Clinical Outcomes of Surgery after Neoadjuvant Chemotherapy in Locally Advanced Pancreatic Ductal Adenocarcinoma

Yoo Na Lee; Min Kyu Sung; Dae Wook Hwang; Yejong Park; Bong Jun Kwak; Woohyung Lee; Ki Byung Song; Jae Hoon Lee; Changhoon Yoo; Kyu-Pyo Kim; Heung-Moon Chang; Baek-Yeol Ryoo; Song Cheol Kim

doi:10.4143/crt.2023.977

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Original Article Gastrointestinal cancer Clinical Outcomes of Surgery after Neoadjuvant Chemotherapy in Locally Advanced Pancreatic Ductal Adenocarcinoma: Yoo Na Lee^1,a), Min Kyu Sung¹, Dae Wook Hwang¹, Yejong Park¹, Bong Jun Kwak¹, Woohyung Lee¹, Ki Byung Song¹, Jae Hoon Lee¹, Changhoon Yoo², Kyu-Pyo Kim², Heung-Moon Chang², Baek-Yeol Ryoo², Song Cheol Kim^1,3,; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2024;56(4):1240-1251.
DOI: https://doi.org/10.4143/crt.2023.977
Published online: June 19, 2024

¹Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

²Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

³Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Correspondence: Song Cheol Kim, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Brain Korea 21 Plus, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
Tel: 82-2-3010-3936 Fax: 82-2-2045-4232 E-mail: drksc@amc.seoul.kr

a)Present address: Department of Surgery, Inje University Haeundae Paik Hospital, Busan, Korea

• Received: August 28, 2023 • Accepted: June 10, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract

Purpose
Clinical outcomes of surgery after neoadjuvant chemotherapy have not been investigated for locally advanced pancreatic cancer (LAPC), despite well-established outcomes in borderline resectable pancreatic cancer (BRPC). This study aimed to investigate the clinical outcomes of patients with LAPC who underwent curative resection following neoadjuvant chemotherapy.
Materials and Methods
We retrospectively reviewed the records of patients diagnosed with pancreatic adenocarcinoma between January 2017 and December 2020.
Results
Among 1,358 patients, 260 underwent surgery following neoadjuvant chemotherapy. Among 356 LAPC patients, 98 (27.5%) and 147 (35.1%) of 418 BRPC patients underwent surgery after neoadjuvant chemotherapy. Compared to resectable pancreatic cancer (resectable PC) with upfront surgery, both LAPC and BRPC exhibited higher rates of venous resection (28.6% vs. 49.0% vs. 4.0%), arterial resection (30.6% vs. 6.8% vs. 0.5%) and greater estimated blood loss (260.5 vs. 213.1 vs. 70.4 mL). However, hospital stay, readmission rates, and postoperative pancreatic fistula rates (grade B or C) did not differ significantly between LAPC, BRPC, and resectable PC. Overall and relapse-free survival did not differ significantly between LAPC and BRPC patients. The median overall survival was 37.3 months for LAPC and 37.0 months for BRPC. The median relapse-free survival was 22.7 months for LAPC and 26.0 months for BRPC.
Conclusion
Overall survival time and postoperative complications in LAPC patients who underwent curative resection following neoadjuvant chemotherapy showed similar results to those of BRPC patients. Further research is needed to identify specific sub-populations of LAPC patients who benefit most from conversion surgery and to minimize postoperative complications.
Key words: Pancreatic neoplasms, Neoadjuvant therapy, Locally advanced pancreatic cancer, Borderline resectable pancreatic cancer

Introduction

Pancreatic cancer has a very low survival rate because majority of the cases are fatal (94.0%). It was the seventh leading cause of death from cancer in both men and women in 2020 worldwide [1]. In many countries, its morbidity and mortality exhibit a stable or slightly increasing trend, which may be associated with the rising prevalence of obesity, diabetes, and alcohol consumption. This trend is projected to continue [2]. Although surgery is the most effective treatment for pancreatic cancer, most cases are already inoperable when diagnosed, thus affecting the prognosis [3,4].

