Abstract
Background/Aim: Evidence on the optimal extent of lymph node dissection for left-sided pancreatic ductal adenocarcinoma (PDAC) is scarce. The aim of the current study was to compare the long-term outcomes of patients who underwent D1 distal pancreatectomy (DP) with D2 DP for left-sided PDAC. Patients and Methods: Patients undergoing DP for left-sided PDAC at the four institutions affiliated to The Jikei University were enrolled in this study. Patients were divided into D1 and D2 groups. Patients’ clinical characteristics, overall survival (OS), and relapse-free survival (RFS) were compared between the two groups before and after propensity-score matched (PSM) analysis. Results: Of 145 patients with left-sided PDAC, 55 patients underwent D1 DP and 90 underwent D2 DP, of whom 38 matched pairs were included in the PSM analytic cohort. In the unmatched cohort, no significant difference was found between the D1 and D2 groups for both OS (median 2.51 vs. 3.07 years; p=0.709) and RFS (median 1.47 vs. 1.27 years; p=0.565). After PSM, OS (median 2.37 vs. 3.56 years; p=0.407) and RFS (median 1.35 vs. 1.11 years; p=0.542) were not significantly different between the two groups. In a comparison of regional and systemic recurrence sites, no significant difference was observed between the two groups (p=0.500). Conclusion: The long-term survival of D1 DP for left-sided PDAC was not inferior to D2 DP. In an era in which the importance of multidisciplinary treatment for PDAC has been documented, unnecessary extended surgery should be avoided.
The development of adjuvant and neoadjuvant chemotherapy for resectable pancreatic cancer (PDAC) has led to a gradual improvement in the long-term outcome of this fatal disease (1-6). Various innovations in surgical techniques have been reported, but no benefit to long-term outcomes has been established. Attempted extended pancreaticoduodenectomy (PD), such as peri-superior mesenteric artery (SMA) plexus nerve dissection or extended lymphadenectomy, were reported not to contribute to long-term survival in randomized controlled trials (RCT) (7-9), and there have been conflicting arguments about the advantages of radical antegrade modular pancreatosplenectomy (RAMPS) regarding long-term outcomes (10-13).
Evidence on the optimal extent of lymph node dissection for PDAC is scarce. D2 lymphadenectomy has habitually been performed for both pancreatic head and body-tail cancer in Japan, but this is also not based on evidence. In a Korean RCT comparing standard PD, which was almost synonymous with D1 lymphadenectomy, and extended PD, which was almost synonymous with D2 lymphadenectomy, standard dissection was reported to be non-inferior regarding 5-year overall survival (OS) and disease-free survival in patients with PDAC (14).
For left-sided PDAC, the expert committee of the International Study Group on Pancreatic Surgery (ISGPS) meeting in 2013 recommended that the standard extent of lymph node dissection in DP should be limited to stations 10, 11, and 18 (the same as D1 dissection in Japan) (15). The rationale for this suggestion was based on the lack of evidence that extended dissection improves long-term survival; however, there was also no evidence that D1 dissection was sufficient for left-sided PDAC. To date, there are no reported RCTs on the long-term prognosis of D1 distal pancreatectomy (DP) vs. D2 DP for left-sided PDAC. In this study, we compared OS and relapse-free survival (RFS) of patients who underwent D1 DP with D2 DP for left-sided PDAC using propensity-score matched (PSM) analysis.
Patients and Methods
Patient selection. From January 2007 to December 2018, 180 patients who underwent DP for left-sided resectable PDAC at the four institutions affiliated to The Jikei University (Department of Surgery, The Jikei University Hospital; The Jikei University Daisan Hospital; The Jikei University Kashiwa Hospital; and The Jikei University Katsushika Medical Center) were screened; 35 were excluded for the reasons shown in Figure 1, and the remaining 145 were enrolled in this study. Eight patients beyond D1 dissection and less than D2 dissection were excluded. This study was approved by the ethics committee of The Jikei University School of Medicine (number 27-177), and the need for informed consent was waived as anonymized data were used. This study was conformed to the provisions of the 1964 Declaration of Helsinki and its later amendments.
Flow chart.
Definitions. D2 lymphadenectomy for DP was defined as complete dissection of lymph node stations 7 (nodes along the left gastric artery), 8 [nodes along the common hepatic artery (CHA)], 9 [nodes around celiac artery (CA)], 10 (nodes at the splenic hilum), 11 (nodes along the splenic artery), 14 (nodes along the SMA) and 18 (nodes along the inferior margin of the pancreas), and D1 as dissection of stations 10, 11, and 18, according to the Classification of Pancreatic Carcinoma by Japan Pancreas Society Fourth English Edition (16). R1 resection was defined as positive for cancer on the surface of the pancreatic stump or the peripancreatic tissue (0 mm rule). Initial recurrence sites were categorized as regional (regional lymph nodes or local retroperitoneal tissue including the periarterial plexus of the CA, CHA, and SMA) or systemic (non-regional lymph nodes, distant organ metastasis, and peritoneal dissemination) or regional plus systemic.
