Gastrectomy with D2 lymphadenectomy for gastric cancer: Morbidity, mortality and survival

Gastrectomy with D2 lymphadenectomy for gastric cancer: Morbidity, mortality and survival

Mohamed I Kassem, MD; Abdel Hamid Ghazal, MD; Magdy A Sorour, MD;

Aymen Azzam, MD; Mohamed El-Riwini, MD; Hassan El-Bahrawy, MD

GJT Surgical Unit, Department of General Surgery, University of Alexandria, Egypt.

Abstract

Background: Gastric cancer is the second leading cause of cancer death worldwide. Ninety percent of gastric cancers are adenocarcinomas. Overall, there is a decline in the incidence of gastric cancer in most countries over the past 50 years. Surgical resection is the most effective treatment for curable gastric cancer.Controversy still surrounds the value of extensive lymph node dissection in the curative treatment of gastric carcinoma.The overall 5-year survival rate among patients with resectable gastric cancer ranges from 10% to 30% in the western world. In contrast, Japanese publications report a marked improvement in survival (between 50% and

62%),  largely attributed to  lymph  node  resection known  as  "D2 lymphadenectomy".

Methods: The study was a prospective follow-up study on 50 consecutive patients with gastric cancer  (without  distant metastasis) between  March  2007 and February  2010 in the Upper Gastrointestinal Surgery Unit, Faculty of Medicine, Alexandria University, Egypt. Patients less than 65 years with histologically  proven and potentially  curable gastric cancer were eligible for the study. Preoperatively, all patients  underwent  upper gastrointestinal endoscopy  with biopsies and histopathologic examination. Computed tomography (CT) scans were done to look for metastases.

Results: Fifty  patients (36 men, 14 women) underwent gastric resection with D2- lymphadenectomy for gastric adenocarcinoma in a three-year period. Mean age was 46.6 years with a range of23-65 years. Almost 44% of patients had preoperative co-morbid disease. Weight loss with epigastric pain and dyspepsia was the most common presenting symptom (80%). Fifty patients  underwent D2 resection, fifteen  patients  with radical  total gastrectomy and intra­ abdominal  oesophagojejunostomy, and thirty five patients with a subtotal distal gastrectomy and gastrojejunostomy. The hospital  mortality rate was 4% (2/50). Morbidity rate was 44% (22/50), some of them presented with more than one complication. The median time of hospital stay was 22 days (mean 22.3, range 13-40). Follow-up  included  clinical, laboratory  and CT examinations of all patients after surgery. In addition, when relapse was suspected, endoscopy with biopsy, and CT scan were performed. During the first 2 years follow-up, locoregional relapses were observed in 2 patients (local lymph nodes relapse). One patient presented with peritoneal  recurrence, and 2 patients showed distant spread. The overall actuarial one-year survival in D2 patients was 92% and 76% at two years.

Conclusion: The results obtained in our series of patients submitted to gastrectomy with D2 lymphadenectomy suggest that this technique offers low morbidity,  mortality and acceptable

2-year survival rates. The survival benefit with D2 is obtained when a tumor invades muscularis

propria or penetrates serosa without invasion of adjacent structures.

Introduction:

Gastric cancer is the second leading cause of cancer  death worldwide, although  its incidence is decreasing. INinety per cent of gastric cancers are adenocarcinomas. Overall,

there is a decline in the incidence of gastric cancer in most countries over the past 50 years.2-6 The reason for this decline remains unknown, but there is speculation that the eradication ofHelicobacter pylori and a change

in  diet  may be   contributing  factors.2

Gastric cancer mortality is  largely attributable to relapse of the disease, manifested in different ways in more  than  one  location simultaneously.7 Gastric cancer relapse and patient survival depend on both the stage  of the disease at the time of diagnosis and on the extent of surgery.8

The  overall 5-year survival rate  among patients with resectable gastric cancer  ranges from  10%  to 30%  in the western world.9  In contrast, Japanese publications report a marked improvement in survival (between 50% and

62%), largely attributed to  lymph node resection known as "D2 lymphadenectomy".10

Some  studies suggest that surgeon expertise not only plays an important role in reducing surgical morbidity and  mortality but  also contributes substantially to improving survivai.ll

