Evaluation of Extended (D2) Lymphadenectomy for Treatment of Gastric Cancer

Evaluation of Extended (D2) Lymphadenectomy for Treatment of

Gastric Cancer

Hossam Abdelkader,1 MD; Haitham Elmaleh,2 MRCS, MD; Rabbah Abdellateef,2 MD; Ismael Morad3, MD

1) Department of General surgery, Menofia University, Menofia, Egypt.

2) Department of General surgery, Ain Shams University, Cairo, Egypt.

3) Department of Surgical oncology, National Cancer Institute, Cairo, Egypt.

Background & objectives: Although gastric cancer is one of the most common causes of cancer-related death, its prognosis remains poor. Surgical resection with lymph node dissection is the only potentially curative therapy for gastric cancer. However, the appropriate extent of lymph node dissection remains controversial. In East Asian countries, D2 lymph node dissection has been performed as a standard procedure. In western countries, D2 dissection was associated with higher mortality and morbidity with no 5-year survival benefit compared to D1 dissection. More recent studies have demonstrated that western surgeons can be trained to perform D2 lymphadenectomies on achieving survival benefits comparable to those of reported in eastern countries. The aim of our study is to evaluate the feasibility, safety and outcome of extended (D2) lymphadenectomy for gastric cancer.

Patients and methods: Between July 2008 and June 2014, patients with gastric cancer in whom surgical resection was indicated, were prospectively included in this study. Enrolled patients underwent gastrectomy with D2 lymphadenectomy. The patients were followed up regularly after the operation. Postoperative parameters, disease-specific mortality & Kaplan- Meier survival analysis were used to assess the outcomes.

Results: 62 patients were included in the study. 33 patients had distal gastrectomy and 29 patients had total gastrectomy. 9 (14.5%) patients had postoperative complications with 2 cases of postoperative mortality recorded. The overall mean survival time was 17.13 ±9.6 months and the disease free mean survival time was 13.4 ±9.39 months. Kaplan-Meier survival analysis showed that the overall survival probability estimate in the study was 100% at 1 year, 88.7% at

2 years, 58.1% at 3 years and 32.3% at 4 years. Nodal disease class & N stage were found to have a statistically significant effect on survival.

Conclusion: D2 lymphadenectomy can be performed safely in well-equipped hospitals by experienced surgeons with acceptable morbidity & mortality. It can provide better survival for patients with gastric cancer and low degree of lymph node metastases (N1 or N0).

Key words: Stomach cancer, D2 lymphadenectomy, extended lymphadenectomy.

Introduction:

Gastric cancer is one of the most common causes of cancer-related death1 and is second only to lung cancer worldwide.2 The wide variation in incidence between eastern and western countries strongly suggests an ethnic background as a risk factor. Egypt falls into the low risk area, with an incidence of 2.9 per

100,000, in comparison to 5.3 per 100.000 populations  in  the  United  States.  These rates are 5 to 15 times lower than in Japan, where the overall incidence is 50 per 100.000 population.2 The prognosis of gastric cancer patients remains poor, with a 5-year overall survival of 25% or less, especially in the USA, Europe, and China.3 Lymph node metastasis

is  an  important  prognostic  indicator  for the patients with gastric cancer. Surgical resection with lymph node dissection is the only potentially curative therapy for gastric cancer. However, the appropriate extent of lymph node dissection to be performed with gastrectomy remains controversial.4 The 5- year survival rate reported in most western series is 10% to 21%, which is a consequence of high proportion of patients that present in advanced stages.5 In East Asian countries, especially Japan and Korea, D2 lymph node dissection has been regularly performed as a standard procedure. In Western countries, surgeons used to perform gastrectomy with D1  dissection  only  because  D2  dissection was associated with higher mortality and morbidity with no 5-year survival benefit compared   to   D1   dissection.6,7    However, more recent studies have demonstrated that western surgeons can be trained to perform D2 lymphadenectomies on western patients with a lower morbidity and mortality, and eventually achieving survival benefits comparable to those of reported in eastern counties.8,9,10 The question of whether these results can be repeated in Egypt is still a matter of research. The aim of our study is to evaluate the feasibility, safety and outcome of performing extended (D2) lymphadenectomy for gastric cancer in Egypt.

