated cases were treated successfully, with the exception of one patient in each group: one D3 patient died of postoperative complications (bleeding; mortality rate, .67%), and one D2 patient died of postoperative pneumonia (mortality rate, .23%). There was no significant difference in mortality rates between the two groups.
Prognostic Factors
Univariate analysis revealed that age, tumor location, tumor diameter, depth of invasion, lymph node metastases, and extent of resection of the stomach influenced disease-specific prognosis. Multivariate analysis of 10 clinicopathologic factors (age, sex, location of tumor, macroscopic appearance, tumor diameter, histological type, depth of invasion, lymph node metastases, lymph node dissection, and extent of resection of the stomach) showed that age, tumor diameter, depth of invasion, and lymph node metastases affected disease-specific prognosis independently. However, the extent of lymph node dissection did not contribute to a positive prognosis (Table 3).
Long-Term Survival
There was no statistically significant difference in overall survival between D2 and D3 patients (5-year survival rates were 56.0% and 50.4%, respectively; Fig. 1). There was also no significant difference in disease-specific survival between the two groups (5-year survival rates were 58.8% and 54.0%, respectively).
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FIG. 1. Overall survival in patients with D2 and D3 gastrectomies. There was no significant difference in survival between the two groups (P = .9899).
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An analysis of the clinicopathologic variables in the two groups revealed a significant difference in disease-specific survival after D2 and D3 gastrectomies in patients with tumor diameters measuring 50 to 100 mm or with pN1 disease (Table 4).
Preoperative diagnosis of lymph node metastasis is difficult, even with appropriate imaging tools. Therefore, tumor diameter, which can be accurately estimated before surgery, was used to investigate the subgroups in which D3 gastrectomy is effective. Analysis of the disease-specific survival of 303 patients with tumor diameters of 50 to 100 mm revealed significant differences between D2 and D3 patients with pN2 disease (Table 5).
Pattern of Recurrence
Overall, recurrence was observed in 247 (42.6%) patients. There was no significant difference in the incidence of recurrence or the recurrence pattern between D2 and D3 patients. Peritoneal metastasis was the most common pattern of recurrence in both groups (Table 6). However, there was a significant difference in the distribution of recurring lymph nodes between D2 and D3 patients in terms of the numbers of second-and third-tier regional lymph nodes, hepatic hilum lymph nodes, and mediastinal or cervical lymph nodes (28, 2, and 7 versus 4, 3, and 5, respectively; P = .0201). The incidence of lymph node recurrence in the surgically dissected area was significantly lower in D3 patients than in D2 patients. Moreover, the incidence of lymphatic recurrence was lower in D3 patients with 50- to 100-mm tumors (Table 7).
Prognostic Factors in Patients With 50- to 100-mm Tumors
A Cox proportional hazards regression model including 9 clinicopathologic factors (age, sex, location of tumor, macroscopic appearance, histological type, depth of invasion, lymph node metastases, lymph node dissection, and extent of resection of the stomach), restricted to 303 patients with tumors measuring 50 to 100 mm, revealed that age, lymph node metastasis, and D3 gastrectomy had independent effects on disease-specific prognosis (Table 8).
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DISCUSSION
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This retrospective study involving multiple institutions indicates that D3 gastrectomy (para-aortic lymph node dissection) is worthwhile only in patients with tumors measuring 50 to 100 mm or with pN1 disease, and it provides survival benefits for patients with pN2 tumors within the former group. The superextended range of the D3 gastrectomy did not always give good long-term results in the advanced gastric cancer patients.
