==== Front J Cancer J Cancer jca Journal of Cancer 1837-9664 Ivyspring International Publisher Sydney 10.7150/jca.51218 jcav12p0539 Research Paper Can Patients with Pancreatic Cancer and Liver Metastases Obtain Survival Benefit from Surgery? A Population-Based Study Su Bing-Bing 1* Bai Dou-Sheng 1* Yu Jiang-Quan 2 Zhang Chi 1 Jin Sheng-Jie 1 Zhou Bao-Huan 1 Jiang Guo-Qing 1✉ 1 Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou 225001, China. 2 Department of Intensive Care Unit, Clinical Medical College, Yangzhou University, Yangzhou 225001, China. ✉ Corresponding author: Guo-Qing Jiang, Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, 98 West Nantong Rd, Yangzhou 225000, China. Tel: +86-514-87373382; E-mail: jgqing2003@hotmail.com.*These authors contributed equally to this work. Competing Interests: The authors have declared that no competing interest exists. 2021 1 1 2021 12 2 539 552 28 7 2020 29 10 2020 © The author(s)2021This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.Background: Surgery for pancreatic cancer with liver metastases (PCL) is not recommended in the international guidelines, and investigation of its clinical significance in patients with PCL is very limited. This study explored whether surgery, especially synchronous resection of the primary tumor and liver metastases (SPL), could improve survival in PCL. Methods: Data of 14,248 patients with PCL from Surveillance, Epidemiology, and End Results database was analyzed. Patients were divided into following groups: SPL, synchronous primary site, and other resection (SPO), single resection of the primary site (SPS), and no resection (NR). Results: In this study, only 93 (0.7%) underwent SPL, 88 (0.6%) for SPO, and 232 (1.6%) for SPS. Multivariate Cox analysis showed surgical procedures of both the primary site and other sites were independent protective prognostic factors for pancreatic cancer cause-specific survival (PCSS) (all P < 0.001). Patients in the SPL group showed the most survival benefit, with a significant and gradually increased difference as compared with the SPO, SPS, and NR groups (median survival: 54, 34, 15, and 3 months, respectively, all P < 0.001). Compared with the NR group, mortalities were significant and gradually declining in the SPS, SPO, and SPL groups, with hazard ratio 0.329 (95% confidence interval [CI], 0.281 to 0.386), 0.220 (95% CI, 0.164 to 0.294), and 0.162 (95% CI, 0.118 to 0.222), respectively (all P < 0.001). Conclusions: Surgical procedures for both primary site and other sites improved survival. SPL, particularly, showed a considerable survival benefit in well-selected patients with PCL. Pancreatic cancermetastasessurgical proceduressurvivalSEER ==== Body Introduction Pancreatic cancer (PC) remains one of the most aggressive malignant tumors. Although the mortality from most cancers is declining, PC moved from the fourth leading cause of cancer-related death to the third in 2016 1. Despite of many efforts, this rate has not improved much over the last 30 years, with a persistently low 5-year survival rate of 8% 2,3. Compared with stages I-III, the overall survival (OS) of patients with stage IV metastatic disease (M1) was worse 4-6. The median survival of locally advanced PC is only 6-10 months, and just 3-6 months in M1 PC 7. Surgery is regarded as the only potentially curative method. However, once distant metastases are identified, surgery is not recommended in the guidelines 8,9. For other malignant tumors, such as colorectal cancer, gastric cancer, and even sarcoma, there is increasing evidence that simultaneous metastasectomy can improve survival in appropriately selected patients who are in good general health and if the surgical procedures are performed carefully 10-12. The question arises whether all patients with M1 PC should face the presently dismal outcomes. Yet, it remains controversial whether there is a survival benefit from synchronous resection of both the primary tumor as well as metastases in patients with M1 PC. A few studies including data from six European pancreas centers have all shown a significant survival benefit, with acceptable morbidity and mortality in patients with PC and liver metastases (PCL) who underwent synchronous resection of the primary tumor and liver metastases (SPL), in comparison with patients with PCL who did not undergo resection 13,14. Conversely, other studies have found no significant difference in survival between patients with PCL who underwent SPL and palliative bypass alone 15,16. Up to the present, the sample sizes of patients undergoing SPL in previous studies have all been very small 13-16, with the largest sample including 69 patients in a collaboration study of six high-volume centers in Europe 14. To reach more robust conclusions, the present study aimed to use data from a larger patient sample to investigate the clinical significance of surgery, especially SPL, in patients with PCL. We extracted data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry to systematically analyze the effect of surgery, especially SPL, on PC cause-specific survival (PCSS) in patients with PCL. Materials and Methods Patient selection in the SEER database The SEER Cancer Statistics Review, which comprises the most recent statistics on cancer incidence, mortality, survival, prevalence, and lifetime risk, is published annually by the Data Analysis and Interpretation Branch of the National Cancer Institute in the United States (US). The current SEER database derives from 18 population-based cancer registries in the US 17. It contains no identifiers and is publicly available for studies of cancer-based epidemiology. We used SEER*Stat 8.3.5 software to identify patients with a histopathologic diagnosis of PC from January 1, 2010, through December 31, 2015, with follow-up through December 31, 2017. SEER registry patients with PC who were eligible for our study cohort included those with the following histologic type, according to the International Classification of Diseases for Oncology, Third Edition: adenocarcinoma (8140, 8141, 8144, 8210, 8211, 8255, 8260, 8263, 8310, 8401, 8440, 8450, 8470, 8480, 8481, 8503, 8574, 8576), neuroendocrine carcinoma (8246) and others (8000, 8001, 8004, 8010, 8012, 8013, 8014, 8020, 8021, 8022, 8031, 8032, 8033, 8035, 8041, 8046, 8070, 8071, 8072, 8120, 8150, 8151, 8152, 8153, 8154, 8160, 8162, 8170, 8240, 8244, 