A comparison of the operative outcomes of D1 and D2 gastrectomy performed at a single Western center with multiple surgeons: a retrospective analysis with propensity score matching

Gastric cancer is the fifth most common malignancy and the third leading cause of cancer death worldwide [1]. In Australia, it is the ninth leading cause of cancer-related death [2]. Surgical resection of a primary tumor provides the best chance of cure for gastric cancer. However, the extent of lymph node resection for curative intent varies between surgeons and centers globally and within the Australian context. The lymph node status in gastric cancer is a key prognostic factor in patient survival [3, 4].

Historically, there has been controversy regarding the extent of lymph node dissection performed between Eastern and Western countries. East Asian countries [5] have consistently recommended the more extensive D2 lymph node dissection as standard care. Western nations have been cautious to adopt the D2 lymphadenectomy based on the short-term follow-up results of randomized control trials. The United Kingdom (UK) MRC-STO1 trial [6] and the Dutch DGCT trial [7] found no statistical difference in survival, but a significantly higher morbidity and mortality in the D2 group compared to D1. This was attributed to poor surgical technique compared to Eastern surgeons and the inclusion of standard distal pancreatectomy and splenectomy as part of the D2 lymphadenectomy. However, a 15-year follow-up of the same Dutch trial demonstrated that there was improved local regional recurrence and fewer gastric cancer-related deaths after a D2 dissection [8]. The Italian Gastric Cancer Study Group (IGCSG) did not show a significant difference in overall 5-year survival between D1 and D2 patients; however, a subgroup analysis indicated a trend towards improved survival for T2–T4 tumors and node-positive disease [9]. More recently, there is increasing consensus on a D2 lymphadenectomy with spleen and pancreas preservation becoming the standard of care, particularly in European centers.

In Australia, there is a relative lack of data on gastric cancer outcomes and more specifically on D1 and D2 lymphadenectomy. Some units have adopted selective criteria for patients undergoing D2 lymphadenectomy, with no significant difference in 5-year survival or mortality [10].

The aim of this study was to evaluate the operative outcomes of patients undergoing D1/D1+ and D2 gastrectomy for gastric adenocarcinoma.

There is now an increasing global consensus on performing a D2 lymphadenectomy for gastric cancer due to long-term results of large Western studies in conjunction with Eastern data [8, 28, 29]. This retrospective analysis of a single low to intermediate volume [30] specialist Western center indicates that a D2 lymphadenectomy can be performed safely, with excellent outcomes.

We performed direct comparison between D1/D1+ lymphadenectomy and D2 lymphadenectomy with regression analysis and also performed propensity score matching between the two groups in order to reduce selection bias. Ten-year overall survival for unmatched D1/D1+ was 52.1% and D2 was 56.6% (p = 0.280). After propensity score matching, OS was 52.1% for D1/D1+ and 76.2% for D2 which was significantly higher (p = 0.008) (Fig. 1.)

Our results showed improved long-term survival outcomes for D2 lymphadenectomy compared to results reported in Western literature and approaches those reported in Eastern studies. In a meta-analysis of four RCTs, the 5-year OS for D2 resections was 47% [31]. Specifically, the Japanese report 5-year OS of 69.2% and 10-year OS of approximately 60% for D2 resections [32]. The Italian IGCSG report 5-year OS of 64.2% (D2) [9] while the Dutch DGCT trial showed an 11-year OS of 35% for D2 groups (p = 0.53) [7] and subsequent 15-year OS 29% for D2 [8]. However surgical expertise and the inclusion of distal pancreatectomy and splenectomy were confounding factors affecting the results of the Dutch trial.

When stratifying the matched cohort according to nodal status, those with N0 status had higher 5-year OS, and there was a survival benefit for the D2 group (90.9%) compared with the D1/D1+ group (76.4%) (p = 0.028) (Fig. 2). A similar paradoxical finding was reported in a different study, whereby patients with clinically node-negative disease had a survival benefit with extended D2 plus para aortic lymph node dissection and may be a result of statistical bias [32]. Other studies have found a benefit for D2 dissection in N2 disease [7]. These findings suggest that an adequate lymph node dissection is important for adequate staging, and there are other poor prognostic indicators present in patients with node-negative disease [33]. Another explanation may be the presence of occult disease or micro metastatic disease in what is histopathologically described as node negative. Studies have shown that occult lymph node metastasis correlates with poor prognosis in node-negative disease and that a D2 resection may be beneficial in patients with node-negative occult disease detected by molecular techniques [34]. Nodal status is determined by histopathological assessment by pathologists, rather than surgeons at our unit, which may affect the accuracy of pathological reporting. Consequently, a thorough lymph node dissection allows capturing of more lymph nodes, in addition to prognostication.

Overall, 10-year DFS for the unmatched cohort was 36.2% for D1/D1+ and 45.1% for D2 (p = 0.282), after PSM, the 10-year DFS was 35% for D1/D1+ and 58.1% for D2 (p = 0.058) (Fig. 1). There was no significant difference between D1/D1+ and D2 in terms of recurrence. Our results are more consistent with long-term data obtained in Western studies, whereby the Dutch trial at 11 years reported risk of relapse was 65% for D2 [7] and 15 years DFS was 28% for D2 [8].

