Originally published as JCO Early Release 10.1200/JCO.2004.10.184 on June 15 2004

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Gastric Cancer Surgery: Morbidity and Mortality Results From a Prospective Randomized Controlled Trial Comparing D2 and Extended Para-Aortic Lymphadenectomy—Japan Clinical Oncology Group Study 9501

From the Gastric Surgery Division, National Cancer Center Hospital; Cancer Information and Epidemiology Division, National Cancer Center Research Institute; Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo; Department of Surgery, Niigata Cancer Center Hospital, Niigata; Department of Surgery, National Shikoku Cancer Center, Matsuyama; Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases; Department of Surgery, Osaka National Hospital; Department of Surgery, Osaka Medical College, Osaka; Department of Surgery, National Cancer Center Hospital East, Kashiwa; Department of Surgery, Aichi Cancer Center, Nagoya, Japan; the Gastric Cancer Surgical Study Group of Japan Clinical Oncology Group

Address reprint requests to Takeshi Sano, MD, Gastric Surgery Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; e-mail: tksano{at}ncc.go.jp

	ABSTRACT

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PURPOSE: Radical gastrectomy with regional lymphadenectomy is the only curative treatment option for gastric cancer. The extent of lymphadenectomy, however, is controversial. The two European randomized trials only reported an increase in operative morbidity and mortality, but failed to show survival benefit, in the D2 lymphadenectomy group. We conducted a randomized controlled trial to compare the Japanese standard D2 and D2 + para-aortic nodal dissection.

PATIENTS AND METHODS: Only experienced surgeons in both procedures from 24 Japanese institutions participated in the study. Patients with potentially curable gastric adenocarcinoma (T2-subserosa, T3, or T4) who were surgically fit were intraoperatively randomized. Postoperative morbidity and hospital mortality were recorded prospectively in a fixed format and were compared between the two groups in this study.

RESULTS: A total of 523 patients were randomized between July 1995 and April 2001. Postoperative complications were reported in 24.5% of all patients. Although the morbidity for the extended surgery group (28.1%) was slightly higher than the standard group (20.9%), there was no difference in the incidence of four major complications (anastomotic leak, pancreatic fistula, abdominal abscess, pneumonia) between the two groups. Hospital mortality was reported at 0.80%: one patient in each group died of operative complications, while one from each group died of rapid progressive cancer while inpatient.

CONCLUSION: Specialized surgeons could safely perform gastrectomy with D2 lymphadenectomy in patients with low operative risks. Para-aortic lymphadenectomy could be added without increasing major surgical complications in this setting.

	INTRODUCTION

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Gastric cancer is the second most common malignancy in the world, and surgical resection remains the only curative treatment option. Lymph node metastases occur during the early stages of this disease, and regional lymphadenectomy is recommended as part of radical gastrectomy. However, the extent of lymphadenectomy to achieve the optimal result is controversial, and there is no worldwide consensus.

Japanese surgeons first introduced the extended lymphadenectomy procedure, known today as D2, in the 1960s.¹ This technique requires the systematic dissection of lymph nodes in the first tier (perigastric) and the second tier (along the celiac artery and its branches). Early studies have reported that between 30% to 40% of patients with positive lymph node metastases including the second tier lymph nodes, have survived longer than 5 years with D2 lymphadenectomy.² However, D2 gastrectomy has a steep learning curve,³ and may be associated with a higher-than-expected operative morbidity and mortality.

Two European randomized controlled trials comparing D1 and D2 gastrectomy revealed a high operative mortality exceeding 10% in the D2 group.^4,5 Based on these reports, the British National Health Service Cancer Guidance discourages the use of D2 technique in routine clinical practice.⁶ In contrast, D2 gastrectomy is considered a standard and safe procedure in Japan, where 100,000 cases of gastric cancers are diagnosed every year. General surgeons are taught this technique early during their surgical training.⁷ The Japanese nationwide registry reported an operative mortality of less than 2%, and in specialized institutions, less than 1% for D2 gastrectomy.^8,9

Since the eighties, even more radical extended lymphadenectomy procedures had been practiced in many Japanese specialized centers. It was reported that 20% to 30% of patients with nonearly gastric cancer had microscopic metastasis present in the para-aortic nodes.^10-13 The 5-year survival for these patients has reached 14% to 30% after extended systematic dissection. In addition to D2 lymphadenectomy, lymph nodes around the upper abdominal aorta were dissected, primarily for ultimate local tumor control. However, this extended dissection may not only increase operative morbidity but also may effect the function of other abdominal organs.

