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10.1245/s10434-006-9063-3
Annals of Surgical Oncology 14:25-33 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Complications after Extended (D2) and Superextended (D3) Lymphadenectomy for Gastric Cancer: Analysis of Potential Risk Factors

Daniele Marrelli, MD, Corrado Pedrazzani, MD, Alessandro Neri, MD, Giovanni Corso, MD, Alfonso DeStefano, MD, Enrico Pinto, MD and Franco Roviello, MD

Department of Human Pathology and Oncology, Unit of Surgical Oncology, University of Siena, Siena, Italy

Correspondence: Address correspondence and reprint requests to: Franco Roviello, MD, Via De Gasperi 5, 53100, Siena, Italy; E-mail: Roviello{at}unisi.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Very few studies from Western centers have compared D2 and D3 dissection in the surgical treatment of gastric cancer. The aim of the prospective observational study reported here was to analyze the postoperative outcome and potential risk factors for complications following D2 and D3 lymphadenectomy.

Methods: A total of 330 consecutive patients, of which 251 submitted to D2 lymphadenectomy and 79 were treated by D3 lymphadenectomy, were enrolled in the study. Twenty potential risk factors for morbidity and mortality were studied by means of univariate and multivariate analysis.

Results: Overall morbidity and mortality rates were 34% (111 patients) and 4% (14 patients), respectively. Abdominal abscess, anastomotic leakage, pleuropulmonary diseases and pancreatitis were the most commonly observed complications. No differences in morbidity, surgical morbidity, mortality rates and mean hospital stay between D2 and D3 lymphadenectomy were found. Multivariate analysis revealed that American Society of Anesthesiologists’ (ASA) class II/III versus class I, perioperative blood transfusions, and low albumin serum levels were independent predictors of postoperative complications. Age, surgical radicality (R1/R2 vs. R0) and low albumin serum levels independently predicted mortality. Mortality rate was .5% in the 203 patients aged 75 years or younger who underwent curative surgery. Most of deaths were observed in patients older than 75 years with low albumin serum levels or treated by non-curative surgery.

Conclusions: D2 lymphadenectomy represents a feasible procedure associated to acceptable morbidity and mortality rates. In specialized centers, D3 lymphadenectomy may be performed without increasing the risk of postoperative complications and associated deaths in carefully selected patients. These techniques should be avoided in subgroups of patients with a high risk of postoperative mortality.

Key Words: Gastric cancer • Lymphadenectomy • Postoperative complications • Morbidity • Mortality


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Surgery is currently considered the best manner to treat gastric cancer. Dependent on the extent of stomach resection, partial gastrectomy offers the same chance of cure as total gastrectomy in distally located neoplasms following potentially curative surgery (R0 resection).1–3 However, to date, there is no consensus on the extent to which the lymphadenectomy should be carried out.

The systematic removal of first and second level lymph nodes (D2 lymphadenectomy) is considered a standard procedure in Japan and other Eastern countries and is associated with excellent early and late results.4,5 In contrast, this procedure is performed by selected centers only in Europe and United States, where a limited lymphadenectomy is generally adopted.6 Observational studies conducted in specialized centers have confirmed the feasibility of D2 lymphadenectomy in Western patients, although two randomized trials demonstrated high morbidity and mortality rates and no survival benefit with respect to D1 dissection.7–13 The final 11-year survival results of the Dutch trial, confirming the concept of a N2-stage-specific survival benefit of D2 surgery, raise the question as to whether it is now the time to recommend D2 surgery as standard clinical practice for experienced surgeons.14,15 In several specialized centers, D2 dissection is already accepted as the standard procedure for resectable gastric cancer.7–11

A more extended technique (D3 dissection), which involves the removal of para-aortic stations, is often used in advanced forms gastric cancer in Japanese centers.16–19 Although D2/D3 surgery can safely be performed by high-volume surgeons, recurrence rates remain alarmingly high, suggesting a clear need for adjuvant systemic treatment.20,21 The final results of the MAGIC trial provide evidence that patients with operable esophagogastric cancer can benefit from perioperative adjuvant chemotherapy.22 Data from the INT-trial show that adding chemoradiation to limited D1 surgery can be of benefit to some patients; however, it appears that a complete D2 surgery alone, in which the spleen is preserved, can be performed more effectively and with fewer disadvantages than D1 surgery plus chemoradiotherapy.23,24