Recently, based on the results of British2 and Dutch3 trials, D1 gastrectomy has been routinely used for the treatment of gastric cancer in Western countries. These trials suggested that a high incidence of postoperative complications after D2 gastrectomy offset the more beneficial surgical results obtained with D2 surgery. However, in Japan, D2 gastrectomy is accepted as the gold standard on the basis of abundant data. For gastric cancer, only potentially curative resection (R0) achieves good outcomes, and, in view of the distribution of lymph node metastases, D1 gastrectomy is insufficient for advanced gastric cancer. Furthermore, the lymphatic flow streams to the para-aortic lymph nodes from the perigastric and suprapancreatic lymph nodes; our previous study showed that the lymphatic drainage, which depends on tumor location, could eventually reach the area of the para-aortic lymph nodes, which are regarded as the terminal regional nodes in advanced gastric cancer. Therefore, it was important to evaluate the indications for D3 gastrectomy from the viewpoint of survival benefit, morbidity/mortality, and quality of life.
Our earlier study retrospectively compared the surgical benefits and morbidity/mortality of D2 (1985–1992) and D3 (1992–1998) patients from a single institution.9 However, there was a statistical bias in the results caused by differences in postsurgical treatment. Although the present multi-institutional study was also retrospective, the statistical bias was reduced. The difference in lymph node metastases was caused by differences in the dissected area between D2 and D3 gastrectomy patients.
In D3 gastrectomy, operation times were longer, blood loss was greater, and blood transfusion was more common than in D2 gastrectomy. Similar observations were made in a randomized controlled study (D2 vs. D3).14 Therefore, D3 gastrectomy clearly entails an excessive burden for patients, and it is essential to carefully consider the eligibility criteria for this procedure. However, the incidence of these adverse factors has recently decreased in our institution as a result of enhanced techniques. With regard to morbidity, respiratory complications and renal dysfunction were frequently observed after D3 gastrectomy, and older patients ( 70 years) predominated among those with such complications. Age ( 70 years) was an independent prognostic factor for survival, and improved surgical results were not expected in the elderly. Hence, the age variable should be included in the indications for superextended lymph node dissection. Recently, patients aged 70 years have been judged ineligible for D3 gastrectomy at our institution.
Pancreatic fistula was the most frequent complication after pancreaticosplenectomy in both D2 and D3 gastrectomy patients. Pancreatic fistula and its associated complications after D2 gastrectomy were emphasized as important risk factors for postoperative morbidity and mortality in the British and Dutch trials. Postoperative mortalities in those trials were 10 and 13%, respectively, which are extremely high compared with D2 gastrectomy in Japan. However, it is clear that pancreatic fistula is the major factor prolonging hospital stay, and the use of this procedure has decreased, even in Japan. The indications for pancreaticosplenectomy in gastric cancer should be strict. Recently, total gastrectomy combined with splenectomy preserving the pancreas has become the standard procedure used in our institution for dissecting lymph nodes along the distal splenic artery and at the splenic hilum, and the incidence of pancreatic fistula seems to have decreased (data not shown). Moreover, the Japan Clinical Oncology Group (JCOG) study 0110 (phase III: total gastrectomy alone vs. total gastrectomy with splenectomy for gastric cancer located in the upper third of the stomach) is currently ongoing. The results of this study are keenly anticipated.
There was no significant difference in disease-specific survival between D2 and D3 gastrectomy. This might imply that D3 gastrectomy does not contribute to improved survival at any stage of gastric cancer. However, our analysis shows that in a subgroup of patients—namely, those with tumors of 50 to 100 mm or pN1 disease (66.0% of D3 patients)—D3 gastrectomy prolonged survival. In addition, patients with pN2 tumors among the group with tumors of 50 to 100 mm showed surgical benefits from D3 gastrectomy. Nonetheless, D3 gastrectomy conferred no survival advantage in either pN0 patients or those with tumor diameters < 50 mm. This suggests that D2 gastrectomy is adequate for patients with relatively early-stage gastric cancer. In addition, D3 gastrectomy did not improve the survival of patients with many lymph node metastases or tumors measuring 100 mm. It might therefore be the case that even superextended gastrectomy is not effective in patients with far-advanced gastric cancers with many metastatic nodes or large diameters, because peritoneal metastasis is thought to be the predominant recurrence pattern in such patients. Surgery alone is limited in efficacy and does not achieve good results in these patients. This outcome was similar to that of our previous study, although the patients undergoing D2 gastrectomy were notably different. Therefore, the finding that D3 gastrectomy is of benefit to patients with moderately advanced gastric cancer seems to be reproducible.