There has never been a prospective study to assess the perioperative morbidity and mortality in Japanese patients after D2 gastrectomy or more extended surgery. To evaluate the survival benefit and operative complications of D2 gastrectomy and extended para-aortic dissection in gastric cancer surgery, a multi-institutional randomized controlled trial was conducted on behalf of the Japan Clinical Oncology Group (JCOG). The accrual closed with 523 patients. We hereby present the data on the operative morbidity and mortality, which are the secondary end points of this trial. Survival analysis is scheduled to take place in August 2006.

	PATIENTS AND METHODS

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Objectives and End Points of the Study
A prospective randomized controlled trial was designed to compare the two surgical techniques: the standard lymphadenectomy and the standard lymphadenectomy with the addition of para-aortic node dissection for gastric cancer. Only surgeons with sufficient experience of para-aortic dissection for gastric cancer participated in the trial. Since the role of neoadjuvant and adjuvant chemotherapy was not established, no patients received chemotherapy until recurrent disease was diagnosed.

The primary end point was the overall survival, while the secondary end points were the relapse-free survival, operative morbidity, hospital mortality, and quality of life. Randomization and data handling for this study was performed by the Data Centre of the JCOG, a government-sponsored organization for multi-institutional clinical trials.¹⁴

Eligibility Criteria
Eligibility criteria for this study are shown in Table 1. Patients with advanced gastric cancer deemed curable and fit for surgery were recruited into the trial following informed consent. Borrmann type 4 tumors (linitis plastica) were excluded because of their very poor prognosis after surgery. Liver cirrhosis and ischemic heart disease were important risk factors for mortality after surgery and hence were excluded from the study. Para-aortic lymph node metastasis is extremely rare in T1 (invasion confined to the mucosa or submucosa) and T2-MP tumors (invasion confined to the muscularis propria); hence, these patients were not eligible for randomization. Only patients diagnosed with T2-SS (subserosal invasion) or deeper tumors at the time of laparotomy were included in the study. T2-SS is clinically recognized as a white discoloration on the serosal surface, without overt tumor serosal exposure.

Random Assignment
While waiting for the result of lavage cytology, the surgeon examined the above eligibility criteria and started the D2 procedure. When the negative cytology result was obtained 30 to 60 minutes later, he informed the JCOG Data Centre for enrollment. Patients were then randomly assigned either to receive standard lymphadenectomy (group A) or extended lymphadenectomy (group B). The sizes of the groups were balanced according to T stage (T2 v T3/T4), tumor growth pattern (expansive v infiltrative growth), and institution. The randomization arm was notified to the surgeon immediately, who then completed the operation according to the allocated protocol.

Surgical Methods
Group A: Standard D2 gastrectomy. Patients were treated with gastrectomy and D2 lymphadenectomy. Depending on the location of the primary tumor, the surgeon performed either a total, proximal subtotal, or distal subtotal gastrectomy. D2 lymphadenectomy was a standard procedure for dissection of tumors located in the upper two thirds of the stomach as defined in the 12th edition of the Japanese Classification (1993)¹⁵ when the study was initially designed. An extended D2 lymphadenectomy was performed for tumors located in the lower third of the stomach, which involves further dissecting the hepatoduodenal nodes (No.12a), retropancreatic nodes (No.13) and nodes along the superior mesenteric vein (No.14v). This technique was frequently performed as a standard procedure in the specialized centers, and thus adopted in this study (all except No.13 have been integrated as "D2" in the 13th edition of Japanese classification¹⁶).