Patients and methods:

The study was conducted in three hospitals in Egypt (National cancer Institute, Menofyia university hospitals & Ain Shams university hospitals) between July 2008 and June 2014, and it was a prospective interventional study. It included patients with gastric cancer in whom surgical resection was indicated.

Preoperative workup involved laboratory investigations (complete blood picture, renal functions, liver functions, serum electrolytes

& coagulation profile); chest X-rays, enhanced computed tomography scans of the abdomen and pelvis, and gastric endoscopy and   biopsy.  All   tumors   were   diagnosed as adenocarcinomas by histopathological assessment of biopsy specimens.

We used the D terminology according to

the guidelines of Japanese Research Society for Gastric Cancer (JRSGS). According to this classification, lymph nodes surrounding stomach are divided into 20 stations and these are classified into three groups depending upon the location of the primary tumor. This grouping system is based on the results of studies of lymphatic flow at various tumor sites, together with the observed survival associated with metastasis to each nodal station. In this grouping system, most perigastric LNs (Right paracardial, Left paracardial,  Right  and  left  gastric,  Right and    Left    gastro-omental,    Suprapyloric, and Subpyloric LNs [stations no. 1-6 respectively]) are defined as group 1, whereas the nodes along the left gastric artery (station no. 7), common hepatic artery (station no.

8), celiac axis (station no. 9), splenic artery (station no. 11) and hepato-dudenal ligament (station no. 12) are defined as group 2. D1 gastrectomy is defined as dissection of all the Group 1 nodes (plus station 7), and D2 is defined as dissection of all the Group 1 and Group 2 nodes.11

All      our      patients      underwent     D2

lymphadenectomy,  splenectomy  was  done for greater curve lesion attached to the spleen. No pancreatectomy was done.

All patients had follow-up visits after discharge from hospital every 3 months for the  first year,  and  twice  a  year  thereafter. The   routine   examination   during   follow- up included a physical examination, blood chemistry tests, chest X-ray, abdominal ultrasound.    Pelvi-abdominal    CT,    bone scan and endoscopy were done for selected patients when indicated.

We used disease-specific mortality for controlling of unrelated causes of death. Stratified and Cox regression analyses were used to evaluate the association between survival and the number of positive node harvested. The parameters analyzed included operative time, blood loss, blood transfusion, morbidity,  number  of  harvested  lymph nodes (HLNs), number of positive LN, T stage, and overall survival. Kaplan-Meier survival analysis was conducted to measure the survival estimates and assess the effect

Figure (1): Location and grouping of the lymph nodes. D1 resection: Removal of the N1 lymph nodes. D2 resection: Removal of the N1 and N2 lymph nodes. {Quoted from Songun et al.12}

Figure (2): Intraoperative view of dissection of LNs along left gastric vessels (group 7).

Figure (3): Intraoperative view of the field after dissection of LNs along the coeliac, hepatic, splenic & left gastric arteries (groups

7, 8, 9 & 10).

different  parameters  on  survival.  P  values

were considered significant if less than 0.05.

Results:

62  patients  were  included  in  the  study,

37 males (59.7%) and 25 females (40.3%),

the mean age of patients was 52.29 ± 15.08 (range: 24-75) years.

According to the 7th AJCC’s TNM staging system for gastric cancer, there were 10, 5,

19 and 28 patients in the N0, N1, N2 and N3 stage, respectively. Patients with low nodal

Figure   (4):    Resected   specimens    of:   A:

Distal  gastrectomy,  B:  Total  gastrectomy

&     splenectomy      both     with      extended lymphadenectomy.

Figure      (5):      Resected      specimen      of total    gastrectomy,    splenectomy     &         D2

Lymphadenectomy  with  different  parts  and enlarged LN groups labeled.

Figure (6): Tumor site & size distribution in the study group.

disease (N 0 or 1) were 15 and were termed early  nodal  disease  patients,  high  or  late nodal disease patients were 47. There were 9,

32 and 21 patients in the T2, T3 and T4 stage, respectively. The patients’ clinicopathological characteristics are shown in Figures (6-8).

