CASE PRESENTATION EXTENDED LYMPH NODE DISSECTION IN GASTRIC CANCER PROS AND CONS. A CASE REPORT AND REVIEW OF LITERATURE

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1 MEDICINĂ, no. 2, 2014 CASE PRESENTATION EXTENDED LYMPH NODE DISSECTION IN GASTRIC CANCER PROS AND CONS. A CASE REPORT AND REVIEW OF LITERATURE N. Bacalbasa 1, Beatrice Lintoiu 2, Irina Balescu 3 1 Carol Davila University of Medicine and Pharmacy, Bucharest, Romania 2 Profesor Dr. Agripa Ionescu Clinical Emergency Hospital, Bucharest, Romania 3 Ponderas Hospital, Bucharest, Romania nicolae_bacalbasa@yahoo.com ABSTRACT Gastric cancer remains one of the most aggressive malignancies worldwide associated with poor prognosis. Unfortunately this type of malignancy has an important capacity of spread via direct invasion and lymphatic route. Surgery is the only potential curative solution and extended lymphadenectomy is recommended as a main component of radical gastrectomy in order to obtain a good control of the disease. Success reported after radical gastrectomy with D2 lymph node dissection encouraged surgeons worldwide to go even furthet with dissection. Nowadays super-extended D3 lymphadenectomy (also known as D2+ or D4) was introduced. This procedure extends lymphadenectomy to para-aortico-caval territories. We present the case of a 45 years old patient diagnosed with advanced gastric cancer with pancreatic invasion in whom we performed a radical total gastrectomy en bloc with spleno-pancreatectomy and total omentectomy with Roux en Y alimentary reconstruction associated with an extended lymphadenectomy including inter-aortico-caval territories. KEYWORDS: gastric cancer, radical resection, extended lymphadenectomy 1. Introduction Gastric cancer is the second cause of cancer related mortality worldwide, with a high incidence in developed countries. [1] One of the most important patterns of spread is the lymphatic route, which is increased especially in cases with tumors presenting over-expression on the gastric serosa [2]. Based on the classification of lymphatic stations related to the distance from the tumor, three different types of lymph-node dissection have been proposed [3-6]. After the introduction of D2 lymph node dissection in the early 1960-s in Japan, an important benefit in terms of survival was obtained [7]. This is how the idea that a radical lymph node dissection is a real cornerstone in treating this aggressive disease raised. In order to improve even more the outcomes of these patients, an extended to para-aortic lymph nodes D3 dissection (also known as D2+ or D4) has been proposed. 2. Case presentation A 45 year old patient admitted for abdominal pain associated with weight loss and anorexia. The upper digestive endoscopy revealed a medio-gastric 15

2 tumor which was biopsied. The results indicated a moderate differentiated gastric adenocarcinoma. Computed tomography showed a medio-gastric tumor with no demarcation line with the anterior surface of the pancreatic body but with no distant metastases which might contraindicate surgery. Large perigastric and inter-aortico-caval adenopathies were found. The patient was submitted to surgery; intraoperatively we found a medio-gastric tumor invading the body of the pancreas (Figures 1-3); a total gastrectomy en bloc with spleno-pancreatectomy, total omentectomy and D4 lymph node dissection was performed (Figures 4-8). The digestive continuity was re-established by a Roux en Y eso-enteral anastomosis. The late postoperative course was uneventful, with no signs of recurrence one year after surgery. Figure 3. Final aspect before sectioning the pancreatic body: specimen includes total gastrectomy en bloc with total omentectomy and splenopancreatectomy. Figure 1. Aspect after sectioning the duodenum gastric tumor invades the body of the pancreas Figure 4. Lymph nodes at the level of the celiac trunk and its branches and those at the level of the hepatic pedicle are removed Figure 2. Pancreatic body completely dissected posteriorly. Celiac trunk and its branches also completely dissected Figure 5. Aspect after removal of the specimen 16