In total or proximal subtotal gastrectomy for proximal tumors, the spleen was removed in principle for splenic hilar lymphadenectomy, while it was preserved in distal subtotal gastrectomy for distal tumors.

Group B: D2 gastrectomy combined with para-aortic lymphadenectomy. Patients in this group had similar procedure to group A, but with additional para-aortic lymph node dissection. The area to be dissected was defined in the Japanese classification (Fig 1). Proximal tumors were treated with the standard D2 lymphadenectomy, and also all "No.16-a2" (para-aortic nodes between the level of the celiac axis and the left renal vein) and "No.16-b1" (para-aortic nodes between the left renal vein and the inferior mesenteric artery) were removed. Standard distal subtotal gastrectomy was performed for the distal tumors including the "No.16-a2" and "No.16-b1" nodes; however, dissection of the left upper lateral nodes ("No.16-a2-lat") was optional.

View larger version (33K): [in this window] [in a new window]   Fig 1. Anatomic definitions of para-aortic lymph nodes.15 The nodes No.16a2 and No.16b1 are defined as "regional nodes" and were dissected in the extended surgery group. Ao, aorta; CA, celiac artery; Eso, esophagus; IMA, inferior mesenteric artery; IVC, inferior vena cava; LRV, left renal vein; SMA, superior mesenteric artery.

Evaluation of Operative Morbidity and Mortality
Operative methods and pathology results were recorded according to the 12th edition of the Japanese Classification of Gastric Carcinoma.¹⁵ The following information was included on the case report form for prospective data collection concerning the four major groups of operative morbidity: presence or absence of anastomotic leak, pancreatic fistula, abdominal abscess, and pneumonia. Anastomotic leak was diagnosed radiologically either on routine postoperative contrast swallow or based on clinical suspicion, and was recorded regardless of its clinical significance. Pancreatic fistula was usually diagnosed when fluid with a high amylase concentration drained from the peripancreatic area for more than 7 days.

Other complications were recorded on a free format. The duration of surgery, blood loss, blood transfusion requirement and reoperation details were also recorded. Hospital mortality was defined as postoperative death of any cause within 30 days, or death within the same hospitalization.

Sample Size
The projected 5-year survival rates for groups A and B patients were 50% and 62%, respectively, and we initially planned to recruit 412 patients (206 each group) to detect this difference with one-sided error of .05 and statistical power of 80%. At first, the recruitment was slow, but it improved as the study progressed. When the planned recruitment was almost achieved, the JCOG Clinical Trial Review Committee approved the amendment to increase the number of patients to 520 (260 each group) to enforce the statistical power to detect 8% difference in the 5-year survival rates, with a 5.5-year accrual period and an additional 5-year follow-up.

Institutions and Quality Control of Surgery
The approval of the institutional review board from all participating institutions was obtained. Initially, the 12 institutions of the Gastric Cancer Surgical Study Group of the JCOG participated in the trial. Twelve institutions were added to increase patient recruitment before February 1999.

All participating surgeons agreed to the technical details for surgery during the planning stages of this trial. Significant experience in gastric cancer surgery, especially experience in extended lymphadenectomy, was a prerequisite for a surgeon's participation in the trial. Surgeons with experience of more than 100 D2 gastrectomies, or institutions with a specialized unit with annual gastrectomy volume of 80 cases or more were selected.

During the recruitment period, participating surgeons and Data Centre representatives met three times per year to monitor the study. In each meeting, videos of para-aortic dissection were presented for critique from four or five institutions, and the technical details were discussed. To assess compliance with lymphadenectomy, dissection, node recovery status in all nodal "stations," and the number of dissected nodes in the para-aortic area were recorded in the case report form, and the results were monitored.

Statistical Methods
The operative morbidity and mortality rates were based on the proportion of the number of cases divided by all registered patients based on the intention-to-treat principle. The differences in proportion between groups were evaluated using Fisher's exact test. Differences in length of hospital stay and blood loss were compared by Wilcoxon test. All P values are two-sided, and statistical analysis was done using SAS (SAS Institute, Cary, NC) version 8.12.