The majority of pancreatic cancer patients present with nonspecific symptoms that have progressed to a stage where surgical treatment is no longer viable. Consequently, surgery is often unfeasible upon diagnosis [5,6]. In addition, the pancreas is very close to major blood vessels, such as the superior mesenteric artery (SMA), superior mesenteric vein (SMV), portal vein (PV), common hepatic artery, and celiac axis (CA), in the abdominal cavity. Hence, when considering the resectability of pancreatic cancer, the degree of invasion and abutment with major blood vessels around the pancreas are evaluated along with lymph node metastasis or distant metastasis [7,8]. Owing to these characteristics of pancreatic cancer, guidelines of the National Comprehensive Cancer Network (NCCN), Americas Hepato-Pancreato-Biliary Association, Society of Surgical Oncology, and the Society for Surgery of the Alimentary Tract were used to define its clinical stages [9,10].

According to the NCCN guidelines, pancreatic cancer with no metastasis can be classified as resectable, borderline resectable, and locally advanced cancers [10]. Recently, intensive chemotherapy strategies, including the use of fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX), and gemcitabine+nab-paclitaxel, have been introduced for patients with borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) [11]. These multimodal treatments, including chemotherapy and radiation therapy, make LAPC and BRPC patients suitable for surgical resection [11-13]. In addition, several recent studies have reported positive effects on prognosis following surgery after neoadjuvant chemotherapy (NACT) in LAPC patients [14-16]. In these patients, surgery presents technical challenges due to the presence of significant vascular complications prior to NACT. Therefore, this study investigated the clinical outcomes of LAPC patients who had undergone surgery after neoadjuvant chemotherapy.

Materials and Methods

1. Patients

We retrospectively reviewed the records of patients who were diagnosed with resectable, borderline resectable, or locally advanced pancreatic adenocarcinoma between January 2017 and December 2020, at the Department of Surgery, Asan Medical Center, Seoul, Korea. A total of 1,358 patients were diagnosed with pancreatic ductal adenocarcinoma (PDAC) and treated; 941 patients ultimately underwent curative resection, and 250 patients got surgery after NACT (IRB approval number: 2016-0902).

Baseline characteristics, pathology, and clinical outcomes were reviewed retrospectively from a database. Clinical staging was determined by computed tomography (CT), magnetic resonance imaging (MRI), and fluorodeoxyglucose– positron emission tomography (PET)-CT. The NCCN Clinical Practice Guidelines, 2022 was used to determine the resectability status based on image studies as follows: contact with > 180º of the celiac trunk or SMA, direct invasion into the aorta, and unreconstructible SMV/PV due to tumor involvement, occlusion, or suspected distant metastases [10]. When a patient was diagnosed with PDAC, the presence of metastasis was determined primarily on PET-CT or other radiologic findings, and the patient underwent palliative chemotherapy. Moreover, to determine the resectability of cancer, the radiologist first reviewed the CT and MRI images, and the operator and oncologist secondarily checked the images. Patients with PDAC without metastasis were classified as having resectable pancreatic cancer, BRPC, or LAPC [10]. If BRPC or LAPC was thought to be on the baseline image, most of the patients underwent NACT and were transferred for surgery, according to the guidelines [10,17].

Endoscopic retrograde cholangiopancreatography was performed to confirm tissue for patients who thought they needed prior chemotherapy. After histological diagnosis of pancreatic ductal adenocarcinoma, NACT was performed. FOLFIRINOX, a first-line chemotherapy that has recently shown improved efficacy, was administered to some patients, while nab-paclitaxel plus gemcitabine was administered to some patients [18-20]. FOLFIRINOX contained oxaliplatin, irinotecan, leucovorin, and fluorouracil. Intravenous infusion of these agents was administered every 2 weeks, and the tumor response was assessed by CT every 6 to 8 weeks.

For adjuvant chemotherapy after surgery, modified FOLFIRINOX (mFOLFIRINOX) was the most frequently administered regimen, followed by gemcitabine monotherapy and gemcitabine-capecitabine. Postoperative mFOLFIRINOX, containing 2,400 mg/m² of 5-fluorouracil continuous intravenous infusion for 46 hours (day 1-2), 400 mg/m² of folinic acid intravenous infusion (day 1), 85 mg/m² of oxaliplatin intravenous infusion (day 1), and 150 mg/m² of irinotecan intravenous infusion (day 1), was administered every 2 weeks for 4 cycles. Gemcitabine was administered every 4 weeks for 3 cycles, with an option of up to 6 cycles at the physician’s discretion.