33  patients  had  distal  gastrectomy  and

29   patients   had   total   gastrectomy.   D2

LN dissection was done in all cases. No intraoperative mortality was recorded. The mean average number of lymph nodes harvested was 33±5 nodes (range: 21-41). The details of operative data are shown in Table (1).

Figure (7): T & N stages distribution in the study group.

Figure (8): Nodal disease class distribution in the study group.

Figure (9): Post operative complications in the study group.

Figure (10): Survival & recurrence data in the study.

The mean follow-up period in our study was

32 months (range 12-48 months). 9 (14.5%) Patients   had   postoperative   complications (3 cases of leakage from esophagojejunal anastomosis after total gastrectomy, 2 duodenal stump blowouts, 2 wound infection and  2  cases  of  pneumonia).  Two  cases (3.2%) of mortality were recorded in the first month after surgery (one after leakage from esophagojejunal anastomosis and 1 after duodenal stump blowout). Postoperative complications are shown in Figure (9).

The overall mean survival time was 17.13

±9.6 months. The disease free mean survival

time was 13.4 ±9.39 months. Kaplan-Meier survival analysis showed that the overall survival probability estimate in the study to be 100% at 1 year, 88.7% at 2 years, 58.1% at

3 years and 32.3% at 4 years. The majority of cases with recurrence had systemic metastasis not local recurrence. In addition, most of the cases of disease related death were from systemic metastasis not local recurrence. Follow up data are shown in Table (2) and Figure (10).

Statistical analysis was done in order to define the relation between disease parameters and survival pattern with D2 resection.

Figure (11): Kaplan-Meier survival analysis curves of the relation between LNs status and survival.

Relation between the numbers of harvested lymph nodes and survival: Cox regression analysis revealed that there was no significant relation between the number of harvested LN and overall survival or disease free survival as shown in Table (3).

Relation between lymph node status and survival: We categorized the patients in study by their metastatic lymph node status into early nodal disease group (N0 and 1) and late nodal disease group (N2 and 3).

Kaplan-Meier  survival  analysis  showed a  highly  significant  difference  in  disease free and overall survival between early and late nodal disease. The mean disease free survival  times  were  25.87  ±3.23  and  9.42

±0.23 months for early and late nodal groups respectively, and the mean overall survival

times were 30 ±3.24 and 13.02 ±0.25 months for early and late nodal groups respectively as shown in Table (4) and Figure (11).

Relation between the N stages and survival: Kaplan-Meier  survival  analysis  showed

a  highly  significant  difference  in  disease free survival and overall survival between different nodal stages. The median disease free survival times were 30, 16, 9 and 9 months for N0, N1, N2 and N3 respectively. The median overall survival times were 39,

18, 13 and 13 months for N0, N1, N2 and N3 respectively, as shown in Table (5) and Figure (12).

Discussion:

The    proper    surgical    management    of

Figure (12): Kaplan-Meier survival analysis curves of the relation between LNs status and disease free survival.

Table (1): Operative data in the study group.

Table (2): Survival data in the study.

Table (3): Cox regression analysis of the relation between harvested LNs and survival.

Table (4): Kaplan-Meier survival analysis of the relation between LNs status and disease free survival.

stomach cancer had been subjected to much debates for years. Despite that, controversy still exists regarding the role of extended lymphadenectomy in the treatment of gastric cancer.5 Radical lymphadenectomy was adopted based on an initial report published in 1981 by Kodama and his colleagues who described a survival benefit for patient with serosal or regional lymph node involvement who underwent D2 or D3 lymphadenectomy.13

There have been significant differences in Eastern and Western philosophies regarding the role and extent of lymph node dissection for gastric cancer. The Eastern view generally contends  that  extensive  lymphadenectomy

provides better cancer clearance and therefore improves   survival,   whereas   the   Western view generally holds that lymphadenectomy provides prognostic information and when done adequately, improves staging and guides adjuvant treatment decisions. From either perspective, there is strong agreement that lymphadenectomy is an integral part of high- quality gastric cancer operation, but debates are still present that eastern results of better survival can be reproduced in other parts of the world.14 Our study tried to address this point from the practice point of view in Egypt.