In practice, it is difficult to diagnose moderately advanced gastric cancer, such as pN1 tumors, even with the latest imaging modalities. However, it is possible to determine the tumor diameter before surgery within a small margin of error. Thus, our present findings have value in the clinical application of tumor diameters, because the results with D3 gastrectomy in patients with 50- to 100-mm tumors who had pN2 disease were better than those seen in the same group of patients who underwent D2 gastrectomy.
The incidence of pN2 among patients with 50- to 100-mm tumors was approximately 27.7% (84 of 303), and intraoperative and immediate pathologic examinations of the regional suprapancreatic lymph nodes should be performed in such patients. In our previous study,15 pN2 involving a lymph node at the root of the left gastric artery independently predicted para-aortic lymph node metastasis. On the basis of these results, pN2 should be a key site for para-aortic lymph node dissection. Moreover, when metastasis in the second-tier lymph node is found during surgery in patients with tumors 50 to 100 mm in diameter, D3 gastrectomy is indicated. Good survival can also be achieved in patients with a few metastatic lymph nodes, as shown in this study.
Other reports have focused on the effectiveness of para-aortic lymph node dissection in advanced gastric cancer. In those reports,6,7 D3 gastrectomy proved to be of value in gastric cancer patients with serosal invasion or fewer metastatic lymph nodes.
Although the overall incidence of lymph node recurrence did not differ between D2 and D3 patients, the incidence of lymph node recurrence in the surgically dissected area was significantly lower in D3 patients. This implies that D3 gastrectomy might be effective for metastatic lymph nodes in the para-aortic regions. Moreover, we found that the incidence of lymphatic recurrence was reduced in D3 patients with tumors measuring 50 to 100 mm. These results point to the utility of para-aortic lymph node dissection for a subgroup of advanced gastric cancer patients. However, the incidence of peritoneal recurrence was high. A treatment for peritoneal metastasis should therefore be urgently sought to improve the therapeutic outcome in patients with advanced gastric cancer.
The JCOG 9501 study (D2 vs. D3 gastrectomy) is currently ongoing in Japan, and the surgical results will be available in 2006. The current study differed from the JCOG study in terms of the eligibility criteria for subjects; the JCOG study excluded patients with Borrmann type 4 (linitis plastica) tumors and patients aged > 75 years. These differences in eligibility criteria might lead to different surgical outcomes. Hence, the results of the current study should provide valuable insights into this operative procedure. Moreover, our para-aortic lymph node dissection technique, which preserves neural tissues, is based on the anatomical evaluation of the para-aortic area.16 The neural tissues were taped, and lymph nodes were carefully dissected by lifting the neural tissue. In the JCOG study, para-aortic lymph node dissection that preserved neural tissue was not used. From the viewpoints of these differences, the current study is also valid.
In conclusion, D3 gastrectomy might be indicated as an experimental operation in patients with advanced gastric cancers measuring 50 to 100 mm in diameter,17 and those with pN2 tumors within this group might benefit from surgery. However, this operative procedure should be performed only in large institutions by experienced surgeons. By contrast, D2 gastrectomy is adequate for patients with tumors x 50 mm. For patients with tumors > 100 mm, combined therapy, such as curative gastrectomy plus chemotherapy, is recommended to prevent peritoneal recurrence. To clarify the indication of D3 gastrectomy, a randomized controlled trial (D2 vs. D3) should be conducted for advanced gastric cancer patients with tumors 50 to 100 mm in diameter.
Received for publication July 15, 2005.
Accepted for publication October 27, 2005.
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ABSTRACT
INTRODUCTION