Our results suggest that even LAPC patients who have more advanced disease than that of BRPC patients can have positive survival outcomes similar to those of BRPC patients following successful neoadjuvant chemoradiation and radical resection. For patients who were considered for surgical resection, surgery was performed 4-6 weeks after the last treatment. We excluded BRPC and LAPC patients who had undergone upfront surgery.

2. Evaluation

CT images of resectable pancreatic cancer showed that the solid tumor was slightly distant from major blood vessels such as the SMV and SMA. In BRPC, invasion of < 180° to the SMV was observed, and the SMV had contour irregularities. Also in BRPC, solid tumors were not attached to the SMA. NCCN guidelines define LAPC patients as follows: > 180º SMA and CA abutment, aortic involvement, and unreconstructible SMV/PV due to tumor involvement or occlusion. After neoadjuvant chemotherapy, the Response Evaluation Criteria in Solid Tumors (RECIST) were used to evaluate the response: complete response, partial response (PR), stable disease (SD), and progressive disease (PD) [21].

The following characteristics of patients were analyzed for each patient: age at surgery, sex, body mass index (BMI), carbohydrate antigen 19-9 (CA 19-9), and carcinoembryonic antigen (CEA). For patients who received neoadjuvant chemotherapy, tumor markers (CEA and CA 19-9) and BMI were measured at the time of initial diagnosis. Operative outcomes were analyzed for each patient: postoperative complications, postoperative pancreatic fistula (POPF), operative time, length of postoperative hospital stay, and estimated blood loss (EBL). Postoperative complications and POPF were retrospectively categorized using established grading systems: the Clavien-Dindo classification for overall complications (grades I-V) and the International Study Group on Pancreatic Fistula classification for POPF (grades A-C). Clavien-Dindo classes I and II mainly refer to cases requiring only pharmacological treatment, class III refers to cases requiring surgical, endoscopic, and radiological intervention, class IV refers to cases requiring admission to an intensive care unit, and class V refers to cases resulting in death [22]. POPF grade A indicates biochemical leakage, grade B refers to cases requiring pharmacological treatment, and grade C refers to cases requiring interventional treatment [23]. Operative time was calculated as the time from skin incision to skin closure. EBL, the amount of blood the patient lost, was calculated using the following formula:

EBV×Hi–Hf(Hi+Hf)2+(400×Tu).

EBV indicates the estimated blood volume (70 cm³/kg), Hi indicates initial hemoglobin (Hgb), Hf indicates immediate postoperative (Hgb), and Tu indicates total transfused packed red blood cells. Negative values imputed into this formula were treated as zero in the statistical analysis [24].

We conducted a retrospective analysis to investigate the efficacy and safety of NACT in LAPC patients. We retrospectively assessed the overall survival, recurrence-free survival, and post-surgical complications in LAPC or BRPC patients who had undergone neoadjuvant therapy followed by surgery. Overall survival was defined as the time from surgery to death from any cause, and recurrence-free survival was defined as the interval between surgery and the first occurrence of either recurrence or death from any cause.

We compared the overall survival between LAPC patients receiving chemotherapy alone after confirmed PR or SD following NACT and those undergoing neoadjuvant therapy followed by surgery. Overall survival was re-defined as the time from chemotherapy initiation to death from any cause in this analysis. This comparison was made to indirectly assess the role of surgery in patients who undergo NACT followed by surgery by comparing those with similar disease conditions in LAPC patients.

3. Statistical analysis

Continuous variables were analyzed using independent t tests and are expressed as means with standard deviations. Categorical variables were analyzed using chi-square or Fisher’s exact test and are expressed as percentages and numbers. Overall survival and recurrence-free survival were evaluated using the Kaplan-Meier method, and comparisons were made between the two groups using the log-rank test. The Cox-proportional hazards model was used to perform univariate and multivariate analyses of the outcomes. Based on the hazard ratio (HR) and 95% confidence intervals (CIs), independent significant factors related to postoperative death and recurrence were analyzed.