Very few studies from Western centers have compared D2 and D3 dissection in surgical treatment of gastric cancer, and these have consisted mostly of a limited group of patients, with varying results.8,25,26 In the prospective observational study reported here we have analyzed the early outcome following D2 and D3 lymphadenectomy and the potential risk factors for postoperative complications.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Beginning in January 1994, our Department (Unit of Surgical Oncology, University of Siena, Italy) started using D2 lymphadenectomy as the standard procedure for surgical treatment of resectable gastric cancer; super-extended lymphadenectomy (D3) has been progressively introduced for treatment of advanced forms. A total of 460 consecutive patients operated on between January 1994 and December 2005 were considered for participation in the present study. Of these, 51 patients who underwent non-resective procedures for advanced disease and a further 79 who had undergone simple removal of perigastric lymph nodes (D1 dissection) were excluded from the final evaluation due to very poor general health conditions, palliative or emergency surgery, or patient refusal to the undergo the extended technique. The final study cohort consisted of 330 patients, of which 251 submitted to D2 lymphadenectomy (mean age: 68 ± 12 years, range: 30–88 years) and 79 were treated by D3 lymphadenectomy (mean age: 64 ± 11 years, range: 30–78 years).

Surgical Treatment
In all patients, a careful preoperative staging of the neoplasm was performed. This included upper digestive endoscopy with biopsy, chest X-ray, liver ultrasound and abdominopelvic computed tomography (CT) scan. Following laparotomy, a complete examination of the peritoneal cavity and liver was performed. For tumors located in the middle and lower third of the stomach, a subtotal gastrectomy was generally preferred, provided that a distance of at least 5 cm between the proximal resection margin and the neoplasm was maintained; in the remaining cases, the entire stomach was removed. An intraoperative frozen section of the surgical resection line was examined histologically in cases of doubt. Gastrectomy was always completed by the removal of the greater omentum and perigastric lymph nodes; the type of lymphadenectomy was prospectively classified according to the criteria described by the Japanese Research Society for Gastric Cancer (JRSGC). As indicated in the 12th edition of the JRSGC classification, D2 lymphadenectomy involved the en-bloc removal of lymph node stations number 7 (left gastric artery), 8a and 8p (common hepatic artery), 9 (celiac artery), 11 (splenic artery) and, optionally, 10 (splenic hilum).27 As described in the 13th edition of the Japanese classification, the removal of stations number 12a and 12p (hepatoduodenal ligament), 13 (retropancreatic) and 14v (superior mesenteric vein) has been particularly associated more recently to patients with tumors located in the lower third of the stomach; these lymph node stations were then removed in 42, 25, and 28% of 251 patients submitted to D2 lymphadenectomy, respectively.5,28 Right paracardial lymph nodes (station 1) were also removed in all patients undergoing subtotal gastrectomy. Infrapyloric lymph nodes were completely removed by ligating the right gastroepiploic vessels at their origin. D3 lymphadenectomy, with respect to D2, involves the Kocher manoeuvre and the removal of para-aortic lymph nodes (number 16; in particular, the a2 and b1 subgroups) as well as the systematic removal of compartment 3 lymph nodes.28 The indications to perform a D3 lymphadenectomy were an advanced preoperative tumor staging (cT2–T4) by CT scan, good general health conditions and a patient age lower than 75 years.5 However, nine patients aged over 75 years with very good general conditions were also treated by D3 lymphadenectomy. This extended technique has been progressively adopted during the study period; in the last sub-period (2003–2005), over 50% of our patients underwent D3 dissection (Fig. 1Go).


Figure 1
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  		FIG. 1. Relative proportion of patients submitted to D2 and D3 lymphadenectomy in different subperiods of the study.

 
Each lymph node station was removed and classified either during the operation or from the resected specimen, and single lymph nodes were retrieved in the fresh specimen and then submitted to histopathological examination.

Distal pancreatectomy was performed only in cases of direct invasion of the pancreatic tail by the tumor (nine cases), and a better lymph nodal clearing never justified this procedure. Lymphadenectomy at the splenic hilum was limited to patients with enlarged nodes or upper third tumors reaching the greater curvature, and it was always achieved by pancreas-preserving splenectomy (24 patients).

A complete bursectomy was also performed in all patients. For reconstruction, the surgeons of our surgical department prefer the Roux-en-Y (after total gastrectomy) and Billroth II techniques (after subtotal gastrectomy), which are two standard procedures in our Department.