	RESULTS

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Recruitment
Recruitment commenced in July 1995, and closed in April 2001. A total of 523 patients were enrolled: 263 in group A and 260 in group B. A large variance was observed for the number of patients recruited between the institutions. Fifty-three percent of all patients were recruited by the five major hospitals.

The JCOG site-visit audit reported that written consent was available for all except nine patients from one institution. In another institution, an additional six patients had informed consent submitted by a family member.

Patients and Surgery
Patient demographics and tumor characteristics are presented in Table 2. The two groups were well balanced, as there were no significant differences in their baseline data.

In another case, the initial histological diagnosis following endoscopic biopsy was poorly differentiated adenocarcinoma but the final histology of the resected stomach revealed gastric lymphoma. We included this patient in the morbidity/mortality analysis, but will exclude their data from the final survival analyses.

Operative Morbidity
The overall operative morbidity rate was 24.5%. The morbidity for group B patients was higher than group A (28.1% and 20.9%, respectively), but the difference did not reach statistical significance (P = .067). The incidence of the four major surgical complications was not different between the two groups (Table 4).

Hospital Mortality
There were four hospital deaths (0.8%)—two in each group. Each group had one patient who died of postoperative complications, and one died of rapidly progressive cancer. All other patients recovered from surgery and were discharged from hospital.

	DISCUSSION

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In this randomized controlled trial, the role of para-aortic dissection will be evaluated in terms of survival benefit, operative morbidity/mortality, and quality of life. The results will provide important information and should guide decision making regarding the choice of operative methods. The quality of life and survival among these patients are still in the follow-up phase, and the analyses will take place in 2004 and 2006, respectively. This report compares the morbidity and mortality rates of D2 plus para-aortic node dissection with standard D2 dissection.

There is a wide variation in operative morbidity and mortality following gastric cancer surgery among countries and institutions. The presence of comorbid disease that affects patient fitness for surgery, surgical experience of the operator, and the workload volume seem to be important factors.^17,18 The mortality for gastrectomy in Western countries often exceeds 5% and approaches 16% in some series.^19-21 Conversely, Japanese studies have consistently reported a mortality rate of lower than 2% in retrospective observations. To date, the present study is the first large-scale prospective randomized controlled trial in Japan to compare surgical techniques under strict quality control and data management. The extremely low hospital death rate after extended para-aortic lymphadenectomy (0.8%) in this multi-institutional setting confirms the findings from previous retrospective reports.

This trial is a striking contrast to the the Dutch⁴ and British⁵ D1/D2 trials, in which D2 lymphadenectomy was associated with operative mortality rates of 10% and 13%, respectively. One important criticism of the European randomized trials was the issue of learning curve, as many British and Dutch surgeons participating in the trials were new to the D2 procedure. Surgical experience, specific anatomic knowledge, and careful postoperative managements by experienced teams are crucial to the success of this type of surgery. An Italian group appropriately carried out a phase 2 study of D2 lymphadenectomy in selected institutions²² until an acceptable operative mortality rate was achieved, before conducting a randomized controlled trial comparing D1 and D2 gastrectomies.

The D2 gastrectomy procedure is known as "extended lymphadenectomy" in Western countries, while Japanese surgeons employ D2 as a standard technique, and reserve the term "extended" for para-aortic dissection. Lymphatic drainage from the stomach flows to the perigastric nodes and then to the nodes around the celiac axis and its main branches. From here it enters the para-aortic nodes before joining the systemic circulation via the thoracic duct. Hence, the para-aortic nodes may be regarded as the final station of nodes that can be dissected to remove the threat of systemic metastases originating from the lymphatic system. Many Japanese surgeons in specialized centers who performed para-aortic dissection found microscopic metastases in this region, and believe that this type of surgery may be potentially worthwhile. However, the risk associated with para-aortic dissection dictates advanced operative skills and intensive postoperative care. Therefore, scientific evidence supporting a survival benefit must be obtained before employing this technique in routine gastric cancer surgery.