Surgical resection is the  most  effective treatment for curable gastric cancer. Controversy still surrounds the  value of extensive lymph node dissection in the curative treatment of gastric  carcinoma. Reports from the  Gastric Cancer Registry and  other retrospective studiesl2-15 have  made  radical gastrectomy with  extended D2  removal of regional lymph nodes the  standard for  the treatment of curable gastric cancer  in Eastern Asia and the United States.16-21

The aim of gastrectomy is to achieve an RO resection. A curative  resection was defined  as RO, and patients with  positive microscopic margins (Rl) and evidence of gross  residual disease (R2) were considered to have palliative resections.  The Japanese Research Society for Gastric Cancer (JRSGC) has  assigned the lymph nodes draining the  stomach into  16 different lymphatic stations and this is divided into  four  echelons (Nl-N4).22 The extent of lymphadenectomy is defined as Dl-D4 depending on the lymph node stations dissected. In the  Western World, removal of the perigastric lymph nodes along the  lesser curvature and  the greater curvature is a D1 resection. D2  gastrectomy, involves D1 resection plus  removal of the omental bursa and the front leaf of the transverse mesocolon and the nodes along the left gastric artery, the

common hepatic artery, the coeliac artery, the splenic  artery and splenic hilum  (N2 nodes). D3 involves D2 plus removal  of nodes in the hepatoduodenalligament, inthe retropancreatic space and along the vessels of the transverse mesocolon. D4  resection involves a  D3 resection and removal of the nodes around the abdominal aorta. In  reality, D3  and  D4 resections are  rarely practiced where D2 resections are the gold standard lymphadenectomy.22

Once the gastric tumor invades the subserosa (stage T2b), the  serosa (stage T3), or  the adjacent  structures (stage T4), metastases can spread to the para-aortic lymph  nodes, which

are termed N3 nodes according to the Japanese

Classification of Gastric Carcinoma,23 and M1 nodes according to the  International Union Against Cancer (UICC) tumor-node-metastasis

(TNM) classification.24

Why  should D2 lymphadenectomy be considered? Firstly; the principle, it is known that second echelon N2 nodes will be involved in a high proportion of gastric cancer cases, and most patients  have node-positive disease. The  excision of this  echelon of  nodes will increase the likelihood of an RO resection, and this may benefit a subset of patients. Secondly, the experience of centers in Japan and the West reported low  operative risks  and  excellent outcomes.25-27 Complete locoregional tumor removal with adequate margins of clearance has been  repeatedly identified and widely accepted as a major factor in  reducing locoregional tumor recurrences and improving survival in patients with gastric  cancer. Safe margins, by this defmition, entail no residual tumor  at resection margins and gastric bed, and no lymph  node with tumor  in the area of lymphatic drainage.28,29

The aim of this study was to evaluate the morbidity, mortality, and survival in the surgical treatment of curable gastric cancer with radical gastrectomy and  D2 lymphadenectomy and the factors that could  influence them,  and to evaluate whether extending the lymph node dissection to N2 level can improve the survival rate and reduce the incidence of locoregional relapse.

Patients and methods:

The study was a prospective follow-up study on 50 consecutive patients with gastric cancer (without distant metastasis) between March

2007 and February 2010 in the Upper Gastrointestinal Surgery Unit, Faculty of Medicine, Alexandria  University, Egypt.

Patients less than 65 years with histologically proven and potentially curable gastric cancer were eligible for the study.

Patients with severe cardiorespiratory, renal or metabolic disease precluding extended resections were excluded, as were those with

distant metastases at preoperative staging.

Preoperatively; all patients underwentupper gastrointestinal endoscopy with biopsies for histopathologic examination, and computed

Figure (1)

tomography (en for staging of gastric cancer and  look  for  metastases  Figure(t,l).

A total of 50 patients with gastric cancer were operated on. Patients who underwent an

en bloc resection of the stomach with extended

02-lymphadenectomy were selected for this

study. The lymph node dissection included

compartments I (No. 1-6) and II (No. 7-15).

The records: Age, gender, co-morbidity, type of gastrectomy, additional organ resection (splenectomy) and pathologic1NM stage were reviewed in the 50 D2 gastrectomies prospectively. Operative mortality   and

morbidity were defined as death  or complications occurred within 30 days after the operation.

Figure (2)

Figure (1,2): CT evidence of cancer stomach (distal third).