Results

1. Patients characteristics

Among 1,358 patients diagnosed with PDAC who received treatment, 569 were confirmed to have resectable pancreatic cancer and immediately underwent upfront surgery, 418 were confirmed to have BRPC, and 356 were confirmed to have LAPC, according to preoperative images (Fig. 1). Among BRPC patients, 100 (23.9%) underwent upfront surgery and 318 (76.1%) received neoadjuvant chemotherapy. After neoadjuvant chemotherapy, 147 (35.1%) among the 418 patients with BRPC underwent surgery. Among LAPC patients, 12 (3.4%) underwent upfront surgery and 344 (96.6%) received neoadjuvant chemotherapy. After neoadjuvant chemotherapy, 98 (27.5%) among the 356 patients with LAPC underwent surgery (Fig. 1).

2. Comparing peri-operative characteristics in resectable pancreatic cancer, LAPC, and BRPC patients who underwent NACT followed by surgery

Among the patients confirmed to have LAPC, 12 patients underwent upfront surgery and 344 patients underwent neoadjuvant chemotherapy. Conversion surgery was performed in cases with PR or SD according to radiographic images, and 98 patients underwent surgery. In addition, NACT was administered to the remaining patients, except for 100 patients who underwent upfront surgery among the BRPC patients, 147 of whom underwent conversion surgery based on imaging.

Table 1 shows the demographic and clinical characteristics of LAPC patients who underwent surgery after neoadjuvant chemotherapy, BRPC patients who underwent surgery after neoadjuvant chemotherapy, and patients with resectable pancreatic cancer who underwent upfront surgery. Among LAPC and BRPC patients, the proportion of younger patients who underwent surgery after NACT was significantly higher than that of patients with resectable pancreatic cancer (< 65 years; 67.3% vs. 61.2% vs. 46.0%; p < 0.001) (Table 1). No significant differences in sex and BMI were observed.

The mean baseline CA 19-9 level in LAPC (1,409.6±370.6 U/mL) and BRPC (1,581.4±734.2 U/mL) patients was significantly higher than in resectable pancreatic cancer (1,037.7 ±638.8 U/mL) patients (Table 1). However, the mean baseline CEA level was highest in LAPC (8.1±1.8 ng/mL) patients, followed by resectable pancreatic cancer (4.3±0.3 ng/mL), and BRPC (3.8±0.2 ng/mL) patients (Table 1). LAPC patients also had a significantly higher proportion of elevated CEA before treatment than that of patients with resectable pancreatic cancer (30.2% vs. 17.7%, p=0.004, chi-square test). However, the proportions of LAPC and BRPC patients with high CA 19-9 did not differ significantly from that of resectable pancreatic cancer patients.

The average initial tumor size in LAPC was 3.70 cm, while in BRPC, it was 3.17 cm, which was not significantly different from the average size of the initial tumor in resectable pancreatic cancer (Table 1). Regarding the tumor status just before surgery in patients who underwent neoadjuvant chemotherapy, we currently lack individual reliable size data. However, we have data on the response status measured by the oncologist. Of the LAPC patients, 58.2% achieved a PR, 39.8% exhibited SD, and 2% exhibited PD.

The location of the tumor at the time of diagnosis was classified as head, body, tail, and multicentric. Among LAPC patients, 52 (53.1%) had pancreatic head cancer, 40 (40.8%) had pancreatic body cancer, five (5.1%) had pancreatic tail cancer, and one (1.0%) had multicentric cancer (Table 1). In BRPC, 119 patients (81.0%) had pancreatic head cancer, 23 (15.6%) had pancreatic body cancer, four (2.7%) had pancreatic tail cancer, and one (0.7%) had multicentric cancer (Table 1). For resectable pancreatic cancer, 304 patients (53.4%) had pancreatic head cancer, 126 (22.1%) had pancreatic body cancer, 137 (24.1%) had pancreatic tail cancer, and two (0.4%) had multicentric cancer (Table 1). No significant difference in overall survival was observed according to location in patients with resectable pancreatic cancer (head vs. body vs. tail; 37.8 months [95% CI, 35.5 to 40.1] vs. 40.9 months [95% CI, 37.1 to 44.7] vs. 36.6 months [95% CI, 32.5 to 40.7]; p=0.392). In LAPC patients, no significant difference was observed according to location (head vs. body vs. tail; 39.4 months [95% CI, 32.7 to 46.1] vs. 33.4 months [95% CI, 25.3 to 41.6] vs. 27.6 months [95% CI, 18.2 to 37.1]; p=0.390). Also, no significant difference was observed according to location in BRPC patients (head vs. body; 39.1 months [95% CI, 33.8 to 44.2] vs. 32.1 months [95% CI, 24.7 to 39.5]; p=0.278).