3 3. Discussions Figure 6. Inter-aortico-caval lymph node dissection Figure 7. Dissection of the portal venous confluent Figure 8. Specimen total gastrectomy with omentectomy and spleno-pancreatectomy Gastric cancer is the fourth most common type of cancer and the second highest cause of cancerrelated mortality worldwide. The incidence of gastric cancer varies widely among different regions globally, with almost two- thirds of all cases in developing countries and 42% in China alone [1]. Efforts to reduce its high mortality rates are currently focused on multidisciplinary management. However, curative-intent surgery (gastrectomy, total or partial, and lymphadenectomy) remains the cornerstone of treatment. There is still controversy as to the extent of lymph node dissection for potentially curable gastric cancer. Surgeons in Eastern countries favor more extensive lymph node dissection, whereas those in the West favor less extensive dissection. The risk of regional nodal involvement in gastric cancer increases with penetration through the gastric wall [2]. Nodal metastases are seen in 3%-5% of the tumors limited to the mucosa, in 11%-25% of those extending to the submucosa, in 50 % of those reaching the muscularis and in 83% of those extending to the serosa (T3) [3]. Local recurrence is represented in 87.5% by nodal metastases to local or regional lymph node stations [4]. The Japanese Classification of Gastric Carcinoma (JGCA, 1998) [5] has defined 16 lymph node stations which drain the stomach. These are subdivided in three levels, according to their distance from the tumor. Thus three types of lymph node dissection (D) can be associated to partial/total gastrectomy: D1, removes perigastric lymph nodes (stations 1 to 6; N1 level), D2 removes perigastric lymph nodes and those located along the main arterial vessels from stations 7 to 12 ( N2 level) and D3 removes stations 13 to 16 (N3 level), as well as those mentioned before [6]. During the 1960s, the Japanese authors first introduced D2 lymphadenectomy [7], which they still 17

4 consider as the standard procedure to associate with curative gastric resection. In Western countries, D2 lymph node dissection is not as common as in Eastern countries. A significant difference between Japanese clinical outcomes and those of other countries has been observed in short-and long-term results and in loco-regional control, in favor of Japanese results. The International Union Against Cancer (UICC) [8] adopted in 1997 a new classification system for lymph node metastases, not based on the anatomic location of positive nodes, but on their number. It was recommended that at least 15 lymph nodes should be removed and examined for proper staging. Randomized controlled trials (RCTs), mainly conducted by Western authors surgeons, since the 1980s, compare short-term and long-term results in D1 and D2 resections. Two large-scale RCTs comparing D1 with D2 were performed by the Dutch Gastric Cancer Group (DutchD1D2- between 1989 and 1993) and the Medical Research Council (MRC, between 1987 and 1994). The authors reported that mortality rates in D2 group gastrectomy reached 10% [11,12] and the extended lymph node dissection offers no survival advantage over limited lymphadenectomy. In the Dutch trial, overall 5-year survival rates were similar in the D1 and D2 groups (45% for D1 and 47% for D2) [9]. In 2004, Hartgrink et al. [10] reviewed results of the this trial after a follow up of more than ten years and concluded that associated higher postoperative mortality offsets its long-term effect on survival. An extended lymph node dissection may offer a cure for patients with N2 disease, suggesting D2 lymph node dissections may add some benefit if morbidity and mortality can be avoided. Recently, results of 15-year follow-up were reported by Songun et al [11]. The overall 15-year survival was 21% for the D1 group and 29% for the D2 group (P =.34). The gastric-cancer related death rate was significantly higher in the D1 group (48%) compared with that in the D2 group (37%). Many patients included in the study underwent pancreatic and/or spleen resection as part of D2 dissection. The authors indicated that because a safer, spleen-preserving D2 resection technique had become available in high-volume centers, D2 lymphadenectomy should be the recommended surgical approach for patients with curable gastric cancer. In the British study (MRC), postoperative complications were significantly higher in the D2 group (46%) than in the D1 group (28%; P <.001), and the postoperative mortality was also significantly higher in the D2 group (13%) than in the D1 group (6.5%; P =.04) [12]. Splenectomy was performed for many patients; pancreaticosplenectomy was carried out in 56% of patients allocated to the D2 group and 4% of the D1 group. The high frequency of postoperative complications was influenced by the excessive surgery, a misunderstanding of the definition of D2 gastrectomy defined by the Japanese Gastric Cancer Association. The 5-year survival rate did not significantly differ between the two groups (33% for D1 and 35% for D2 ) [13]. Unlike these two large European trials, the Italian Gastric Cancer Study Group (IGCSG) has shown the safety of D2 dissection with pancreas preservation in a one-arm phase I-II trial [14]. This study concluded that the more extensive Japanese procedure with pancreas preservation can be regarded as a safe radical treatment for gastric cancer in selected Western patients treated at experienced centers. In 2004, Degiuli et al. [15] had also shown morbidity and mortality after extended gastrectomy may have been as low as those reported by Japanese authors in very experienced centers. These data were updated in 2010, confirming that the rate of complications following D2 dissection is much lower than that published in previous randomized western 18