8249, 8430, 8452, 8453, 8490, 8500, 8507, 8523, 8550, 8560, and 8980). We extracted the following data: sex, race, age at diagnosis, year of diagnosis, primary site, pathological grade, histologic type, T stage, N stage, tumor size, insurance status, marital status, county percentage with a bachelor's degree, county percentage unemployed, county-level median household income, residential area, surgical procedure for the primary site, surgical procedure for other sites, radiotherapy, chemotherapy, SEER cause-specific death classification, SEER other cause of death classification, survival months, and vital status. In this analysis, we included only adult patients with PC and liver metastases, with TNM stage IV, according to the criteria described in the American Joint Committee on Cancer Staging Manual (7th edition). We excluded patients as follows: those with bone metastasis, lung metastasis, brain metastasis, other primary cancer, unknown surgical history, unknown bachelor's degree status, and cause of death missing/unknown or attributable to causes other than PC. Statistical analysis The primary endpoint of this study was PCSS. PCSS was defined as the time from the date of diagnosis to the date of death owing to PC. Baseline patient demographics and tumor characteristics were compared using the chi-square test. The PC survival rate was compared between subgroups using Kaplan-Meier analysis. All prognostic factors with P < 0.1 in Kaplan-Meier analysis were investigated using multivariate Cox analysis to identify predictors of PCSS. All statistical analyses were performed using IBM SPSS, version 22 (IBM Corp, Armonk, NY, USA). Statistical significance was set at two-sided P <0.05. All patients were categorized as those receiving surgery for the primary site (PSP), those who were recommended but did not undergo surgery for the primary site (RN-PSP) group, and those who were not recommended and did not have surgery for the primary site (NRN-PSP). The PSP group was divided into the SPL group, synchronous primary tumor, and other resection (SPO) groups, and no synchronous resection for other sites group also called single resection of the primary site (SPS). A surgical procedure of other sites was defined as any of the following: (1) non-primary surgical procedure for liver; (2) non-primary surgical procedure for other regional sites; (3) non-primary surgical procedure for distant lymph node(s); (4) any combination of surgical procedures for other regional sites, distant lymph node(s), and/or liver; and (5) non-primary surgical procedure performed without detail information. Apart from non-primary surgical procedures for the liver, the remaining surgical procedures for other sites were defined as other resection. Results Baseline patient characteristics We identified a total of 14,248 eligible patients with PCL between 2010 and 2015, with 7,711 male and 6,537 female patients. Of these, 93 (0.7%) underwent SPL, 88 (0.6%) received SPO, 232 (1.6%) received SPS, 414 (2.9%) PSP, 320 (2.3%) RN-PSP, 13,514 (94.8%) NRN-PSP and 13,503 (94.8%) patients received no resection (NR). Mean ages of patients were 58.5 ± 12.4 (range: 25-82) years in the SPL group, 55.7 ± 13.2 (range: 20-87) years in the SPO group, 60.6 ± 12.5 (range: 20-93) years in the SPS group, and 67.5 ± 12.1 (range: 20-103) years in the NR group. In within-group comparisons, the SPL group had the highest proportion (53.8%) of body/tail site, greater frequency (36.0%) of well/moderately differentiated pathology grade, highest prevalence (41.9%) of neuroendocrine carcinoma, a greater proportion (72.0%) of T3 stage, and less (33.3%) chemotherapy, which were all statistically significant (P < 0.001). Baseline patient demographics and tumor characteristics according to different surgical procedures are described in Table 1. Effect on PCSS of surgical procedures for primary and other sites Patients who underwent PSP had better survival (n = 13,834, 97.1%) than those who did not undergo surgery for the primary site (5-year PCSS: 33.4% vs. 0.19%, median survival: 24 vs. 3 months, P < 0.001). Five-year PCSS was 33.4% in the PSP group, 4.0% in the RN-PSP group, and 1.8% in the NRN-PSP group; survival was significantly different in Kaplan-Meier analysis (median survival: 24, 2, 3 months, respectively, P < 0.001). Surprisingly, the median survival of the RN-PSP group was significantly shorter than that of the NRN-PSP group (P < 0.001). Moreover, for surgical procedures of other sites, 5-year PCSS was 17.5% in the liver resection group, 16.9% in the other resection group, and 2.4% in the NR group; survival was also significantly different in Kaplan-Meier analysis (median survival: 8, 11, 3 months, respectively, P < 0.001). As shown in Table 2, after univariate analysis and multivariate Cox analysis, surgical procedures of the primary site, surgical procedures of other sites, radiotherapy, and chemotherapy were all validated as independent protective prognostic factors for survival (all P < 0.001). Effect on PCSS of synchronous surgical procedure for primary and other sites Among patients with PSP, only one had unknown surgery status for other sites; this patient was omitted from the following analyses. The 181 (43.8%) patients who received surgical procedures for other sites had better survival than the 232 (56.2%) patients who did not (5-year PCSS: 44.5% vs. 24.6%, median survival: 43 vs. 15 months, P < 0.001). As shown in Table 3, after univariate and multivariate Cox analyses, the synchronous surgical procedure of other sites was validated as an independent prognostic positive factor for survival (P < 0.001). Notably, radiotherapy and chemotherapy were not independent prognostic factors for survival in patients with PSP (Table 3). Effect of radiotherapy/chemotherapy on PCSS in patients without surgery The 367 (2.7%) patients without surgery who received radiotherapy (WSR) had better survival than the 13,136 (97.3%) patients without surgery who received no/unknown radiotherapy (N-WSR) (2-year PCSS: 11.2% vs. 5.5%, median survival: 6 vs. 2 months, P < 0.001) (Table 4). The 6671 (49.4%) patients without surgery who received chemotherapy (WSC) had better survival than the 6832 (50.6%) patients without surgery who received no/unknown chemotherapy (N-WSC) (2-year PCSS: 8.4% vs. 3.0%, median survival: 6 vs. 1 months, P < 0.001) (Table 4). As shown in Table 4, after