Comparing the NACT regimen in LAPC and BRPC patients, no significant difference was observed in the proportion of patients that received FOLFIRINOX (80.8% vs. 84.4%, p=0.337) (Table 1). However, when comparing the duration of neoadjuvant chemotherapy, a significant difference was observed between LAPC and BRPC (4.71 months vs. 2.97 months, p < 0.001) (Table 1).

LAPC patients (93.9% vs. 84.2%, p=0.012) and BRPC (97.3% vs. 84.2%, p < 0.001) who underwent surgery after NACT had higher compliance with postoperative adjuvant chemotherapy than patients with resectable pancreatic cancer who underwent upfront surgery. Adjuvant chemotherapy regimen can be classified into three groups: gemcitabine-based chemotherapy, mFOLFIRINOX, and others. Compared to the group that underwent upfront surgery, the rate of using FOLFIRINOX as the adjuvant chemotherapy regimen was significantly higher in the LAPC (57.6% vs. 16.9%, p < 0.001) and BRPC (46.9% vs. 16.9%, p < 0.001) groups (Table 1).

In Table 2, we compared the surgical characteristics of LAPC patients who underwent surgery after NACT, BRPC patients who underwent surgery after NACT, and patients with resectable pancreatic cancer who underwent surgery. Among LAPC patients, 40 (50.0%) underwent pancreaticoduodenectomy, 41 (41.8%) underwent distal pancreatectomy, and eight (8.2%) underwent total pancreatectomy (Table 2). Among BRPC patients, 118 (80.3%) underwent pancreaticoduodenectomy, 24 (16.3%) underwent distal pancreatectomy, and five (3.4%) underwent total pancreatectomy (Table 2). Among patients with resectable pancreatic cancer, 336 (59.1%) underwent pancreaticoduodenectomy, 226 (39.7%) underwent distal pancreatectomy, and seven (1.2%) underwent total pancreatectomy (Table 2). This confirmed that there was a significant difference in the proportion of tumor location between LAPC patients (p < 0.001), BRPC (p < 0.001), and resectable pancreatic cancer (Table 2). A higher proportion of LAPC patients underwent venous resection (28.6% vs. 4.0%, p < 0.001) and arterial resection (30.6% vs. 0.5%, p < 0.001) than that of patients with resectable pancreatic cancer (Table 2). Even in BRPC patients, venous resection (49.0% vs. 4.0%, p < 0.001) and arterial resection (6.8% vs. 0.5%, p < 0.001) were confirmed in a higher proportion than in patients with resectable pancreatic cancer (Table 2).

The median EBL of LAPC patients was 260.5 mL (standard deviation, 488.4), whereas that of BRPC patients was 213.1 mL (standard deviation, 30.9) (Table 2). EBL was significantly greater in LAPC and BRPC groups than in the resectable pancreatic cancer group (Table 2). However, no significant difference in mean operative time was observed among the three groups (Table 2). In LAPC patients, the average length of hospital stay was 12.9 days (standard deviation, 10.8), and the difference was not statistically significant compared to that of patients with resectable pancreatic cancer (> 14 days; 17.3% vs. 14.6%; p=0.480) (Table 2). In BRPC patients, the average length of hospital stay was 12.7 days (standard deviation, 6.7), and the difference was also not statistically significant compared to that of patients with resectable pancreatic cancer (> 14 days; 24.5% vs. 14.6%; p=0.729) (Table 2). Three LAPC patients (3.1% vs. 4.0%; p=0.643) and nine BRPC patients (6.1% vs. 4.0%; p=0.277) were discharged and re-hospitalized after surgery, and no significant difference was observed in patients with resectable pancreatic cancer (Table 2).