Following total gastrectomy the anastomosis was routinely checked prior to the patient resuming oral intake by means of radiological examination with water-soluble contrast on postoperative day 7 or before, if clinically indicated. Conversely, oral intake was resumed on postoperative day 4 without radiological examination after subtotal gastrectomy. Antibiotic and thromboembolic prophylaxes were administered to all patients.

Surgical radicality was classified according to the Union Internationale Contra le Cancer (UICC) criteria.1

Risk Factors for Morbidity and Mortality
The occurrence of postoperative complications was prospectively recorded for all patients. All surgical or medical complications that occurred during the hospital stay were considered for classification of morbidity. Anastomotic leakage and abdominal abscesses were always diagnosed by means of radiological examinations. Severe lymphorrea occurring for more than 1 week was considered to be a complication.5 All deaths or complications that occurred during the hospital stay or within 1 month after surgery were considered in the computing of postoperative mortality and/or morbidity.

A detailed analysis of risk factors for morbidity and mortality was conducted out for all of the patients operated on. Patient-, tumor- and treatment-related variables were considered to be risk factors. Patient-related variables were: gender (female, male), age (≤60, 61–75, >75), cardiac diseases (absent, present), vascular diseases (absent, present), pleuro-pulmonary diseases (absent, present), diabetes (absent, present), serum creatinine level (<1.5, ≥ 1.5 mg/ dL), serum albumin level (≥3.0, <3.0 g/dL), hemoglobin level (≥10, <10 g/dL), American Society of Anesthesiologists’ (ASA) class (I, II, III) and body mass index (BMI) (<25, ≥25 Kg/m2). Tumor-related variables were: tumor location (upper third, middle third, lower third, diffuse), depth of invasion (pT1, pT2, pT3–T4) and nodal status (N-negative, N-positive). Treatment-related variables were: extent of resection (subtotal, total), extent of lymphadenectomy (D2, D3), splenectomy or splenopancreatectomy (not performed, performed), number of removed lymph nodes (<25, 25–44, ≥45), surgical radicality (R0, R1/R2) and perioperative blood transfusions (not performed, performed). In total, 20 potential risk factors were considered.

For the definition of the different risk factors, cardiac diseases were assessed as electrocardiographic or echocardiographic abnormalities, or as pathologies for which the patient was under specific treatment. Vascular pathologies, as hypertension treated with specific drugs, or cerebrovascular pathologies; pleuropulmonary diseases, as abnormal spirometry, or pathologies for which the patient was on medication.29 The cut-off values for albumin and creatinine serum levels, hemoglobin, and BMI were established on the basis of our previous reports or other authors’ experience.29–31

Statistical Analysis
Comparison among groups was performed by means of the chi-square test, whereas numerical variables were compared by the analysis of variance (ANOVA) test.

Factors predictive of morbidity and mortality were investigated by means of a logistic regression model; the parameters of the model were estimated using the maximum-likelihood method.21 Significant variables were included in the model with a forward stepwise selection: starting with a model containing only the constant, at each step the variable with the smallest significance value was entered into the model, with a default level of P < .05. The significance value of each factor was reassessed at each step; if a variable in a forward stepwise block exceeded a significance level of .1, it was removed from the model. Removal testing was based on the probability of the likelihood-ratio statistic. The Statistical Package for the Social Sciences software (version 11.0) (SPSS, Chicago, Ill.) was used for statistical analysis.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A mean of 36 ± 15 lymph nodes (median: 34, range: 12–99) after D2 lymphadenectomy and 53 ± 20 lymph nodes (median: 49, range: 16–110) after D3 lymphadenectomy were removed (P < .001) (Fig. 2Go). In 200 pN+ patients, we found a mean of 14 ± 13 positive lymph nodes (median: 10, range: 1–74) after D2 and 17 ± 18 (median 11, range: 1–86) after D3 (P = .263). In 79 patients submitted to D3 lymphadenectomy, a mean of 6 ± 5 lymph nodes (median: 4, range: 1–22) were removed from para-aortic stations, and nodal involvement was diagnosed in 11 patients (13.9%) (median positive nodes: 3, range: 1–17).


Figure 2
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  		FIG. 2. Number of removed lymph nodes according to the extent of lymphadenectomy. The difference is statistically significant (P < .001).