Results:

Fifty patients (36 men, 14 women) underwent gastric resection with  D2- lymphadenectomy for gastric adenocarcinoma in a three-year period. Mean age was 46.6 years with a range of 23-65 years. Patients with a histopathological diagnosis other than

adenocarcinoma were excluded, as were those with synchronous neoplasm, and those with tumors located at the oesophagogast:ric junction. There were no exclusions due to co-morbidity or age, except for those patients for whom

surgery did not intend to be radical due to the extent of illness, or patients for whom surgery was exclusively palliative.

Almost 44% of patients had preoperative co-morbid disease (some of patients presented with more than one co-morbidity). The factors of co-morbidity (n=29) in the 22 patients were

diabetes mellitus (n=9),ischemic heart disease (n=8), hypertension (n=7),chronic obstructive pulmonary disease (n=4) and chronic cardiac

and dyspepsia was 1he most common presenting symptom (80%), anorexia and dysphagia (10%), upper abdominal discomfort (6%), and haematemesis (4%).

Fifty patients underwent D2 resection, fifteen patients with radical total gastrectomy and  intra-abdominal oesophagojejunal

anastomosis  Figures(3,4), and thirty five patients with a subtotal distal gastrectomy and gastrojejunostomy Figures(S-15).Six patients underwent splenectomy,one patient underwent distal  pancreatectomy, and one patient underwent transverse colectomy in an attempt to achieve RO resections inthe locally advanced tumors. Distal subtotal gastrectomy was reserved for those patients with tumors located inthe distal thirdof the stomach, corresponding to the Lauren intestinal type, and which, on macroscopic examination, appeared not to invade the gastric serosa. The remaining patients underwent total  gastrectomy.

Resection was extended to the neighboring

-&iiihl!fiii!ffNtiiDftJ:&II                                                                                       -

failure (n =1). Weight loss with epigastric pain

organs when tumor invasion was suspected.

Splenectomy was performed in patients with advanced proximal tumors with suspected splenic infiltration, or with apparently invaded splenic hilar lymph nodes. In the 6 patients in whom a splenectomy was carried out, 2 were for tumors at the upper part of the stomach, 3 for the tumors of the middle part, and one for the tumors diffusely affect the stomach (3 patients had T4 tumors and 3 patients had localized tumors near the splenic hilum with

Figure (3)

suspicion  of lymphatic  invasion). A distal pancreatectomy was performed in patients with suspected  tumor infiltration or metastatic disease in the lymph nodes of the splenic artery chain. Distal pancreatectomy was done in one patient with T3/T4 tumors and the tumor invasion was confirmed. Transverse colectomy with primary anastomosis was done in one patient with T4 tumor invasion of the transverse mesocolon.

Figure(4)

Figures (3,4): Total gastrectomy for diffuse type of cancer stomach.

Figure (5)

Figure (7)

Figure(6)

Figure(8)

Figure (9)

Figure (11)

Figure (13)

Figure(10)

Figure(12)

Figure(l4)

Figure (15)

Figures(5-14):Distal gastrectomywith D2lymphadenectomy forcancerstomachof the pyloric antrum and gastrojejunostomy Figure (15).

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The clinicopathological characteristics of the 50 patients, the pathologic TNM stages of the patients, and the lymph nodes  in the D2 dissections   are  shown  in  Table(1).

Disease staging was  based on  the  TNM

classification included in the fifth edition (2005)

of the TNM  atlas:illustrated guide to the TNM classification of  malignant tumors, of  the International Union  Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC).30

Table (1): Clinicopathological characteristics of the 50 patients (gastrectomy with D1 lymphadenectomy).

NO: No positive nodes

N1: One to 6 positive nodes

N2: Seven to 15 positive nodes

N3: More than 15 positive nodes

The hospital mortality rate was 4% (2/50). The two patients undeiWent total gastrectomy; the first one, 64 years old, was hospitalized before the gastric operation with serious gastric bleeding from the stomach cancer; after blood transfusion and  correction  of the general condition, he was operated on and died on the

12th postoperative  day due to anastomotic dehiscence  (oesophagojejuno stomy), septicemia and respiratory distress secondary to pneumonia. The second patient, 60 years old, had hypertension and chronic cardiac failure as a co-morbidity preoperatively, and despite preoperative hospitalization and control of hypertension and chronic cardiac failure, the patient died on the 25th postoperative day because of heart failure and chest infection.