5 trials. D2 dissection was, therefore, considered a safe option for the radical management of gastric cancer in an appropriate setting and became the recommended surgery approach for advanced resectable gastric cancer in Europe [16]. In Japan, pancreaticosplenectomy for lymph node (LN) dissection around the splenic artery (station no. 11) and splenic hilus (station no. 10) had been widely performed, because this procedure was proposed as a radical dissection of metastatic LN along the splenic artery [17]. However, Japanese retrospective analyses proved that there was no survival benefit of these procedures. Recently, pancreas-preserving splenectomy has been considered a safe and effective procedure without decreasing surgical curability [18]. In Western countries as well, pancreaticosplenectomy had a marked adverse effect on both mortality and morbidity in two large RCTs [9,12]. Currently, pancreaticosplenectomy is considered beneficial only when the primary tumor or metastatic LN directly invades the pancreas, but is not performed for prophylactic dissection of lymph nodes around the splenic artery (station no. 11). Splenectomy is recommended for curative resection of the proximal advanced gastric cancer with infiltration to the greater curvature in the Gastric Cancer Treatment Guidelines 2010 [19 ]. There are two important RCTs comparing gastrectomy with splenectomy and gastrectomy alone in patients with gastric cancer [20,21]. In the first one, Csendes et al. reported 187 patients who underwent total gastrectomy between 1985 and Postoperative complications were more frequent in the splenectomy group than in the gastrectomy alone group. There were no significant differences in hospital mortality or in the 5-year survival [20]. The second trial, JCOG 9501, reported by Yu et al. was carried out in Korea between 1995 and Two hundred seven patients with gastric cancer were divided randomly into two groups, total gastrectomy and total gastrectomy plus splenectomy. There is a significant difference in postoperative morbidity rate (11.5% vs 27.5%), favoring spleen-preserving D2- gastrectomy. The 5-year survival rates did not differ statistically between the two groups. There was no 5- year survivor among patients with lymph node metastasis at the splenic hilum in either group [21]. Spleen-preserving No10 lymphadenectomy is also a succesfull technique described by the japonese authors [22]. In a very recent systematic review from the Cochrane Database [23], McCulloch and colleagues concluded that D2 dissection carries increased mortality risks associated with spleen and pancreas resection, and probably also associated with operator inexperience and low case volumes. However total gastrectomy with splenectomy has still been recommended for patients with T3 proximal gastric cancer who have 10-station lymph node metastasis [24]. The current Japanese gastric cancer treatment guidelines continues to include splenectomies as part of the definition of D2 lymphadenectomies in more than T2 proximal third tumors eligible for a total gastrectomy [25]. Preliminary results of the ongoing JCOG 0110 trial confirmed greater blood loss and operative morbidity in the group who underwent splenectomies. Final results from this trial will allow us to establish definitively whether splenectomies can be avoided without compromising patient survival in cases involving proximal tumors [26]. The extent of lymph node dissection is still the subject of debate. This debate is mainly due to Japanese surgeons who routinely perform more extensive lymphadenectomy. The arguments favoring an extended lymphadenectomy ( D2 or D3/D4) are that removing a larger number of nodes more accurately stages disease extent and that failure to remove these nodes leaves behind disease in as many as one-third of patients [27]. A consequence of more 19