 
Postoperative complications for the patients participating in the study are listed in Table 1Go. Abdominal abscess, anastomotic leakage, pancreatitis and pleuropulmonary diseases were the most commonly observed complications. Overall morbidity and mortality rates were 34% (111 patients) and 4% (14 patients), respectively. No differences in morbidity, surgical morbidity, mortality rates and mean hospital stay between patients undergoing D2 and D3 lymphadenectomy were found. Abdominal abscess and lymphorrea were more frequent in the D3 group, whereas bleeding and pleuropulmonary complications were more frequent after D2 dissection; the re-operation rate was lower after D3 lymphadenectomy.


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  		TABLE 1. Postoperative complications in patients submitted to D2 and D3 lymphadenectomy
 
The results of univariate analysis of morbidity and mortality according to the different variables under study are reported in Table 2Go. ASA class, perioperative blood transfusions, low albumin serum levels, surgical radicality and splenectomy or splenopancreatectomy were significantly associated with the incidence of postoperative complications. The highest percentages of complications were recorded in patients with low albumin serum levels (58%) or when splenectomy or splenopancreatectomy was performed (52%). Conversely, a low risk was observed in patients with ASA score I (16%) and aged 60 years or younger (24%). Risk factors for postoperative mortality were advanced age, low albumin serum levels, ASA class, female gender, surgical radicality and the presence of cardiac diseases. Very high mortality rates were observed in patients with low albumin serum levels (16%), aged more than 75 years (12%) and who had submitted to non-curative surgery (11%). No deaths occurred in patients younger than 61 years or in those with ASA class I.


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  		TABLE 2. Univariate analysis of risk factors for morbidity and mortality in 330 patients included in this study. Only significant variables are reported
 
Multivariate analysis of 20 potential risk factors for morbidity and mortality was performed by means of a logistic regression model (Table 3Go). ASA class II/III versus I, perioperative blood transfusions and low albumin serum levels were found to be independent predictors of postoperative complications. Age, surgical radicality (UICC R1/R2 vs. R0), and low albumin serum levels independently predicted mortality. No significant differences were found for the other variables under study, including the extent of lymphadenectomy.


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  		TABLE 3. Multivariate analysis of risk factors from morbidity and mortality in 330 patients included in this study (logistic regression model)
 
A combined analysis of the three independent risk factors for mortality was also conducted (Table 4Go). High mortality rates were observed in three subgroups: (1) patients younger than 76 years when non-curative surgery and low albumin serum levels were simultaneously present; (2) patients aged over 75 years with low albumin serum levels; (3) patients aged over 75 years when non-curative surgery was performed.


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  		TABLE 4. Postoperative mortality according to age, surgical radicality and albumin serum levels
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although many Eastern and Western surgeons recommend the removal of perigastric and regional lymph nodes in order to increase surgical radicality or simply to obtain a correct staging of gastric cancer, at the present time limited lymphadenectomy remains the standard treatment in Western countries.6 Performing an extended (D2) lymphadenectomy allows the removal of at least 15 lymph nodes and a correct staging of the disease in about 95% of all cases.32 Furthermore, the incidence of lymph node metastases in second tier nodes is definitely not negligible, being present in over 25% of all cases.11 D2 lymphadenectomy is a safe procedure in specialized centers, where it is associated with a low risk of postoperative complications and mortality.7–11,20 The risk of complications can be reduced by avoiding resection of the pancreatic tail and spleen.31,33 These associated procedures were the strongest factors influencing morbidity and mortality in the two European randomized trials, without offering any potential improvement in long-term survival.12–14,23 In the present series, splenectomy or splenopancreatectomy was performed in a minority of the cases (10%). Consequently, the resulting overall morbi-mortality was much lower than that found in the MRC and Dutch trials, and overlap with results reported by other Western specialized centers.7–10

The reported incidence of metastases to para-aortic lymph nodes ranged between 6 and 26%; in advanced forms and in upper third tumors the incidence can reach 36%.16–18 The results of a recent multi-institutional study suggest that D3 dissection may confer a survival advantage with respect to D2 dissection in patients with tumor diameters measuring 50–100 mm and pN2 disease.19 A randomized trial conducted in Japan did not show differences in terms of morbidity and mortality between D2 and D3 dissection, but the survival results of this trial are still unavailable.5 In our experience, a significantly higher number of lymph nodes were removed by D3 lymphadenectomy. Even though this technique may be associated with an increased incidence of abdominal abscess and lymphorrea, as reported by others, the overall risk of postoperative complications and mortality overlapped with that D2 dissection.5,34 Nevertheless, we stress that most of the D3 procedures were carried out in more recent times, when an adequate learning curve for D2 lymphadenectomy had been obtained. Furthermore, by this time we had adopted strict selection criteria, in particular with respect to patients’ age and general diseases. Bearing these factors in mind, we confirm that D3 lymphadenectomy may be performed in specialized centers with an acceptable operative risk. The final results of the Japanese randomized trial are awaited for the identification of subgroups of patients who may have a long-term survival benefit from this technique.5