Morbidity rate was 44% (22/50), some of them  presented with  more  than  one complication. Chest infection (n = 12); two of these  patients  had respiratory failure  and required intensive support at the intensive care

unit  (ICU)   but  none  required artificial ventilation, wound infection (n=lO), diabetic ketoacidosis (n=3), atrial fibrillation (n=2), upper gastrointestinal hemorrhage (n=2); which resolved spontaneously, deep vein thrombosis (n=l), pulmonary embolism (n=1), and intra­ abdominal  abscess  (n=l). There were two patients with oesophagojejunalleak; one patient died postoperative because of intraabdominal abscess and respiratory failure and the other patient  was treated conservatively with percutaneous drainage and medical treatment. Another patient with gastrojejunal anastomotic leak was successfully managed conservatively with  percutaneous drainage  and  medical treatment (the anastomotic leak proved by a systematic water  soluble  X-ray  imaging performed on the seventh postoperative day). No patient required surgical re-interventions. The statistics of the parameters according to mortality and morbidity are shown in Table(l).

Table (1): Postoperative complications (morbidity) and mortality.

The median time of hospital stay was 22 days (mean 22.3, range 13--40). Follow-up included clinical, laboratory and  CT examinations of all patients during the first two years after surgery. In addition, when relapse was suspected, endoscopy with biopsy, and CT scan were performed. Tumor markers were performed; carcinoembryonic  antigen (CEA) and carbohydrate antigen (CA) 19-9. Recurrences were classified as locoregional, peritoneal, or distant metastasis. Locoregional recurrences were included (those located in the surgical bed, retroperitoneal lymph nodes of the upper abdomen, or in the site of anastomosis). Peritoneal recurrences were included [those affecting the ovaries, (Krukenberg tumor), carcinomatosis, and positive cytology]. Distant recurrences were those detected in other non-regional lymph

nodes or other organs.

During the first 2 years  follow-up, locoregional relapses  were  observed  in 2 patients  (local lymph  nodes relapse). One patient presented with peritoneal recurrence, and  2  patients  showed distant  spread.

The survival curve following D2 resections is shown in Figures(16,17).

The overall actuarial one-year survival in

D2 patients was 92%  and 76% at two years.

Statistical analysis:

The SPSS version 12.0.1 statistical package was used for statistical analysis. Values for qualitative variables were given as percentages and those for quantitative variables were given as medians and ranges. Survival curves were calculated using the Kaplan-Meier  method.

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Figure (17): The overall actuarial survivalcurve for patients after total and distal subtotal gastrectomy for gastric cancer (2-year Kaplan-Meier survival curve).

Discussion:

Despite its recent decline, gastric cancer is

still a common lethal disease in western countries.31 For apparently resectable cancers, surgery offers the best locoregional control; but unfortunately,average 5-year survival rates for treated patients remain low in the western world,ranging fi:om15 to 30%.32,33 The benefit

of D2 gastrectomy's potential for reducing locoregional recurrence may be nullified by the significant increase of post-operative morbidity andmortality_31

There is controversy over the use ofD2 as a curative procedure for gastric cancer.Japanese surgeons have advocated its use since the 1960s and it is now the standard surgical treatment

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for gastric cancer in Japan and in many centers in Hong Kong, Korea and China. Its use in Europe and the US has been limited to specialist units. This  may  reflect some  therapeutic nihilism to  gastric and  other upper gastrointestinal cancers in the Western World, but  in  greater part  it reflects the  lack  of supporting evidence from randomised studies which claim no survival benefit yet enhanced operative morbidity  and mortality  from the extended lymphadenectomy. The  Medical Research Council (MRC) studied 400 patients undergoing gastrectomy  (200 in both the D1 and D2 groups) in a multicentre trial and found significantly higher post-operative morbidity (33% D2 vs.21% Dl) and mortality (13% D2 vs. 6.5%  Dl) following D2 resection.34 In support of this view, Wanebo et ai35 reviewed a prospectively gathered  database of 18,346 cases of gastric carcinoma in the US. Among the  3,804 patients undergoing curative resection, five year survival rates for patients with  N2, N1 and  NO nodes  removed  were

26.3%,  30% and 35.6%  respectively. They

concluded that lymph node dissection (D2) of N2 nodes did not confer a survival advantage. Overall mortality was very low, at 0.6%. This rate is comparable to those shown by eastern authors in series from experienced centers, and is strikingly different  from the rates of both arms reported in MRC and Dutch trials.36,37

Although morbidity and mortality rates of gastrectomy for gastric cancer were different, in a data analysis  of 22 cancer centers;  the mortality rate was reported between 3.1% and

31%.38

Inthis study, the hospital mortality rate was

4%, and the mortality rate at one year was 8%

and this is in agreement with literature reports.