Determination of the extent of lymphadenectomy. Generally, the extent of the lymph node dissection and whether to undertake RAMPS were determined by the attending surgeons at each institution. Surgeons had different policies in selecting the degree of dissection; for example, some surgeons performed D2 dissection in all cases regardless of preoperative stage or patient background, while others only performed D1 dissection in all cases, even if there were obvious lymph node metastases. Surgical records were stored in a common multicenter database, and the extent of lymph node dissection was prospectively noted by D1, D2, or station sampling in addition to D1. For the authenticity of the D2 dissection, in addition to the database records, descriptions in the surgical record were rechecked, as were photographs of the surgical field after the resection.
Postoperative follow-up. Following radical resection, patients received adjuvant chemotherapy for 6 months with gemcitabine up to 2013 and for 6 months with S-1 after 2014. Patients underwent physical examinations and blood tests, including CA19-9 levels every 1 to 2 months at each institution, and contrast-enhanced computed tomography (CT) of the chest and abdomen or magnetic resonance imaging (MRI) scan of the abdomen every 3-4 months to check for recurrence. Patients who developed relapse were treated with S-1, gemcitabine, nab-paclitaxel plus gemcitabine, FOLFIRINOX, or best supportive care, depending on their physical condition or medical history. The median follow-up period was 2.46 years.
Propensity-score matching. Patients who underwent DP were divided into two groups: D1 and D2. PSM analysis was performed to reduce differences in the baseline characteristics between patients undergoing D1 and D2 procedures. The propensity scores were calculated using the baseline characteristics in a logistic regression model. Baseline characteristics included age, sex, body mass index, preoperative serum CA19-9 level, neoadjuvant chemotherapy, adjuvant chemotherapy, year of surgery before or after 2014, tumor location, tumor grading, lymphovascular invasion, perineural invasion, pathological T stage (UICC 8th edition), pathological N stage (UICC 8th edition), and pathological TNM stage (UICC 8th edition). The D1 and D2 groups were matched in a 1:1 ratio by PSM using a caliper width of 0.2.
Statistical analysis. Data were analyzed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria) (17). More precisely, EZR is a modified version of R commander (version 2.7-1) designed to add statistical functions frequently used in biostatistics. Continuous data were expressed as medians with interquartile ranges and compared using the Mann–Whitney U-test. Categorical data were expressed as frequencies with percentages and compared using Fisher’s exact test. OS was calculated from the date of the first treatment to the date of death, and RFS was defined as the time from the date of the first treatment to the date of CT or MRI confirmation of recurrence. Kaplan–Meier curve was used to estimate cumulative survival probabilities, and the log-rank test was performed to compare survival distributions between groups.
Results
Baseline characteristics before propensity-score matching. Of 145 patients with left-sided PDAC, 55 patients underwent D1 DP and 90 underwent D2 DP. Characteristics of patients in the unmatched D1 and D2 groups are shown in Table I. The D1 group was older and had fewer patients who underwent DP after 2014 than the D2 group. Perioperative and oncological outcomes in each unmatched group are shown in Table II. There were significantly fewer RAMPS procedures, operating times were shorter, examined lymph nodes were fewer, and postoperative hospital stay was shorter in the D1 group compared to that in the D2 group.
Comparison of baseline characteristics between D1 and D2 distal pancreatectomy (DP) group in the entire and propensity score matched cohort.
Comparison of perioperative and oncological outcomes between D1 and D2 distal pancreatectomy (DP) group in the entire and propensity score matched cohort.
No significant differences were observed between the D1 and D2 groups for both OS (median 2.51 years in D1 group vs. 3.07 years in D2 group; p=0.709) and RFS (median 1.47 years in D1 group vs. 1.27 years in D2 group; p=0.565) (Figure 2).
Kaplan–Meier curves of overall survival (A) and recurrence-free survival (B) in the entire cohort.
Comparisons of matched groups. After PSM, patient characteristics and pathological variables were well balanced between the two groups, with no significant differences (Table I). Compared with the D2 group, the D1 group had fewer RAMPS procedures (D1: 47.4% vs. D2: 81.6%, p=0.004), shorter operating times [269 min, interquartile range (IQR)=225-323 min] vs. 364 min (IQR=299-420 min), p<0.001), and fewer examined lymph nodes [11 (IQR=5-20) vs. 19 (IQR=13-27), p=0.005] (Table II). There were no significant differences in the length of postoperative hospital stay, which was significantly different in the overall comparison. In the comparison of regional and systemic recurrence sites, no significant differences were observed between the two groups (p=0.500). OS (median 2.37 years in D1 group vs. 3.56 years in D2 group; p=0.407) and RFS (median 1.35 years in D1 group vs. 1.11 years in D2 group; p=0.542) were not significantly different between the two groups (Figure 3). In a subgroup analysis of lymph node-positive patients, OS (median 2.04 years in D1 group vs. 1.66 years in D2 group; p=0.890) and RFS (median 1.03 years in D1 group vs. 0.73 years in D2 group, p=0.114) were similar in the D1 and D2 groups (Figure 4).