univariate analysis and multivariate Cox analyses, radiotherapy and chemotherapy were validated as independent positive predictors of survival in patients without surgery (all P < 0.001). Subgroup analysis of the effect on PCSS of surgical procedures for the primary site, according to the primary site As shown in Table 5, Kaplan-Meier analysis and multivariate Cox analyses showed that at each primary site, including the pancreatic head, body/tail, and other sites, patients receiving PSP had better survival than those receiving RN-PSP and NRN-PSP (all P < 0.001). Subgroup analysis of the effect on PCSS of surgical procedures for other sites, according to the primary site As shown in Table 5, Kaplan-Meier and multivariate Cox analyses showed that at each primary site, including the pancreatic head, body/tail, and other sites, patients receiving NR had a worse survival than those in the liver resection and other resection groups (all P < 0.001). Subgroup analysis of the effect on PCSS of radiotherapy in patients without surgery, according to the primary site As shown in Table 5, Kaplan-Meier and multivariate Cox analyses all showed that at each primary site, including the pancreatic head, body/tail, and other sites, patients receiving WSR had better survival than those with N-WSR (all P < 0.001). Subgroup analysis of the effect on PCSS of chemotherapy in patients without surgery, according to the primary site As shown in Table 5, Kaplan-Meier and multivariate Cox analyses all showed that at each primary site, including the pancreatic head, body/tail, and other sites, patients receiving WSC had better survival than those with N-WSC (all P < 0.001). Subgroup analysis of the effect on PCSS of histology As seen in Table 6, the 5-year PCSS was significantly different and gradually declined in the following groups: 49.7% in the SPL group, 39.1% in the SPO group, 24.6% in the SPS group, and 1.9% in the NR group (P < 0.001) (Figure 1A). The SPS, SPO, and SPL groups showed significantly and gradually longer median survival of 15, 34, and 54 months, respectively, compared with 3 months for the NR group (all P < 0.001) (Table 6). Compared with the NR group, mortalities were significantly and gradually declining in the SPS, SPO, and SPL groups, with hazard ratio (HR) 0.329 (95% confidence interval [CI], 0.281-0.386), 0.220 (95% CI, 0.164-0.294), and 0.162 (95% CI, 0.118-0.222), respectively (all P < 0.001) (Table 6). Compared with the NR group, there had increasingly improved survival benefits of 2-year PCSS for SPS, SPO, and SPL among adenocarcinoma, neuroendocrine carcinoma, or other groups (all P < 0.05) (Table 6, Figure 1B-D). Moreover, compared with the NR group, mortalities were significantly and gradually declining for SPS, SPO, and SPL among the adenocarcinoma, neuroendocrine carcinoma, or other groups (all P < 0.05) (Table 6). Compared with the neuroendocrine carcinoma group, those who receiving SPS, SPO, SPL, or NR all had gradually worse PCSS for other histology and adenocarcinoma groups (all P < 0.05) (Table 6, Figure 2A-D). Moreover, compared with the neuroendocrine carcinoma group, mortalities were all significantly and gradually increased for other histology and adenocarcinoma groups receiving SPS, SPO, SPL, or NR (all P < 0.05) (Table 6). Subgroup analysis of the effect on PCSS of combined surgery and adjuvant therapy Compared with patients receiving no/unknown adjuvant therapy, there were no significant differences in survival for chemoradiotherapy and chemotherapy with no/unknown radiotherapy among the SPL, SPO, or SPS groups in Kaplan-Meier and multivariate analyses with Cox regression (all P > 0.05) (Table 6). Compared with patients receiving no/unknown adjuvant therapy, those with NR had increasingly improved survival benefits for radiotherapy with no/unknown chemotherapy, chemotherapy with no/unknown radiotherapy, and chemoradiotherapy (median survival: 1, 3, 6, and 8 months, respectively, all P < 0.001) (Table 6). Moreover, compared with patients receiving no/unknown adjuvant therapy, mortalities was significantly and gradually declining for the radiotherapy with no/unknown chemotherapy, chemotherapy with no/unknown radiotherapy, and chemoradiotherapy groups, with HR 0.569 (95% CI, 0.462-0.699, P < 0.001), 0.394 (95% CI, 0.379-0.408, P < 0.001), and 0.332 (95% CI, 0.292-0.377, P < 0.001), respectively (Table 6). Discussion Current therapeutic approaches for patients with M1 PC are palliative and mainly based on tumor cell targeting. Some palliative chemotherapies' for patients with M1 PC have recently been established, such as the use of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine with nab-paclitaxel, which have shown an increased median OS of 11 and 8.5 months, respectively, compared with 6.7-7 months for single gemcitabine 5; nevertheless, the survival outcome of patients with M1 PC remains poor. Palliative resection for advanced pancreatic cancer is controversial. Tachezy et al. deemed that palliative resection for M1 PC was not advisable because of its lack of survival benefit (5.1 months [n = 22] vs. 5.8 months [n = 46]) and higher surgery-related morbidity (59% vs. 33%, P = 0.035) and mortality (27% vs. 7%, P = 0.049), compared with bypass surgery 18. Macroscopically complete resection has been demonstrated to be one of the most important and protective prognostic factors for survival; however, the performance of additional vessel resections and/or synchronous metastasis resections should be carefully weighed to avoid increasing morbidity and mortality caused by these surgical procedures 19-21. International guidelines do not recommend surgery for PC when distant metastasis has occurred 1,9. Our outcomes showed that SPS was associated with significantly improved survival compared with no resection. The present rationale for proposing SPS in patients with PC and metastatic disease has been revisited in subgroup analyses. McKenzie et al. revealed significant survival benefits of 4.7 months in patients with M1 PC receiving SPS (median survival: 6.3 months, n = 92) compared with those who did not receive surgical resection (median survival: 1.6 months, n = 2606) 22. Likewise, although synchronous resection for patients with PC and oligometastatic disease is controversial and not recommended in the international guidelines 1,9, with the increasing surgical safety of pancreatic