In this study, the overall 30-day mortality was 2.4% (unmatched) and 1.2% (after PSM), which is comparable to other units. The 2016 National Oesophago-Gastric Cancer Audit of England and Wales reports 2.2% in-hospital mortality and 30-day mortality rates range between 4.5 and 1.9% [35]. The D2 operative mortality was 1% in the unmatched cohort, consistent with other units [9, 32, 36].

The overall postoperative complication rate was 61% (unmatched) and 51% (after PSM) (Table 2). The majority were minor complications (Clavien-Dindo grades I and II). With respect to postoperative complications and 30-day mortality, there were no differences between the D1/D1+ and D2 groups for both matched and unmatched cohorts.

Factors associated with complications Clavien-Dindo grades I to IV, and post-operative death (Clavien-Dindo grade V, or 30-day mortality) are listed in Table 3. The tumor location between D1/D1+ and D2 groups were not significantly different (Table 1). In unmatched cohorts, there was an association with tumor location and complications (p = 0.009), this was no longer present after PSM (p = 0.07). Total gastrectomy was associated with postoperative complications in both matched and unmatched cohorts (before PSM, p = 0.020; after PSM, p = 0.018), which has been shown in other studies [7, 37]. Total gastrectomy was not associated with 30-day mortality after propensity score matching (p = 0.076), suggesting the influence of confounding factors in the unmatched cohort in which there was an association (p = 0.021) (Table 3).

Patients over the age of 70 years have increased morbidity and mortality associated with gastrectomy in Western studies [7]. In this study, advanced age (≥ 70 years) was associated with postoperative complications (before PSM, p = 0.008; after PSM, p = 0.006); however, these were mostly Clavien-Dindo grade I and II complications. Older age was not associated with 30-day mortality (Table 3). These findings highlight the importance of postoperative strategies required to optimize positive outcomes in the elderly to ensure safe delivery of surgical treatment [38].

Body Mass Index was not associated with post-operative morbidity or mortality. The mean BMI was significantly higher in the unmatched cohort between the D1/D1+ (26 kg/m²) vs D2 group (24 kg/m²) (p = 0.049) (Table 1), there was no difference in BMI after PSM. The average BMI in our patient cohort is similar to other Western units [10] and is higher than those reported in Japanese studies, where the median BMI is 23 kg/m² [11].

Pancreaticosplenectomy was not routinely performed as part of the D2 lymphadenectomy and subsequently not associated with the post-operative complications or 30-day mortality. This is supported by other studies, whereby a D2 lymphadenectomy with spleen preservation avoids operative morbidity without affecting survival [11]. The Japanese have reported that no. 10 lymph nodes are often left untouched and can be dissected if judged easily removable in lean patients. Western studies have also reported that a modified D2 gastrectomy (with splenic preservation) is associated with improved survival, particularly in stage III gastric cancer [39].

Some surgeons who are proponents of D1/D1+ prefer to do so in Western patients who often have a higher BMI, arguing that a D2 is technically easier in slimmer, Eastern patients. The results for our cohort, with BMI < 30 kg/m², indicate that an extended lymph node dissection with spleen and pancreas preservation can be performed in the Western cohort with no added morbidity.

The use of perioperative chemotherapy in the management of gastric cancer has been a major development over the past decade, with increased survival in perioperative chemotherapy versus surgery alone [26]. The number of patients receiving perioperative chemotherapy in this unit has increased over time, reflecting this change. The intention was for patients undergoing perioperative chemotherapy to follow the MAGIC protocol, with three cycles of epirubicin, cisplatin, and flurouracil (ECF) preoperatively and postoperatively [26]. The number of patients receiving chemotherapy did not differ between the groups. While it is recognized that receiving neoadjuvant chemotherapy would be more relevant to the perioperative complications and 30-day mortality than adjuvant therapy, perioperative chemotherapy usage was not associated with post-operative morbidity or mortality in our unit.

The results of our morbidity and mortality are similar to those reported in the literature, thus suggesting that identification of high-risk factors may allow more rational patient selection or systemic therapy [40]. In assessing prognostic factors for patients undergoing gastrectomy with D1/D1+ or D2 lymphadenectomy, univariate analysis demonstrated that patients with higher TNM stage (stages III and IV), a local lymphadenectomy (D1/D1+), total gastrectomy, and postoperative complications were significantly associated with poor prognosis. Furthermore, multivariate analysis showed that a higher TNM stage (stages III and IV), a D1/D1+ lymphadenectomy, and the presence of postoperative complications were prognostic factors (Table 4). This is similar to other Western studies which have shown higher TNM stage and lymphadenectomy to be prognostic indicators [6, 39].

Our results indicate that D2 lymphadenectomy with spleen/pancreas preservation is not associated with poor short-term and long-term outcomes whereas a D1/D1+ dissection was one of the factors that predicted poor overall survival in our unit. This finding is comparable to results of a recent meta-analysis [41] that pooled data from the UK MRC-STO1 trial [6], Dutch DGCT trial [8], and Taiwan trial [42] revealing a combined overall survival benefit in D2 lymphadenectomy with spleen and/or pancreas preservation.

The Australian experience within this single unit shows that D2 lymphadenectomy with spleen and pancreas preservation can be performed safely on patients with gastric adenocarcinoma with excellent survival outcomes. Significant improvement in overall survival is observed in patients who underwent D2 lymphadenectomy, without increased surgical morbidity and mortality. This survival benefit was also seen in a subgroup analysis of N0 patients who underwent a D2 lymphadenectomy. This paper supports the notion of global consensus for D2 lymphadenectomy, particularly in the Western context.