The very low operative morbidity and mortality achieved in this JCOG trial can be attributed to several factors: (1) we selected a group of fit patients who could tolerate para-aortic dissection in the study. (2) Only specialist surgeons with an established track record of extended lymphadenectomy participated in the trial. (3) High-throughput centers were selected for their operative skills and standardized postoperative management. (4) Pancreatectomy was avoided whenever possible, while splenectomy accompanied total gastrectomy in most cases. We report that there was no significant difference in the overall complications between the two groups; however, the para-aortic dissection group had significantly higher "other" complications (on free format) compared with standard D2. Lymphorrhea and paralytic ileus were more specific to this operation. This observation may be biased because of the surgeon's awareness of the patient's randomization arm of para-aortic dissection.

In the British and Dutch trials, splenectomy with or without distal pancreatectomy was highlighted as a major risk factor for operative morbidity and mortality.^5,23 Total gastrectomy for proximal tumor requires more advanced surgical skill and is associated with a higher morbidity compared to distal gastrectomy. Proximal gastric tumors are rapidly increasing in number in the western countries,^24,25 while the incidence remains stable in Japan,²⁶ and this may partly explain the superior results obtained in Japanese studies. However, no difference was observed in the distribution of the primary tumor location between the Dutch⁴ and the Japanese cohort. The proportion of total to distal gastrectomy was also very similar. Therefore, variation in tumor location and type of gastrectomy could not account for the difference in morbidity/mortality, at least between these trials. JCOG recently launched a randomized controlled trial to evaluate the role of splenectomy combined with total gastrectomy in proximal tumors.²⁷

Gastric cancer, though decreasing in incidence worldwide, remains a major health problem in many countries. R0 (no residual disease) resection is the only curative measure; but the more extended the surgery, it is believed the greater is the risk of operative morbidity and mortality. The type of gastrectomy and the extent of lymphadenectomy must be carefully planned for each individual patient with gastric cancer. The Japanese guidelines clearly define D2 gastrectomy as standard surgery²⁸ based on the excellent results in Japanese studies, while the British cancer guidance⁶ discourages D2 based on the poor results of their randomized trial. This contrast should be addressed by surgeons' efforts, such as establishment of specialized standard training systems or production of evidence by high-quality randomized trials in specialized centers.

In conclusion, this study has shown that specialized surgeons could safely perform gastrectomy with D2 lymphadenectomy in patients with low operative risks. Extending the surgery to para-aortic lymphadenectomy did not increase the major operative complications and hospital deaths. However, compared with the D2 procedure, para-aortic dissection requires a longer operation time, leads to a larger volume of blood loss, and longer hospital stay. Until survival benefits are clarified when the data mature sufficiently, para-aortic lymphadenectomy for gastric cancer should be regarded as experimental surgery²⁸ and only performed in specialized institutions within the context of a well-designed clinical trial.

	Appendix

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List of participating institutions in order of patient recruitment: National Cancer Center Hospital, Niigata Cancer Center Hospital, National Shikoku Cancer Center, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka National Hospital, National Cancer Center Hospital East, Tokyo Metropolitan Komagome Hospital, Aichi Cancer Center, Osaka Medical College, International Medical Center of Japan, Sakai City Hospital, Kanagawa Cancer Center, Tokyo Metropolitan Bokuto Hospital, Nagaoka Chuo General Hospital, Niigata City General Hospital, Cancer Institute Hospital, Kyoto Second Red Cross Hospital, Saitama Cancer Center, Hiroshima City Hospital, Kanazawa University (Gastroenterologic Surgery), Gifu Municipal Hospital, Kagoshima University, Iwate Medical University (Department of Surgery 1), Okayama University.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
This study was supported by the Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare, and the Second Term Comprehensive 10-Year Strategy for Cancer Control by the Ministry of Health and Welfare, Japan.

Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002 (abstract 697).

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
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Submitted October 24, 2003; accepted January 16, 2004.

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