and liver resection and unceasing pursuit for better survival in patients with M1 PC, SPL in carefully selected patients with PCL is being increasingly considered. Small studies, including case reports, have described the use of aggressive “curative” SPL in selected patients with PCL 10,23,24. Two studies showed no survival benefit in PCL patients who underwent SPL, as compared with palliative bypass alone (median survival: 5.9 [n = 22] vs. 5.6 [n = 66] months; median survival: 6 [n = 11] vs. 4 [n = 22] months; all P > 0.05, respectively) 15,16. Conversely, a previous study revealed significant survival benefits of 5.5 months in PCL patients who received SPL as compared with NR (median survival: 11.4 [n = 11] vs. 5.9 [n = 118] months; P = 0.0384) 13. A retrospective multicentral analysis in six European pancreas centers reported that the median OS of patients after SPL tended to be significantly longer than in those with NR (median survival: 14.5 [n = 69] vs. 7.5 [n = 69] months; P < 0.001) 14. This study showed that surgical procedures of both the primary site and other sites were independent positive prognostic factors for survival. On the one hand, a good survival effect was seen in this study in that the SPS group had a 12-month increase in median survival compared with the NR group (P < 0.001). On the other hand, the median survival of the liver resection and other resection groups had 5- and 6-month increased survival in comparison with the NR group, respectively (all P < 0.001). Furthermore, regardless of whether the primary site was at the head, body/tail, or another location, resection of both the primary site and of other sites all significantly improved survival as compared with the NR group. In this study, the SPL group showed the best survival benefit, with a significant and gradual increase in median survival of 20, 39, and 51 months, respectively, compared with the SPO, SPS, and NR groups (all P < 0.001). The mortality risk in the NR group was the highest, over six times that of the SPL group, nearly five times that of the SPO group, and over three times that of the SPS group. The median survival of the SPL group in this study was superior to that of the abovementioned studies 13-16. This difference may be owing to many factors including patients' performance status, surgical skills, perioperative management, management of operative indications, and in this study high rate of neuroendocrine carcinoma patients. This study found that, among different histology groups, the neuroendocrine carcinoma group had the best survival for those who receiving SPS, SPO, SPL, or NR. On the contrary, the adenocarcinoma group had the worst survival. On the other hand, patients receiving SPL had a 29.7%, 42.4%, and 48.2% gradual increase in 2-year PCSS compared with whose receiving NR in adenocarcinoma, other histology, and neuroendocrine carcinoma groups respectively. In the study, we identified a total of 683 eligible PCL patients with neuroendocrine carcinoma. Fortunately, some of them, 112 (16.4%) received surgery, 39 (5.7%) underwent SPL, 32 (4.7%) received SPO, and 41 (6.0%) had SPS. PCL patients with neuroendocrine carcinoma after SPS, SPO, SPL were associated with gradual improved 5-year PCSS (54.9%, 60.7%, and 66.5%, respectively). Another interesting finding of our study is that survival also improved in the other resection group. The median survival of the SPO group showed a 31-month increase compared with that of the NR group (P < 0.001). This finding is similar to a report by Shrikhande et al. that synchronous resection of interaortocaval lymph nodes (n = 9) and peritoneal metastases (n = 9) showed 7- and 21.1-month increase of median survival, respectively, compared with NR (n = 118) 13. Because of improved survival owing to adjuvant therapy, this is recommended for patients who have PC with or without surgical resection in the international guidelines 1,9; however, it is not mentioned as a treatment regimen for patients with M1 PC who receive synchronous multivisceral resection. Furthermore, clinical studies concerning the curative effect of adjuvant therapy in patients with M1 PC who receive synchronous multivisceral resection is very limited. Reportedly, postoperative chemotherapy and radiotherapy have no apparent influence on survival in patients with M1 PC who undergo synchronous multivisceral resection 19,22. The conclusions of this study were consistent with the abovementioned outcomes; even chemoradiotherapy did not significantly prolong postoperative survival. It is worth investigating why the addition of adjuvant therapy in patients with M1 PC who receive synchronous multivisceral resection is not associated with improved prognosis. We found that the RN-PSP group had an even worse survival than the NRN-PSP group. This may be owing to patients' heavy psychological burden, rejecting surgery, or a lack of palliative therapy. Our study had several limitations. First, surgery-related morbidity and mortality are not included in the SEER database. Second, recurrence data were unknown. Third, the data for radiation or chemotherapy were denoted “No/Unknown”; this is somewhat unclear and means that in the analysis, we did not have a patient group that did not receive either therapy. Fourth, it is clear that all patients had liver metastasis without metastasis to other common sites, such as bone, lung, and brain; however, whether patients had an uncommon metastatic disease is unknown. Fifth, the sequence concerning chemotherapy and surgery was unavailable. Sixth, details of chemotherapy including medications and dosage were not provided. Finally, detailed information on liver metastases was unavailable, including tumor size, number, and site. To our best knowledge, the sample sizes of patients with PCL who underwent SPL, SPO, and SPS in this study may be the largest to date. We revealed that surgical procedures of both the primary site and other sites were independent protective predictors for survival in patients with PCL. Among the different treatment regimens, SPL in particular provided a considerable survival benefit. Besides, adjuvant therapies were not associated with improved postoperative survival in patients with PCL. According to recent evidence, several guiding principles should be followed when performing SPL in patients with PCL. Surgical procedures should be carried out at a