A detailed analysis of potential risk factors for postoperative complications and mortality was performed on our series of patients. Advanced age was a strong determinant of postoperative mortality, and most of patients who died were over 75 years of age. Only one death out of 203 curative surgical operations (.5%) was observed in patients younger than 76 years. This rate overlaps with the results of the recent Japanese randomized trial in which patients undergoing non-curative surgery and/or older than 75 years were excluded from the study protocol.5 Advanced age seems to have a particular effect in enhancing the lethality of complications rather than increasing their occurrence. This is probably due to the fact that elderly patients poorly tolerate the occurrence of postoperative complications.29

Multivariate analysis revealed that, in addition to advanced age, low albumin serum levels and non-curative surgery are independent variables influencing mortality. The combination of these three factors allowed the identification of subgroups of patients with very high or very low mortality rates, respectively. High risk groups were patients aged over 75 with low albumin serum levels or having submitted to non-curative surgery, and younger patients with low albumin levels treated by non-curative surgery. Patients aged over 75 showed a moderate risk of mortality (5%) only when the surgery was curative and the albumin serum levels were normal.

Patients with an ASA class I had a very low incidence of morbidity, whereas no significant difference between ASA class II and ASA class III was found. In addition to ASA score, perioperative blood transfusions and low albumin serum levels increased the risk of morbidity. The influence of perioperative blood transfusions on postoperative complications has been reported in several studies in different surgical settings.35 In particular, this factor seems to be related to the development of septic complications. The majority of abdominal abscesses and wound infections observed in our experience (17 cases out of 27) occurred in patients who received transfusions. In the light of these results, we suggest that particular care be given to intraoperative blood loss and the avoidance of perioperative blood transfusions, unless strictly necessary.

Several papers have reported a correlation between preoperative albumin serum levels and the development of postoperative complications.29,30,36 Serum albumin level, in addition of being an important nutritional index, represents a physiologically active protein fraction, and it indirectly reflects the synthesis of other important visceral proteins. Of our patients, 9% had an albumin serum level lower than 3.0 g/dL, and it was in this group that the highest percentages of morbidity and mortality were recorded. Several authors have suggested nutritional support in order to correct malnutrition in the preoperative period and reduce the risk of morbidity and mortality.37

Cardiac and pleuropulmonary diseases were not significant predictors of complications in our patients. Patients with severe general diseases were excluded from extended lymphadenectomy, and this may explain why in the present study these factors lacked correlation with morbidity and mortality.

A curative resection was not possible in 17% of our patients, mainly because of microscopic residual tumor or positive peritoneal cytology. In some cases, however, even though surgical treatment was classified as non-curative it was performed with a non-palliative intent, resulting in the removal of regional lymph nodes.38 This group of patients experienced high postoperative morbidity and, above all, very high mortality rates. Even if some authors suggest a potential benefit of extended lymphadenectomy after non-curative surgery, the clinical utility of this procedure is questionable when a complete macroscopic and microscopic removal of the tumor cannot be obtained.39 In the light of our results, we do not recommend this procedure in patients aged over 75 when an R0 resection cannot be performed. A potential increase in the risk of complications and mortality even in younger patients should be taken into account when making a decision on the extent of lymphadenectomy in non-curative operations.

In conclusion, it is our opinion that in specialized centers D2 lymphadenectomy represents a feasible procedure and is associated with acceptable morbidity and mortality rates. D3 lymphadenectomy may be performed without increasing the risk of postoperative complications and associated deaths in carefully selected patients. We found that ASA class, perioperative blood transfusions and low albumin serum levels were associated with a higher risk of postoperative complications. Stratified analysis identified three subgroups of patients at very high risk of death: patients younger than 76 years who underwent non-curative surgery with low albumin serum levels; patients older than 75 years who underwent non-curative surgery; patients older than 75 years with low albumin serum levels. In the light of these results, we suggest avoiding extended lymphadenectomy in such cases.


   ACKNOWLEDGMENTS
 
This work has been supported by grant PAR 2004, University of Siena, Italy

Received for publication May 15, 2006. Accepted for publication May 18, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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