6 accurate staging is to minimize stage migration (the Okie phenomenon, as described by Will Rodgers). The resulting improvement in stage-specific survival may explain, in part, the better results in Asian patients [28]. Furthermore, the influence of total lymph node count on stage-specific survival has been extensively studied and also proved to be significantly better as more nodes were examined in every stage subgroup [29]. Asian surgeons have also proposed a more radical lymph node dissection in order to improve survival for patients with stage T2-4 tumors. In this extensive procedure, designated as D4 dissection, paraaortic lymph nodes are removed in combination with D2 dissection. The incidence of microscopic metastases in the paraaortic nodes (section no. 16) in patients with gastrectomy undergoing D3 lymph node dissection ranged from 6% to 33%, and the 5-year survival rate had been reported to range from 12% to 23% in patients undergoing gastrectomy with D3 dissection [30,31]. Perhaps the greatest criticism of reports from Japan and other Asian countries, demonstrating significant benefits and modest morbidity from extended lymph node dissection for gastric cancer, has been the retrospective nature of the data. These critics are challenged with the reports of the Japan Clinical Oncology Group (JCOG) study of lymphadenectomy. Sano et al. completed this ambitious trial of D2 lymph node dissection compared with a more extensive D2 lymphadenectomy plus paraaortic lymph node dissection (PAND) [32]. The JCOG trial randomly assigned patients at surgery, after confirming the ability to perform a curative resection (R0) to either a D2 dissection or to a more radical node dissection that included the nodal tissue along the aorta. Surgeons in this study had to have personally performed more than 100 gastric resections or be at an institution with a specialized unit where more than 80 gastric resections were performed annually. There are relatively few surgeons in the United States who would have been able to participate in this study. The rates of surgery-related complications among patients assigned to D2 lymphadenectomy alone and those assigned to D2 lymphadenectomy plus PAND were 20.9% and 28.1%, respectively (P =.07). There were no significant differences between the two groups in the frequencies of anastomotic leakage, pancreatic fistula, abdominal abscess, pneumonia, or death from any cause within 30 days after surgery The 5-year overall survival rate was 69.2% for the group assigned to D2 lymphadenectomy alone and 70.3% for the group assigned to D2 lymphadenectomy plus PAND. There were no significant differences in recurrence-free survival between the two groups [32]. There are some possible explanations for the low mortality rate in the JCOG study. First, patients had to be considered very fit for a major operation. The median age for all patients was only 61 years, and no patient was older than 75 years. Second, surgeons and their centers were highly experienced in performing the procedures. Third, surgeons in the JCOG trial, though frequently employing splenectomy (in 36.5% of all patients) to effect a complete node dissection, avoided pancreatectomy, (in 4.2% of all patients) unless absolutely necessary. What is not addressed in this study are other risk factors likely to be very different between Asian and Western patients. We do not know what the ranges were for body mass index in this study, but it can be assumed that they would be significantly less than most American patients. With numerous reports of the increasing obesity in the population of US, the impact on surgical morbidity and mortality should not be underestimated. In addition, operations in these patients are more difficult. A single-institutional small-scale RCT has reported from Taiwan that there were no significant 20

7 differences in the postoperative and mortality between patients undergoing D1 and D3 gastrectomy. This was the only trial that showed a significantly higher 5-year disease-specific survival in patients with D3 surgery than in those with D1 surgery [33]. Three meta-analyses of RCTs evaluating D1 vs D2 vs D3 lymphadenectomy for operable gastric carcinoma were conducted in 2009 [34], 2011 [35], and 2012 [36]. X.C.Chen et al. [37] reported results of metaanalyses, including three RCTs, comparing D2 to D2 with PAND. This meta-analyses showed that D2+ PAND can be performed as safely as a standard D2 resection without increasing postoperative mortality but failed to benefit overall survival in patients with advanced gastric cancer. Gastrectomy with D2 lymphadenectomy plus PAND cannot be recommended as a routine practice for the surgical treatment of gastric cancer. Also, two Japanese trials rigorously exploring this issue concluded that D2 lymphadenectomy plus paraaortic lymph node dissection (PAND) does not improve the survival rate in curable gastric cancer when compared with standard D2 lymphadenectomy alone. Thus, systematic D4 dissection has not been recommended for treatment of stomach cancer because it failed to benefit overall survival in patients with potentially curable advanced gastric cancer [38]. Over the last few years, it has been demonstrated that the number of removed lymph nodes in radical gastrectomy is closely correlated with the patients survival rate. Seevaratnam et al. [36] reported this statement and demonstrated that patients with T1 T2 cancer, from whom 15 lymph nodes were removed, or patients with T3 T4 cancer, from whom 20 lymph nodes were removed, had significantly higher survival rates compared to those of patients with cancer of identical stage from whom less lymph nodes were removed (P<0.05). The extent of lymph node dissection for any given patient should be carefully selected based on Borrmann type, location, size, depth of invasion and histological type of the cancer [39]. Recently, the Union for International Cancer Control (UICC)/ American Joint Committee on Cancer (AJCC) and the Japanese Gastric Cancer Association (JGCA) [40] have put a great deal of effort into working together and establishing a common language to express the clinical experience and results. The new pn categories and the new definitions of types of lymphadenectomies attempt to simplify and standardize the surgical management of gastric cancer taking into account the type of gastrectomy to be performed. Therefore, a D1 lymphadenectomy has been considered the dissection of the perigastric lymph nodes whereas a D2 lymphadenectomy, involves removal of nodes along the hepatic, left gastric, celiac and splenic arteries as well as those in the splenic hilum (stations 1-11). The D3 dissection comprises the superextended lymphadenectomy, a term that has been used by some to describe a D2 lymphadenectomy plus the removal of nodes within the porta hepatis and periaortic regions (stations 1-16), while others use the term to denote a D2 lymphadenectomy plus periaortic nodal dissection (PAND) alone. A global study using unified criteria is necessary to establish a safe and effective worldwide treatment standard including gastrectomy with LN dissection. Nowadays, in both Eastern and Western countries, D2 lymph node dissections have been considered a more appropriate procedure at highvolume centers or for skilled surgeons, and this is recommended by most current gastric cancer guidelines for resectable disease [25,41,42]. Gastric cancers are now often treated by a multimodal approach including perioperative chemotherapy or chemoradiation. The benefit of an extensive dissection may become more limited if some highly effective perioperative therapies 21