high-volume PC center by a multi-disciplinary team including surgeons experienced in procedures involving the pancreas, liver, and so on; also, patients should have good performance status, no invasion of the adjacent vessels, and resectability in limited liver metastases. Further studies may be required, to develop qualification criteria for which PC center is qualified to perform SPL and operative indications for which patients with PCL are appropriate for SPL. In this population-based study, among 14,248 patients with PCL, only 93 (0.7%) received SPL, with a satisfactory 5-year PCSS (49.7%). In the future, it can be expected that increasingly more well-selected patients could benefit from SPL. The authors acknowledge the efforts of the SEER program in the creation of the SEER database. Funding This work was supported by the Project of Invigorating Health Care through Science, Technology and Education: Jiangsu Provincial Medical Youth Talent (QNRC2016331) and Yangzhou Social Development Project (YZ2018075). Abbreviations PCpancreatic cancer PCLpancreatic cancer with liver metastases SPLsynchronous resection of the primary tumor and liver metastases SPOsynchronous primary tumor and other resection SPSsingle resection of the primary site NRno resection PCSSpancreatic cancer cause-specific survival PSPreceiving surgery for the primary site RN-PSPrecommended but did not undergo surgery for the primary site NRN-PSPnot recommended and did not have surgery for the primary site WSRwithout surgery who received radiotherapy N-WSRwithout surgery who received no/unknown radiotherapy WSCwithout surgery who received chemotherapy N-WSCreceived no/unknown chemotherapy SEERSurveillance, Epidemiology, and End Results HRhazard ratio CIconfidence interval OSoverall survival NAnot applicable NInot included in multivariate survival analysis Figure 1 Survival curves in patients with pancreatic cancer and liver metastases treated with different surgical procedures. (A) Overall: χ2 = 113.429, P < 0.001; (B) Adenocarcinoma: Log rank χ2 = 84.148, P < 0.001; (C) Neuroendocrine carcinoma: Log rank χ2 = 74.889, P < 0.001; (D) Other: Log rank χ2 = 220.033, P < 0.001. SPL: synchronous resection of the primary tumor and liver metastases; SPO: synchronous primary tumor and other resection; SPS: single resection of the primary site; NR: no resection. Figure 2 Survival curves in patients with pancreatic cancer and liver metastases treated with different histology. (A) SPL: χ2 = 19.873, P < 0.001; (B) SPO: Log rank χ2 = 14.658, P < 0.001; (C) SPS: Log rank χ2 = 47.873, P < 0.001; (D) NR: Log rank χ2 = 634.958, P < 0.001. Abbreviations: SPL: synchronous resection of the primary tumor and liver metastases; SPO: synchronous primary tumor and other resection; SPS: single resection of the primary site; NR: no resection. Table 1 Baseline demographic and tumor characteristics of different surgical procedures for pancreatic cancer with liver metastases in the SEER database Characteristic SPL, N (%)(n = 93) SPO, N (%)(n = 88) SPS, N (%)(n = 232) NR, N (%)(n = 13503) P Sex 0.525 Male 52 (55.9) 41 (46.6) 128 (55.2) 7312 (54.2) Female 41 (44.1) 47 (53.4) 104 (44.8) 6191 (45.8) Race 0.572 White 76 (81.7) 76 (86.4) 182 (78.4) 10608 (78.6) Black 10 (10.8) 6 (6.8) 30 (12.9) 1847 (13.7) Other* 7 (7.5) 6 (6.8) 20 (8.6) 1048 (7.8) Age <0.001 <65 64 (68.8) 68 (77.3) 137 (59.1) 5552 (41.1) ≥65 29 (31.2) 20 (22.7) 95 (40.9) 7951 (58.9) Year of diagnosis 0.539 2010-2011 26 (28.0) 27 (30.7) 69 (29.7) 4096 (30.3) 2012-2013 29 (31.2) 36 (40.9) 84 (36.2) 4468 (33.1) 2014-2015 38 (40.9) 25 (28.4) 79 (34.1) 4939 (36.6) Primary Site <0.001 Head 32 (34.4) 25 (28.4) 123 (53.0) 4899 (36.3) Body/Tail 50 (53.8) 45 (51.1) 70 (30.2) 4856 (36.0) Other 11 (11.8) 18 (20.5) 39 (16.8) 3748 (27.8) Grade <0.001 Well/Moderate 56 (60.2) 50 (56.8) 116 (50.0) 1040 (7.7) Poor/Anaplastic 21 (22.6) 28 (31.8) 71 (30.6) 1431 (10.6) Other 16 (17.2) 10 (11.4) 45 (19.4) 11032 (81.7) Histology <0.001 Adenocarcinoma 20 (21.5) 22 (25.0) 86 (37.1) 9845 (72.9) Neuroendocrine carcinoma 39 (41.9) 32 (36.4) 41 (17.7) 546 (4.0) Other 34 (36.6) 34 (38.6) 105 (45.3) 3112 (23.0) T stage <0.001 T0 0 (0.0) 0 (0.0) 0 (0.0) 119 (0.9) T1 4 (4.3) 3 (3.4) 10 (4.3) 337 (2.5) T2 17 (18.3) 15 (17.0) 41 (17.7) 3848 (28.5) T3 67 (72.0) 58 (65.9) 146 (62.9) 3280 (24.3) T4 4 (4.3) 10 (11.4) 16 (6.9) 2216 (16.4) TX 1 (1.1) 2 (2.3) 19 (8.2) 3703 (27.4) N stage <0.001 N0 32 (34.4) 24 (27.3) 90 (38.8) 7173 (53.1) N1 60 (64.5) 60 (68.2) 132 (56.9) 3904 (28.9) NX 1 (1.1) 4 (4.5) 10 (4.3) 2426 (18.0) Tumor Size <0.001 ≤2 cm 7 (7.5) 5 (5.7) 19 (8.2) 714 (5.3) 2-4 cm 37 (39.8) 34 (38.6) 99 (42.7) 4600 (34.1) >4 cm 45 (48.4) 45 (51.1) 98 (42.2) 5367 (39.7) Unknown 4 (4.3) 4 (4.5) 16 (6.9) 2822 (20.9) Insurance status 0.073 Insured 82 (88.2) 73 (83.0) 204 (87.9) 10999 (81.5) Medicaid 7 (7.5) 9 (10.2) 21 (9.1) 1790 (13.3) Uninsured/Unknown 4 (4.3) 6 (6.8) 7 (3.0) 714 (5.3) Marital status <0.001 Married 59 (63.4) 52 (59.1) 156 (67.2) 7210 (53.4) Unmarried 30 (32.3) 32 (36.4) 66 (28.4) 5662 (41.9) Unknown 4 (4.3) 4 (4.5) 10 (4.3) 631 (4.7) County % with bachelor degree 0.511 Below median 37 (39.8) 40 (45.5) 90 (38.8) 5815 (43.1) Above median 56 (60.2) 48 (54.5) 142 (61.2) 7688 (56.9) County % with unemployed 0.779 Below median 40 (43.0) 43 (48.9) 107 (46.1) 6443 (47.7) Above median 53 (57.0) 45 (51.1) 125 (53.9) 7060 (52.3) County-level median household income 0.039 Below median 41 (44.1) 41 (46.6) 91 (39.2) 6532 (48.4) Above median 52 (55.9) 47 (53.4) 141 (60.8) 6971 (51.6) Residence area 0.301 Metropolitan 88 (94.6) 80 (90.9) 215 (92.7) 12054 (89.3) Urban/rural 5 (5.4) 8 (9.1) 17 (7.3) 1433 (10.6) Missing 0 (0.0) 0 (0.0) 0 (0.0) 16 (0.1) Radiotherapy <0.001 Yes 7 (7.5) 8 (9.1) 11 (4.7) 367 (2.7) No/Unknown 86 (92.5) 80 (90.9) 221 (95.3) 13136 (97.3) Chemotherapy <0.001 Yes 31 (33.3) 49 (55.7) 133 (57.3) 6671 (49.4) No/Unknown 62 (66.7) 39 (44.3) 99 (42.7) 6832 (50.6) *, Other includes American Indian/Alaska Native, Asian/Pacific Islander, and unknown. SPL: synchronous resection of the primary tumor and liver metastases; SPO: synchronous primary tumor and other resection; SPS: single resection of the primary site; NR: no resection. Table 2 Univariate and multivariate Cox analysis to identify predictors of pancreatic cancer cause-specific survival Variable Total (n=14248) 2-year PCSS 5-year PCSS Univariate analysis Multivariate