Both LAPC and BRPC presented with overall complication rates (Clavien-Dindo) similar to that of resectable pancreatic cancer: 29.6% (29 patients) for LAPC and 24.5% (36 patients) for BRPC, compared to 21.8% in resectable pancreatic cancer (p=0.090 and p=0.484, respectively). Clinically significant POPF (grade B and C) rates did not differ significantly between LAPC and resectable pancreatic cancer patients: 8.1% (8 patients) in LAPC vs. 7.2% (8 patients) in resectable pancreatic cancer (p=0.737) (Table 2). Similarly, no significant difference in POPF was observed between BRPC patients and those with resectable pancreatic cancer: 5.4% (8 patients) vs. 7.2% (8 patients) (p=0.450) (Table 2).

Regarding pathological characteristics, the median tumor size in LAPC was significantly smaller than that in resectable pancreatic cancer (2.4 cm vs. 3.0 cm, p=0.010) (Table 3). However, no significant difference in tumor size was observed between BRPC and resectable pancreatic cancer (2.6 cm vs. 3.0 cm, p=0.293) (Table 3). In terms of T category, the ratio of T1 was significantly higher in LAPC than in resectable pancreatic cancer (35.7% vs. 22.0%, p < 0.001). The ratio of T1 was also significantly higher in BRPC than in resectable pancreatic cancer (30.6% vs. 22.0%, p=0.041) (Table 3). In LAPC, the rate of positive nodes was significantly lower than that of resectable pancreatic cancer (36.7% vs. 51.0%, p=0.034); however, no significant difference was observed between that of BRPC and resectable pancreatic cancer (48.3% vs. 51.0%, p=0.688) (Table 3). LAPC and BRPC used ypTNM staging after NACT. The proportion of stage I was significantly higher in LAPC patients than in those with resectable pancreatic cancer (50.0% vs. 43.9%, p < 0.001). It was also significantly higher in BRPC patients than in those with resectable pancreatic cancer (49.7% vs. 43.9%, p=0.018) (Table 3). The confirmed lymphovascular invasion (LVi) rate was significantly lower in LAPC patients than in those with resectable pancreatic cancer (29.6% vs. 50.2%, p < 0.001); it was also significantly lower in BRPC patients than in those with resectable pancreatic cancer (42.9% vs. 50.2%, p < 0.001) (Table 3). In terms of perineural invasion (PNi), the positive rate was significantly lower in LAPC patients than in those with resectable pancreatic cancer (62.2% vs. 73.1%, p=0.028); however, no significant difference was observed between that of BRPC and resectable pancreatic cancer (67.3% vs 73.1%, p=0.166) (Table 3). The R1 rate was not significantly different between LAPC and BRPC, compared to that of resectable pancreatic cancer (15.3% vs. 12.9% vs. 17.0%) (Table 3).

3. Comparing survival after NACT followed by surgery in LAPC vs. BRPC patients

The median overall survival of patients in the cohort was 43 months (range, 0 to 71 months). Seventy-three BRPC patients (49.7%) who underwent surgery after NACT died, while 54 LAPC patients (55.1%) who underwent surgery after NACT died. Fig. 2 shows the survival curves of BRPC patients who underwent surgery after NACT, and of LAPC patients who underwent surgery after NACT. The median overall survival of LAPC patients who underwent surgery after NACT was 37.3 months (95% CI, 32.4 to 42.2), while the median overall survival of BRPC patients who underwent surgery after NACT was 37.0 months (95% CI, 32.6 to 41.3). No statistically significant differences were observed between the groups (p=0.822).

Recurrence occurred in 470 patients (57.7%) in the cohort. The number of recurrences among BRPC patients who underwent surgery after NACT was 98 (66.7%), while that for LAPC patients who underwent surgery after NACT was 73 (74.5%). Fig. 3 shows the relapse-free survival curves of BRPC patients who underwent surgery after NACT, and of LAPC patients who underwent surgery after NACT. The median recurrence-free survival of LAPC patients who underwent surgery after NACT was 22.7 months (95% CI, 17.9 to 27.5) and the median overall survival of BRPC patients who underwent surgery after NACT was 26.0 months (95% CI, 21.7 to 30.3). No statistically significant difference was observed between the groups (p=0.228).