In our study, 62 patients with stomach cancer underwent       D2       lymphadenectomy

Table (5): Kaplan-Meier survival analysis of the relation between N stage and survival.

in 3 large referral hospitals by experienced surgical teams. All cases were completed without intraoperative morbidity or mortality. The mean average number of lymph nodes harvested was 33 ±5 nodes. 9 (14.5%) Patients   had   postoperative   complications (3 anastomotic leakage, 2 duodenal stump blowout, 2 wound infection and 2 had pneumonia). Two cases (3.2%) of mortality were recorded in the first month after surgery. The overall mean survival time was 17.13

±9.6 months. The disease free mean survival time was 13.4 ±9.39 months. 89% of patients had recurrence during the follow up period. The overall survival probability estimate in the study was 100% at 1 year, 88.7% at 2 years, 58.1% at 3 years and 32.3% at 4 years.

Comparing our results to the published literature  outside  Japan.  In  2006,  Wu  and his   colleagues15    from   Taiwan   published their   randomized   controlled   trial   of   D1 versus ‘‘D3’’ dissection in Lancet Oncology. The   D3   lymphadenectomy   described   in this study essentially included a JGCA D2 lymphadenectomy together with nodes around the retropancreatic region and superior mesenteric vein. The study included

221 patients, and the primary endpoints were

5-year  overall-  and  disease-free  survival. At a median follow-up of 95 months, there was a 5-year overall survival rate of 63%

for patients who underwent D3 surgery and

58% for patients undergoing D1 surgery (p

=0.006). The recurrence rate at 5 years was

51% after D1 surgery and 40% after D3 surgery.15 The Dutch Gastric cancer Group had a study of 711 patients undergoing surgical treatment of stomach cancer, their first results were published at 2004. In 2010, the Dutch trial was updated with a 15-year follow-up results.12 Gastric cancer-related death was 37% for the D1 group and 48% for the D2 group (p =0.01), whereas death from other causes was the same in both groups.12

Hanna and his colleagues published in 2012 their   experience   with   D2   gastrectomy.16

From 2003 to 2010, 100 patients underwent gastrectomy. He reported anastomotic leak rate of 2%. Postoperative mortality and technical complications for gastric cancer resections were similar to Japanese rates. Kaplan-Meier estimates of overall survival after gastrectomy was 90.6% at 1 year, 74.3% at 2 years, 67.8% at 3 years, 64% at 4 years and

58.4% at 5 years.16 The early postoperative

morbidity   and   mortality   results   in   our study are higher than those published in the studies mentioned. Also, our survival results especially after 2 years are significantly worse than those reviewed being only close to those of the Dutch trial. That can be explained by two reasons. First, the majority of our patients

had advanced disease (86% were T stage 3 or

4 and 76% were N stage 2 or 3). This fact may be the cause of high recurrence rates. Second, the volume of cases is less than those reported  in  the  mentioned  trials  especially the one done in Taiwan, meaning that we are still in the phase of gaining experience. The higher case volume results in better surgical experience and improved technical expertise leading to better overall results. In spite of that, our study showed that the recurrence was mainly metastatic not local, meaning that D2 lymphadenectomy had actually improved the outcome regarding the local control of the disease.

Lymph  node  metastasis  is  one  of  the most important prognostic factors in gastric cancer. We tried to assess the effect of different parameters related to LN metastases on survival after D2 dissection. Our study found that there was no significant relation between the number of harvested LN and overall or disease free survival. On the contrary, analysis demonstrated a significant relation between N-stage and survival with patients  with  late  nodal  disease  (N  stage

2 or 3) having shorter disease free survival and overall survival times (9 and 13 months respectively) than those with early nodal disease despite the extended nodal dissection done. These findings are opposite to those of the Dutch trial, which had found that patients with N2 disease have benefited from the extended lymphadenectomy.12

Our study have its limitation. The number of cases is not large enough as other trials and follow up period was variable and no 5 year follow up data were documented.

Conclusion:

D2 lymphadenectomy can be performed safely in well-equipped hospitals by experienced surgeons with acceptable morbidity   and   mortality.   It   can   provide hope for better survival for patients with gastric cancer and low degree of lymph node metastases (N1 or N0). Further studies with larger case numbers and longer follow up period are needed to address the limitations of our study.

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