Cox analysis P HR (95%CI) P Sex 0.392 NI Male 7711 0.071 0.032 Female 6537 0.070 0.026 Race <0.001 0.018 White 11204 0.073 0.030 Reference Black 1946 0.055 0.021 1.061 (1.008-1.116) 0.023 Other* 1098 0.073 0.032 0.954 (0.894-1.019) 0.161 Age <0.001 <0.001 <65 5991 0.112 0.047 Reference ≥65 8257 0.041 0.017 1.306 (1.260-1.355) Year of diagnosis <0.001 <0.001 2010-2011 4335 0.059 0.22 Reference 2012-2013 4729 0.076 NA 0.955 (0.916-0.997) 0.034 2014-2015 5184 0.076 NA 0.915 (0.878-0.955) <0.001 Primary Site <0.001 0.016 Head 5236 0.065 0.024 Reference Body/Tail 5113 0.080 0.036 1.054 (1.012-1.098) 0.011 Other 3899 0.066 0.028 1.045 (0.998-1.094) 0.020 Grade <0.001 <0.001 Well/Moderate 1301 0.252 0.126 Reference Poor/Anaplastic 1592 0.055 0.021 1.776 (1.639-1.925) <0.001 Other 11355 0.052 0.019 1.525 (1.427-1.630) <0.001 Histology <0.001 <0.001 Adenocarcinoma 10248 0.039 0.008 Reference Neuroendocrine carcinoma 683 0.294 0.247 0.292 (0.265-0.322) <0.001 Other 3317 0.084 0.047 0.893 (0.855-0.931) <0.001 T stage <0.001 0.004 T0 123 0.065 NA Reference T1 360 0.092 0.038 0.829 (0.670-10.26) 0.085 T2 3993 0.069 0.029 0.819 (0.654-1.026) 0.082 T3 3656 0.098 0.041 0.769 (0.615-0.961) 0.021 T4 2314 0.060 0.023 0.781 (0.624-0.977) 0.031 TX 3802 0.052 0.021 0.838 (0.670-1.046) 0.118 N stage <0.001 0.100 N0 7514 0.070 0.026 Reference N1 4257 0.084 0.041 1.044 (1.003-1.087) 0.034 NX 2477 0.050 0.018 1.007 (0.958-1.058) 0.794 Tumor size <0.001 <0.001 ≤2 cm 765 0.087 0.041 Reference 2-4 cm 4890 0.072 0.024 1.093 (0.962-1.242) 0.170 >4 cm 5664 0.076 0.036 1.214 (1.069-1.379) 0.003 Unknown 2929 0.054 0.020 1.185 (1.040-1.350) 0.011 Insurance status <0.001 <0.001 Insured 11627 0.075 0.032 Reference Medicaid 1871 0.049 0.021 1.098 (1.041-1.157) <0.001 Uninsured/Unknown 750 0.051 0.010 1.181 (1.091-1.278) <0.001 Marital status <0.001 <0.001 Married 7658 0.088 0.035 Reference Unmarried 5920 0.048 0.020 1.122 (1.081-1.163) <0.001 Unknown 670 0.080 0.044 0.982 (0.904-1.067) 0.671 County % with bachelor degree <0.001 0.002 Below median 6146 0.066 0.024 Reference Above median 8102 0.075 0.034 0.939 (0.902-0.977) County % with unemployed 0.007 0.738 Below median 6788 0.076 0.034 Reference Above median 7460 0.066 0.025 0.994 (0.958-1.031) County-level median household income <0.001 0.110 Below median 6905 0.064 0.024 Reference Above median 7343 0.077 0.034 0.967 (0.929-1.007) Residence area 0.183 NI Metropolitan 12718 0.072 0.028 Urban/rural 1514 0.063 0.035 Missing 16 0.125 NA Surgical procedure of primary site <0.001 <0.001 Not recommended 13514 0.058 0.018 Reference Performed 414 0.492 0.334 0.390 (0.339-0.448) <0.001 Recommended but not Performed 320 0.049 0.040 0.910 (0.811-1.021) 0.107 Surgical procedure of other sites <0.001 <0.001 No resection 13735 0.062 0.024 Reference Liver resection 288 0.298 0.175 0.714 (0.622-0.818) <0.001 Other resection 218 0.286 0.169 0.772 (0.660-0.904) 0.001 Unknown 7 NA NA 1.261 (0.599-2.652) 0.541 Radiotherapy <0.001 <0.001 Yes 405 0.132 0.027 Reference No/Unknown 13843 0.069 0.029 1.303 (1.174-1.447) Chemotherapy <0.001 <0.001 Yes 7079 0.096 0.030 Reference No/Unknown 7169 0.046 0.028 2.477 (2.384-2.573) *, Other includes American Indian/Alaska Native, Asian/Pacific Islander, and unknown. PCSS: pancreatic cancer cause-specific survival; HR: hazard ratio; CI: confidence interval; NA: not applicable; NI: not included in multivariate survival analysis. Table 3 Univariate and multivariate Cox analyses to identify predictors of pancreatic cancer cause-specific survival in patients undergoing surgical procedures of the primary site Variable Total (n=413) 2-year PCSS 5-year PCSS Univariate analysis Multivariate Cox analysis P HR (95%CI) P Sex 0.858 NI Male 221 0.050 0.344 Female 192 0.485 0.324 Race 0.782 NI White 334 0.494 0.334 Black 46 0.485 0.304 Other* 33 0.498 0.409 Age <0.001 0.014 <65 269 0.579 0.405 Reference ≥65 144 0.335 0.210 1.406 (1.071-1.846) Year of diagnosis 0.394 NI 2010-2011 122 0.466 0.287 2012-2013 149 0.499 NA 2014-2015 142 0.515 NA Primary Site <0.001 0.019 Head 180 0.324 0.210 Reference Body/Tail 165 0.633 0.405 0.697 (0.503-0.967) 0.031 Other 68 0.586 0.487 0.566 (0.357-0.897) 0.016 Grade <0.001 <0.001 Well/Moderate 222 0.673 0.476 Reference Poor/Anaplastic 120 0.272 0.174 2.425 (1.774-3.313) <0.001 Other 71 0.320 0.188 1.772 (1.190-2.639) 0.005 Histology <0.001 <0.001 Adenocarcinoma 128 0.237 0.097 Reference Neuroendocrine carcinoma 112 0.833 0.457 0.252 (0.161-0.394) <0.001 Other 173 0.691 0.328 0.541 (0.392-0.747) <0.001 T stage 0.002 0.471 T0 0 NA NA T1 17 0.635 0.635 Reference T2 73 0.478 0.298 1.054 (0.330-3.362) 0.930 T3 271 0.512 0.352 1.026 (0.336-3.134) 0.965 T4 30 0.527 0.287 0.926 (0.273-3.145) 0.902 TX 22 0.156 0.104 2.195 (0.578-8.339) 0.248 N stage 0.067 0.162 N0 146 0.505 0.357 Reference N1 252 0.501 0.332 1.174 (0.864-1.597) 0.305 NX 15 0.240 0.160 1.870 (0.940-3.721) 0.075 Tumor Size 0.001 0.343 ≤2 cm 31 0.562 0.515 Reference 2-4 cm 170 0.430 0.280 1.866 (0.885-3.934) 0.101 >4 cm 188 0.573 0.384 1.863 (0.869-3.996) 0.110 Unknown 24 0.231 0.116 1.254 (0.460-3.421) 0.658 Insurance status 0.236 NI Insured 359 0.505 0.347 Medicaid 37 0.392 0.281 Uninsured/Unknown 17 0.463 NA Marital status 0.051 0.041 Married 267 0.497 0.340 Reference Unmarried 128 0.448 0.281 1.173 (0.885-1.556) 0.267 Unknown 18 0.769 0.684 0.351 (0.134-0.922) 0.034 County % with bachelor degree 0.042 0.080 Below median 167 0.448 0.285 Reference Above median 246 0.524 0.371 0.767 (0.570-1.033) County % with unemployed 0.040 0.439 Below median 190 0.522 0.409 Reference Above median 223 0.468 0.268 1.129 (0.830-1.537) County-level median household income 0.002 0.034 Below median 173 0.428 0.268 Reference Above median 240 0.540 0.386 0.709 (0.516-0.975) Residence area 0.104 NI Metropolitan 383 0.507 0.339 Urban/rural 30 0.323 0.277 Synchronous surgical procedure <0.001 0.011 SPS 232 0.392 0.246 Reference SPL 93 0.683 0.497 0.544 (0.373-0.793) 0.009 SPO 88 0.551 0.391 0.656 (0.461-0.934) 0.033 Radiotherapy 0.513 NI Yes 26 0.498 0.249 No/Unknown 387 0.491 0.337 Chemotherapy 0.001 0.056 Yes 213 0.414 0.228 Reference No/Unknown 200 0.580 0.451 1.365 (0.992-1.878) *, Other includes American Indian/Alaska Native, Asian/Pacific Islander, and unknown. PCSS: pancreatic cancer cause-specific survival; HR: hazard ratio; CI: confidence interval; SPL: synchronous resection of the primary tumor and liver