Additionally, we retrospectively analyzed the survival outcome of patients with resectable pancreatic cancer who underwent upfront surgery (Fig. 4). Fig. 4 shows the survival outcomes of patients with resectable pancreatic cancer who underwent upfront surgery. It includes overall survival and recurrence-free survival curves. The median overall survival of resectable pancreatic cancer was 38.4 months (95% CI, 36.6 to 40.2) and the median recurrence-free survival of resectable pancreatic cancer was 32.3 months (95% CI, 30.2 to 34.4).

4. Comparing overall survival in LAPC between patients who underwent NACT followed by surgery and chemotherapy-only treatment

Ninety-eight LAPC patients underwent curative resection after NACT, and chemotherapy was continued in 246 (Fig. 1). Among the 211 LAPC patients who received only chemotherapy, 28 and 183 were confirmed to have PR or SD, respectively, after NACT.

The median overall survival of LAPC patients who underwent surgery after NACT was 43.2 months (95% CI, 38.4 to 48.1 months), while that of LAPC patients who received only chemotherapy despite SD or PR after NACT was 21.5 months (95% CI, 19.7 to 23.3 months). Fig. 5 shows the overall survival curves of patients who underwent surgery after NACT and patients who were confirmed to have PR and SD among patients who received only chemotherapy. Overall survival was re-defined as the time from chemotherapy initiation to death from any cause in this analysis. In LAPC, patients who underwent surgery after NACT showed a better survival rate than those who received only chemotherapy, as confirmed by PR and SD (p < 0.001).

Discussion

Our comparison of operative outcomes between patients who underwent surgery after NACT for LAPC and those who underwent surgery for resectable pancreatic cancer yielded similar results to our corresponding comparison between BRPC and resectable pancreatic cancer patients. The rate of receiving adjuvant therapy after surgery was significantly higher in LAPC and BRPC patients than in patients with resectable pancreatic cancer. In terms of operative characteristics, significant differences in tumor location, high vascular resection rates, and high EBL for LAPC and BRPC were observed, compared with those of resectable pancreatic cancer. Notably, while operation times for BRPC were longer than that of resectable pancreatic cancer, this difference was not statistically significant for LAPC. However, no significant differences were observed in indicators of patient outcomes after surgery, such as hospital stay, readmission rate, complication rate, and POPF rate. In terms of pathological outcomes, LAPC patients exhibited smaller tumor size, higher T1 ratios, higher N0 ratios, higher stage I ratios, and significantly lower LVi and PNi ratios than those of resectable pancreatic cancer. For BRPC, higher stage 1 and LVi positive ratios than that of resectable pancreatic cancer were observed. No significant differences in overall survival and recurrence-free survival were observed between LAPC and BRPC patients who underwent surgery after NACT. Particularly for LAPC patients, those who underwent surgery after NACT had significantly better survival rates than patients who received only chemotherapy, although initial NACT outcomes were similar.

Our study revealed that indicators such as T category, stage, and LVi were significantly better for both LAPC and BRPC than for resectable pancreatic cancer. This favorable outcome is likely attributed to the effect of NACT [25,26]. Notably, LAPC patients had significantly smaller tumor sizes, higher N0 ratios, and a lower prevalence of positive PNi than patients with resectable pancreatic cancer, which contrasts with BRPC results. The mean operative times for LAPC and BRPC were longer than that for resectable pancreatic cancer. This difference was not statistically significant for LAPC (4.71 vs. 2.97 months, p < 0.001) [26].

The proximity of the pancreas to major vessels, such as the PV, SMV/artery, hepatic artery, and celiac trunk, explains why invasion of these vessels is common in advanced pancreatic cancer. The NCCN guideline defines BRPC as a case with < 180º involvement of the SMV and PV. The focus on vein invasion in BRPC, compared to the emphasis on involvement of major arteries in LAPC, suggests a difference in the surgical approach [15]. Consequently, BRPC patients primarily require vein resection, whereas LAPC patients may need arterial and/or vein resection. Consistent with this, our results show a higher percentage of arterial resections in LAPC than that in BRPC (30.6% vs. 6.8%). Therefore, the distinct surgical needs likely stem from the differences in tumor location at diagnosis reflected in the definitions of LAPC and BRPC [27].