8 (including target therapy) are available. Whether these therapies may replace more extensive surgical procedure (possibly at a much higher cost) remains unclear. Current data have favored the adoption of some adjuvant therapy even after a D2-dissection [43]. The CLASSIC trial [44] has demonstrated improved 3-year overall and disease-free survival by adding adjuvant oxaliplatin and capecitabine to D2- gastrectomy. Similarly, the ARTIST trial [45] reported 3- year disease-free survival of 74.2% for D2-gastrectomy plus adjuvant capecitabine/cisplatinbased chemotherapy. Previously, the Japanese ACTS- GC trial had also confirmed that oral fluoropyrimidine derivative S-1 significantly improved overall survival [46]. As for radiation added to adjuvant chemotherapy after a D2- dissection, the ARTIST trial [45] failed to demonstrate any advantage. According to Lee and colleagues,[45] some improvement was seen only in the lymph node-positve subgroup, but this needs to be interpreted with caution after a longer follow up or/and after a subsequent phase III trial (ARTIST-II) planned to confirm the benefit of adjuvant chemoradiation for patients with D2 lymph node dissection and pathological lymph node-positive disease. In Japan, adjuvant chemotherapy with S-1 is a standard treatment for patients with stage II/III gastric cancer after curative gastrectomy with D2 LN dissection [47]. Studies evaluating the recurrence stated that lymph node dissection proved to be a main factor in the spread of viable free cancer cells into the peritoneal cavity and itself appears to play a role in peritoneal dissemination of gastric cancer. Marutsuka and colleagues [48] clearly revealed the existence of free cancer cells in the peritoneal cavity after lymphadenectomy, even when the gastric serosa was not disrupted. This may explain the high rates of peritoneal recurrence after curative operations, despite neither the apparent existence of abdominal free cancer cells nor overt peritoneal metastasis before surgery. These authors advocated that extensive intraoperative peritoneal lavage (EIPL) should be a standard prophylactic strategy for peritoneal dissemination in advanced gastric cancer [48,49]. 4. Conclusions Surgery is the main treatment for curing gastric cancer. The extent of lymphadenectomy surgery has been under debate for a long time. In East Asian countries, especially Japan, Korea, and Taiwan, gastrectomy with D2 dissection is routinely performed. By contrast, in most Western countries, gastrectomy with D1 dissection is performed, due to lower mortality and morbidity. Acceptance of D2 surgery is increasing in these countries because: Western surgeons can be trained to performed D2 lymph node dissection; modified D2 lymphadenectomy (preservation of pancreas and spleen) improves operative morbidity and mortality; and D2 resection decreases locoregional recurrence and prolongs survival. Modified D2 dissection is recommended by current guidelines in the United States and Europe, but needs to be performed by high-volume centers with experienced surgeons. Adjuvant or perioperative chemotherapy should be prescribed for gastric cancer with Stage II or III disease. Targeted therapy with trastuzumab should be considered in patients with HER-2/neu overexpression who have a higher response rate and a longer survival. Patients with inoperable advanced gastric cancer should receive chemotherapy to improve their survival and quality of life. References 1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61: Lawson JD, Sicklick JK, Fanta PT. Gastric cancer. Curr Probl Cancer. 2011;35: de Gara CJ, Hanson J, Hamilton S. A population-based study of tumor-node relationship, resection margins, and surgeon volume on gastric cancer survival. Am J Surg. 2003;186:

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