metastases; SPO: synchronous primary tumor and other resection; SPS: single resection of the primary site; NA: not applicable; NI: not included in multivariate survival analysis. Table 4 Univariate and multivariate Cox analyses to identify predictors of pancreatic cancer cause-specific survival in patients receiving no resection Variable Total (n=13503) 2-year PCSS 5-year PCSS Univariate analysis Multivariate Cox analysis P HR (95%CI) P Sex 0.298 NI Male 7312 0.057 0.022 Female 6191 0.056 0.016 Race 0.004 0.019 White 10608 0.059 0.021 Reference Black 1847 0.045 0.013 1.059 (1.006-1.116) 0.030 Other* 1048 0.059 0.019 0.950 (0.889-1.016) 0.133 Age <0.001 <0.001 <65 5552 0.088 0.029 Reference ≥65 7951 0.035 0.013 1.295 (1.247-1.344) Year of diagnosis <0.001 0.001 2010-2011 4096 0.046 0.014 Reference 2012-2013 4468 0.061 NA 0.962 (0.921-1.004) 0.077 2014-2015 4939 0.062 NA 0.922 (0.883-0.963) <0.001 Primary Site <0.001 0.004 Head 4899 0.054 0.016 Reference Body/Tail 4856 0.061 0.023 1.062 (1.019-1.107) 0.005 Other 3748 0.050 0.019 1.069 (1.020-1.121) 0.005 Grade <0.001 <0.001 Well/Moderate 1040 0.163 0.055 Reference Poor/Anaplastic 1431 0.034 0.008 1.708 (1.569-1.859) <0.001 Other 11032 0.050 0.018 1.476 (1.379-1.581) <0.001 Histology <0.001 <0.001 Adenocarcinoma 9845 0.036 0.007 Reference Neuroendocrine carcinoma 546 0.391 0.062 0.298 (0.269-0.330) <0.001 Other 3112 0.172 0.030 0.911(0.872-0.951) <0.001 T stage <0.001 0.006 T0 119 0.060 NA Reference T1 337 0.064 0.012 0.855 (0.689-1.064) 0.156 T2 3848 0.059 0.025 0.809 (0.643-1.018) 0.070 T3 3280 0.063 0.016 0.761 (0.606-0.956) 0.019 T4 2216 0.052 0.018 0.769 (0.612-0.968) 0.025 TX 3703 0.050 0.021 0.829 (0.660-1.040) 0.106 N stage <0.001 0.183 N0 7173 0.060 0.019 Reference N1 3904 0.056 0.022 1.037 (0.996-1.081) 0.079 NX 2426 0.048 0.017 0.998 (0.949-1.050) 0.950 Tumor Size <0.001 <0.001 ≤2 cm 714 0.065 0.021 Reference 2-4 cm 4600 0.058 0.014 1.102 (0.966-1.258) 0.148 >4 cm 5367 0.058 0.024 1.228 (1.076-1.400) 0.002 Unknown 2822 0.052 0.020 1.183 (1.033-1.354) 0.015 Insurance status <0.001 <0.001 Insured 10999 0.060 0.021 Reference Medicaid 1790 0.041 0.015 1.094 (1.036-1.154) 0.001 Uninsured/Unknown 714 0.043 0.007 1.164 (1.074-1.262) <0.001 Marital status <0.001 <0.001 Married 7210 0.071 0.024 Reference Unmarried 5662 0.038 0.014 1.116 (1.075-1.158) <0.001 Unknown 631 0.061 0.025 1.000 (0.919-1.089) 0.997 County % with bachelor degree <0.001 0.003 Below median 5815 0.053 0.016 Reference Above median 7688 0.060 0.023 0.941 (0.903-0.980) County % with unemployed 0.008 0.688 Below median 6443 0.062 0.023 Reference Above median 7060 0.052 0.017 0.992 (0.956-1.030) County-level median household income <0.001 0.182 Below median 6532 0.053 0.018 Reference Above median 6971 0.060 0.022 0.972 (0.932-1.013) Residence area 0.696 NI Metropolitan 12054 0.056 0.018 Urban/rural 1433 0.058 0.030 Missing 16 0.125 NA Radiotherapy <0.001 <0.001 Yes 367 0.112 0.009 Reference No/Unknown 13136 0.055 0.020 1.330 (1.194-1.483) Chemotherapy <0.001 <0.001 Yes 6671 0.084 0.024 Reference No/Unknown 6832 0.030 0.014 2.509 (2.413-2.608) *, Other includes American Indian/Alaska Native, Asian/Pacific Islander, and unknown. PCSS: pancreatic cancer cause-specific survival; HR: hazard ratio; CI: confidence interval; NA: not applicable; NI: not included in multivariate survival analysis. Table 5 Univariate and multivariate Cox analyses of pancreatic cancer cause-specific survival according to primary site Variable Total Median survival (months) 2-year PCSS 5-year PCSS Univariate analysis Multivariate Cox analysis P HR (95%CI) P Surgical procedure of primary site Primary Site: Head 5236 3 <0.001 <0.001 Performed 181 13 0.322 0.209 Reference Recommended but not performed 95 2 0.037 NA <0.001 3.615 (2.759-4.737) <0.001 Not recommended 4960 3 0.056 0.016 <0.001 2.681 (2.249-3.197) <0.001 Body/Tail 5113 3 <0.001 <0.001 Performed 165 38 0.633 0.405 Reference Recommended but not performed 100 2 0.061 0.037 <0.001 5.749 (4.275-7.730) <0.001 Not recommended 4848 3 0.061 0.022 <0.001 4.926 (3.952-6.141) <0.001 Other 3899 2 <0.001 <0.001 Performed 68 53 0.586 0.487 Reference Recommended but not performed 125 1 0.050 NA <0.001 5.872 (3.947-8.735) <0.001 Not recommended 3706 2 0.057 0.019 <0.001 5.197 (3.644-7.414) <0.001 Surgical Procedure of Other Sites Primary Site: Heada 5235 3 <0.001 <0.001 Not performed 5022 3 0.058 0.019 Reference Liver resection 125 8 0.239 0.140 <0.001 0.519 (0.426-0.633) <0.001 Other resection 88 8 0.196 0.103 <0.001 0.549 (0.436-0.691) <0.001 Body/Tailb 5111 3 <0.001 <0.001 Not performed 4926 3 0.069 0.028 Reference Liver resection 106 11 0.372 0.229 <0.001 0.395 (0.314-0.497) <0.001 Other resection 79 13 0.382 0.245 <0.001 0.376 (0.287-0.492) <0.001 Otherc 3895 2 <0.001 <0.001 Not performed 3787 2 0.060 0.024 Reference Liver resection 57 7 0.283 0.136 <0.001 0.513 (0.383-0.687) <0.001 Other resection 51 11 0.298 0.201 <0.001 0.413 (0.299-0.568) <0.001 Radiotherapyd Primary Site: Head 4899 3 <0.001 <0.001 Yes 173 6 0.103 NA Reference No/Unknown 4726 3 0.052 0.018 1.431 (1.225-1.673) Body/Tail 4856 3 <0.001 <0.001 Yes 111 5 0.122 0.030 Reference No/Unknown 4745 2 0.060 0.023 1.439 (1.184-1.750) Other 3748 2 <0.001 <0.001 Yes 83 8 0.121 NA Reference No/Unknown 3665 2 0.053 0.019 1.736 (1.377-2.190) Chemotherapyd Primary Site: Head 4899 3 <0.001 <0.001 Yes 2453 7 0.077 0.018 Reference No/Unknown 2446 1 0.031 0.014 2.572 (2.422-2.731) Body/Tail 4856 3 <0.001 <0.001 Yes 2579 6 0.088 0.028 Reference No/Unknown 2277 1 0.031 0.017 2.540 (2.390-2.699) Other 3748 2 <0.001 <0.001 Yes 1639 6 0.089 0.029 Reference No/Unknown 2109 1 0.027 0.012 2.456 (2.291-2.632) a, Excluding one patient in whom surgical procedures of other sites was unknown. b, Excluding two patients in whom surgical procedures of other sites was unknown. c, Excluding four patients in whom surgical procedures of other sites was unknown. d, Patients who did not undergo resection. PCSS: pancreatic cancer cause-specific survival; HR: hazard ratio; CI: confidence interval; NA: not applicable. Table 6 Univariate and multivariate Cox analyses to evaluate pancreatic cancer cause-specific survival with histology and combined therapies Variable Total Median survival (months) 2-year PCSS 5-year PCSS Univariate analysis Multivariate Cox analysis P HR (95%CI) P Total 13916 3 <0.001 <0.001 No resection 13503 3 0.057 0.019 Reference