The morbidity rate of our study was 44%, This figure is higher than the percentages reported by other authors in literature in which the morbidity  has been reported  as being 8-

31%.39,40 Varies studies41,42 have demonstrated

that the morbidity increased with age but no significant correlation was found;  however other  studies emphasized that the age is a predictor factor  of morbidity.43,44 In our experience; the mortality and morbidity increased with age but no significant correlation was found.

The  most common non-abdominal complications in our series were of a respiratory nature, in agreement with many other literature sources_34,45-54 Among the abdominal complications, anastomotic leakage rates reported in the literature ranged from 2.1% to more than 8%.34,45-52,54 The overall incidence

of   dehiscence  in   our   series  was   6%.

It is now acceptedthat pancreatic and splenic resections are only justified in the rare situations where there is direct contiguous involvement of these organs by the gastric tumor and that a compete D2 lymphadenectomy can be effectively and  safely performed with preservation of these organs.55  In our study, six patients underwent splenectomy, one patient a distal  pancreatectomy, and one patient  a transverse colectomy in an attempt to achieve RO resections in the locally advanced tumors.

The incidence of disease  relapse varies greatly among the different series published in the literature. This is due to a number of factors, including the extent of surgery and the tumor stage at the time of the operation. Accordingly, the published relapse rates range from 20% to more than 60%; this figure is higher than the percentages  reported  by this study (recurrence rate was 10%) and this is because it includes both RO and Rl patients, unlike many other studies that include only RO patients.56-64 It is generally accepted that most relapses occur within the first 2 years after curative surgery for gastric cancer.8,60,65 Yoo et al57 on classifying relapse into early and late groups (according to whether relapse occurred before or after 2 years), found 73% of all disease relapses to occur early. D'Angelica et al60 in turn, reported a higher relapse rate, of

79%, in the first 2 years after surgery; this figure reached 94% before the fourth year.In our series, recurrence within the first 2 years after surgery was seen in 5 patients. Gastric cancer survival according to the type of surgery performed has  been  the  subject of  many studies- including those of  Bonenkamp et al66 and Cuschieri et ai34 who recommended  the obviation of routine D2 gastrectomy due to its high morbidity and mortality, and because the overall 5-year survival  in their group of D2 lymphadenectomized patients was  not significantly different from that of the group

submitted to more conservative surgery. Other authors  have also  reported  overall  5-year survival rates of fewer than 50%, with results in   the   range  of   30%-47%.47,48,67-69

The 5-year survival rates show marked differences between patients from the West and East,  and  although  the  prognosis of resectable gastric  carcinoma  in  the West remains poor, in Japan it is two-fold to three­ fold higher than those in the West mainly because extended lymph node dissection has been standard procedure during the last three decades_70,71 In recent years, the results of treatment in the West have also shown evidence of improvement. The 5-year survival rate after all resections has increased significantly from

21% in the series ending before 1970 to 28%

in those ending before 2000, and the 5-year survival rate after curative resection has risen from 38% to 55% over the same period.72,73

In our study; the overall one-year survival in

D2 patients was 92% and 76% after two years.

Conclusion:

Our experience is consistent with reports from other units in Western, European and the US and indicates that the extended lymph node dissection with gastrectomy can be performed with a low risk of mortality and morbidity, and acceptable outcomes. In conclusion, the results obtained in our series of patients submitted to  gastrectomy with D2 lymphadenectomy suggest that this technique offers low morbidity, mortality and acceptable

2-year survival rates of76%. We consider it essential for such surgery to be performed by specialized surgeons. In principle, the survival benefit with D2 is obtained  when a tumor invades muscularis propria or penetrates serosa without  invasion of  adjacent   structures.

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