Kaplan–Meier curves of overall survival (A) and recurrence-free survival (B) in the matched cohort.
Kaplan–Meier curves of overall survival (A) and recurrence-free survival (B) of node-positive patients in the matched cohort.
Discussion
D1 DP was not inferior to D2 DP regarding both OS and RFS. Although pancreatic resection is the only treatment to achieve radical cure of PDAC, the recurrence rate in this study was as high as 75%, which is comparable to previous reports of 60%-90% (14, 18, 19). Moreover, the systemic recurrence rate in the recurred patients was 69%, which is also consistent with previous reports of 46%-83% (8, 14, 18, 19), meaning that nearly half of patients are already in systemic disease at the time of pancreatectomy. Extended lymph node dissection is performed to expect improvement in local control but, in this study, no difference in local recurrence rates was found between the D1 and D2 groups. In addition, a subgroup analysis of lymph node-positive patients did not demonstrate the superiority of the D2 group in OS or RFS. These results may indicate that systemic therapy is a fundamental treatment for PDAC and that lymph node dissection provides limited benefit. A previous RCT (14) comparing standard PD and extended PD for pancreatic head cancer did not demonstrate the superiority of extended lymphadenectomy for long-term prognosis and local control in both node-negative and node-positive patients, which follows our results and may also be relevant for left-sided PDAC.
In PSM, the only advantage of the D2 group over the D1 group was the number of lymph nodes harvested. The ISGPS consensus meeting recommended that a minimum of 15 lymph nodes should be examined for accurate staging (15). In this study, the median number of examined lymph nodes in the D1 and D2 groups was 11 and 19, respectively; hence, the stage may have been underestimated in the D1 group. Despite this speculation, it is worth noting that the long-term prognosis of the D1 group was not inferior to that of the D2 group. Large cohort studies using the SEER database have shown that a greater number of examined lymph nodes is associated with better OS (20, 21); however, these analyses have not included any information on chemotherapy. Because of the high recurrence rate of PC, the type of chemotherapy regimen and the aggressiveness of the oncologist regarding the treatment after recurrence have a significant impact on OS (22-24). Therefore, if adjuvant chemotherapy is equivalent, RFS is a more appropriate measure to compare surgical outcomes than OS. In this study, the proportion of patients according to the time period was similar in both groups when divided by the date of surgery for PSM patients before and after 2014, when the adjuvant chemotherapy regimen was changed. The Kaplan–Meier curves for RFS in the two groups were almost the same, suggesting an equivalence of surgical effects with lower bias.
Determination of the optimal extent of lymph node dissection is very complicated. Many reports have mapped lymph node metastasis and proposed a range of indicated dissections based on the probability of metastasis for each station; however, it is difficult to agree with their recommendations without a prospective study comparing prognosis with and without that range of dissection. As for the extent of lymph node dissection for PDAC, evidence needs to be established to avoid unnecessary extended surgery rather than to determine the optimal approach.
The present study had some limitations. First, this study was retrospective and did not include many patients; however, this is the first report to compare a given number of patients using a PSM analysis. It is hoped that an RCT will be attempted based on the results of this study. Second, although the choice of degree of dissection was left to the basic policy of the surgeon, selection bias still could have been introduced by patient background and preoperative assessment. Third, this study did not include data on post-relapse chemotherapy in its survival analysis. As mentioned above, detailed information on treatment after recurrence is mandatory for comparing OS. Therefore, the results on OS should be considered as informative only. Fourth, factors that affect RFS have attempted to minimize treatment allocation bias by applying PSM analysis, but there may be other significant factors as well. Finally, the possibility of variation in pathology evaluation and reporting among facilities is a serious limitation. These need to be standardized across the board.
In conclusion, D1 DP for left-sided PDAC was not inferior to D2 DP regarding long-term prognosis. In an era in which the importance of multidisciplinary treatment for PDAC has been documented, unnecessary extended surgery may be avoided.
Acknowledgements
The Authors thank H. Nikki March, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
Footnotes
Authors’ Contributions
All Authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Taro Sakamoto, Takeshi Gocho, Masashi Tsunematsu, Yoshihiro Shirai, Ryoga Hamura, Koichiro Haruki, Kyohei Abe, Hironori Shiozaki, Ryota Iwase and Yu Kumagai. The first draft of the manuscript was written by Taro Sakamoto and all Authors commented on previous versions of the manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors have no related conflicts of interest to declare in relation to this study.
Funding
This work was supported by JSPS KAKENHI Grant Number JP22K16501.
- Received November 17, 2022.
- Revision received November 29, 2022.
- Accepted November 30, 2022.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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