SPS 232 15 0.392 0.246 <0.001 0.329 (0.281-0.386) <0.001 SPL 93 54 0.683 0.497 <0.001 0.162 (0.118-0.222) <0.001 SPO 88 34 0.551 0.391 <0.001 0.220 (0.164-0.294) <0.001 Histology Adenocarcinoma 9973 3 <0.001 <0.001 No resection 9845 3 0.036 0.006 Reference SPS 86 9 0.191 0.065 <0.001 0.495 (0.394-0.621) <0.001 SPL 20 8 0.343 NA <0.001 0.360 (0.215-0.614) <0.001 SPO 22 11 0.333 0.133 <0.001 0.361 (0.224-0.581) <0.001 Neuroendocrine carcinoma 658 21 <0.001 <0.001 No resection 546 15 0.391 0.172 Reference SPS 41 NA 0.863 0.549 <0.001 0.290 (0.173-0.486) <0.001 SPL 39 NA 0.873 0.665 <0.001 0.193 (0.103-0.363) <0.001 SPO 32 NA 0.746 0.607 <0.001 0.278 (0.152-0.506) <0.001 Other 3285 1 <0.001 <0.001 No resection 3112 1 0.062 0.030 Reference SPS 105 15 0.367 0.283 <0.001 0.312 (0.244-0.398) <0.001 SPL 34 43 0.673 0.443 <0.001 0.191 (0.115-0.318) <0.001 SPO 34 24 0.486 0.312 <0.001 0.251 (0.158-0.400) <0.001 SPS 232 15 0.472a 0.705 No/Unknown 97 15 0.420 0.352 Reference Chemoradiotherapy 9 18 0.444 NA 0.839 1.084 (0.493-2.382) 0.841 Chemotherapy* 124 15 0.362 0.178 0.423 1.152 (0.826-1.607) 0.403 Radiotherapy# 2 - - - SPL 93 54 0.182b 0.198 No/Unknown 60 NA 0.749 0.589 Reference Chemoradiotherapy 5 23 0.400 NA 0.615 1.480 (0.342-6.401) 0.600 Chemotherapy* 26 42 0.321 NA 0.071 1.838 (0.945-3.576) 0.073 Radiotherapy# 2 - - - SPO 88 33 0.340c 0.353 No/Unknown 38 53 0.673 0.438 Reference Chemoradiotherapy 7 34 0.536 0.357 0.662 1.266 (0.426-3.768) 0.671 Chemotherapy* 42 16 0.436 0.355 0.145 1.577 (0.849-2.929) 0.149 Radiotherapy# 1 - - - No resection 13503 3 <0.001 <0.001 No/Unknown 6736 1 0.029 0.015 Reference Chemoradiotherapy 271 8 0.119 0.011 <0.001 0.332 (0.292-0.377) <0.001 Chemotherapy* 6400 6 0.083 0.025 <0.001 0.394 (0.379-0.408) <0.001 Radiotherapy# 96 3 0.091 NA <0.001 0.569 (0.462-0.699) <0.001 *, No/unknown radiotherapy. #, No/unknown chemotherapy. a, Analysis did not include the radiotherapy group because there were only two patients who received radiotherapy. b, Analysis did not include the radiotherapy group because there were only two patients who received radiotherapy. c, Analysis did not include the radiotherapy group because there was only one patient who received radiotherapy. PCSS: pancreatic cancer cause-specific survival; HR: hazard ratio; CI: confidence interval; SPL: synchronous resection of the primary tumor and liver metastases; SPO: synchronous primary tumor and other resection; SPS: single resection of the primary site; NA: not applicable. ==== Refs 1 Tempero MA NCCN Guidelines Updates: Pancreatic Cancer J Natl Compr Canc Netw 2019 17 603 5 31117041 2 Siegel RL Miller KD Jemal A Cancer statistics, 2017 CA Cancer J Clin 2017 67 7 30 28055103 3 Silverberg E Lubera J Cancer statistics, 1987 CA Cancer J Clin 1987 37 2 19 3099992 4 Heinemann V Haas M Boeck S Systemic treatment of advanced pancreatic cancer Cancer Treat Rev 2012 38 843 53 22226241 5 Conroy T Desseigne F Ychou M FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer N Engl J Med 2011 364 1817 25 21561347 6 Moore MJ Goldstein D Hamm J Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group J Clin Oncol 2007 25 1960 6 17452677 7 Allendorf JD Lauerman M Bill A Neoadjuvant chemotherapy and radiation for patients with locally unresectable pancreatic adenocarcinoma: feasibility, efficacy, and survival J Gastrointest Surg 2008 12 91 100 17786524 8 Seufferlein T Porzner M Becker T S3-guideline exocrine pancreatic cancer Z Gastroenterol 2013 51 1395 440 24338757 9 Tempero MA Malafa MP Behrman SW Pancreatic adenocarcinoma, version 2.2014: featured updates to the NCCN guidelines J Natl Compr Canc Netw 2014 12 1083 93 25099441 10 Klein F Puhl G Guckelberger O The impact of simultaneous liver resection for occult liver metastases of pancreatic adenocarcinoma Gastroenterol Res Pract 2012 2012 939350 23258977 11 Stein A Bokemeyer C How to select the optimal treatment for first line metastatic colorectal cancer World J Gastroenterol 2014 20 899 07 24574764 12 Pawlik TM Vauthey JN Abdalla EK Results of a single-center experience with resection and ablation for sarcoma metastatic to the liver Arch Surg 2006 141 537 543 16785353 13 Shrikhande SV Kleeff J Reiser C Pancreatic resection for M1 pancreatic ductal adenocarcinoma Ann Surg Oncol 2007 14 118 27 17066229 14 Tachezy M Gebauer F Janot M Synchronous resections of hepatic oligometastatic pancreatic cancer: disputing a principle in a time of safe pancreatic operations in a retrospective multicenter analysis Surgery 2016 160 136 44 27048934 15 Gleisner AL Assumpcao L Cameron JL Is resection of periampullary or pancreatic adenocarcinoma with synchronous hepatic metastasis justified? Cancer 2007 110 2484 92 17941009 16 Takada T Yasuda H Amano H Simultaneous hepatic resection with pancreato-duodenectomy for metastatic pancreatic head carcinoma: does it improve survival? Hepatogastroenterology 1997 44 567 73 9164539 17 Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 18 Regs Custom Data (with additional treatment fields), Nov 2018 Sub (1975-2016 varying) - Linked To County Attributes - Total U.S, 1969-2017 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, released April 2019, based on the November 2018 submission 18 Tachezy M Bockhorn M Gebauer F Bypass surgery versus intentionally incomplete resection in palliation of pancreatic cancer: is resection the lesser evil? J Gastrointest Surg 2011 15 829 35 21359594 19 Burdelski CM Reeh M Bogoevski D Multivisceral resections in pancreatic cancer: identification of risk factors World J Surg 2011 35 2756 63 21938586 20 Bockhorn M Burdelski C Bogoevski D Arterial en bloc resection for pancreatic carcinoma Br J Surg 2011 98 86 92 21136564 21 Bockhorn M Cataldegirmen G Kutup A Crossing the Rubicon: when pancreatic resection with curative intent ends in an R2 status. Impact of “desmoplastic pseudo-pancreatitis” and anatomical site of irresectability Ann Surg Oncol 2009 16 1212 21 19225843 22 McKenzie S Mailey B Artinyan A The incidence and outcomes of pancreatectomy in patients with metastatic pancreatic adenocarcinoma JOP 2010 11 341 7 20601808 23 Michalski CW Erkan M Hüser N Resection of primary pancreatic cancer and liver metastasis: a systematic review Dig Surg 2008 25 473 80 19212120 24 Dünschede F Will L von Langsdorf C Treatment of metachronous and simultaneous liver metastases of pancreatic cancer Eur Surg Res 2010 44 209 13 20571276