While the average operative time was longer for both LAPC and BRPC than that for resectable pancreatic cancer, this difference was not statistically significant for LAPC. When undergoing surgery after NACT in LAPC and BRPC, technical difficulties are anticipated, especially compared with surgery for resectable pancreatic cancer [28]. However, no significant differences in postoperative outcomes were observed in both LAPC and BRPC, compared with that in resectable pancreatic cancer. Hence, NACT is not likely to adversely affect postoperative outcomes [29]. Recurrence after surgical resection of PDAC is unfortunately still common. Recurrence is relatively lower in R0 resection, but after R0 resection [30], the rate reaches 80% [31]. In addition to recurrence, previous studies have shown that there is no significant difference in overall survival in cases of resection, regardless of disease status before surgery [32]. Therefore, our results confirmed that recurrence-free survival was not significantly different from preoperative PDAC status, irrespective of whether resectable pancreatic cancer, LAPC, or BRPC. Furthermore, as no significant difference was observed between overall survival and recurrence-free survival in all three groups of patients, surgery after NACT can be considered for LAPC patients, if technically possible [26,29]. Our findings are comparable to those of previous studies related to conversion surgery in LAPC [13-16,33-35].

Fig. 5 shows a significant difference in overall survival between patients who underwent surgery after NACT and those who received only chemotherapy without surgery, specifically among LAPC patients with PR or SD. This result suggests a favorable role of curative resection after NACT in LAPC, similar to that in BRPC. However, a randomized study is needed to confirm this suggestion.

Chemotherapy for pancreatic cancer has been evolving since gemcitabine was first introduced [34,36]. Recently, patients have been opting for chemotherapy using the FOLFIRINOX regimen to improve median survival [18]. Burris treated patients with advanced pancreaticoduodenectomy with gemcitabine and 5-fluorouracil, observing median survival rates of 5.65 and 4.41 months, respectively [36]. Subsequently, FOLFIRINOX was administered. In a study by Conroly et al. [18], the median overall survival was 11.1 months in the FOLFIRINOX group and 6.8 months in the gemcitabine group. This confirmed FOLFIRINOX as a favorable option for treating advanced pancreatic cancer (HR, 0.57; 95% CI, 0.45 to 0.73; p < 0.001) [18].

Furthermore, recent studies suggest that the introduction of such chemotherapy is believed to extend the survival period of LAPC patients. In another recently published study, surgery after NACT and surgery in advanced pancreatic cancer had a significantly better prognosis than that of chemotherapy alone without surgery (median overall survival: 16 months vs. 9 months, p=0.001; median progression-free survival: 11 months vs. 7.5 months, p=0.038) and upfront surgery (median overall survival: 16 months vs. 9 months, p=0.018; median progression-free survival: 11 months vs. 5.5 months, p < 0.001) [35]. These results are similar to those observed in our study. Considering these, NACT has been confirmed to be beneficial for patients with LAPC. However, more research is still needed, as the optimal chemotherapy regimen for patients with advanced pancreatic cancer, such as LAPC, has not yet been precisely determined.

This study had some limitations. First, it was conducted as a retrospective cohort study. Second, it was conducted based on the population obtained from a single tertiary institution and contained a small number of patients with LAPC. These factors could cause selection bias. Third, this study targeted patients who were diagnosed with pancreatic cancer and underwent NACT. Since NACT is a recent treatment modality for pancreatic cancer, the follow-up period after treatment was short. Lastly, while we compared survival between patients who underwent resection and those who did not undergo curative resection with LAPC after NACT achieving a PR or SD after NACT, we can assume that there were underlying clinical reasons preventing resection in the latter group (e.g., elevated tumor markers, continued invasion of major vessels, poor patient performance, comorbidities). To draw more definitive conclusions, further well-designed prospective studies are needed.

Despite these limitations, this study addressed the improved prognosis associated with surgery after NACT in LAPC patients, a topic that has received limited attention thus far. Nonetheless, further research is required to determine the sub-populations of LAPC patients that would benefit most from conversion surgery.

In conclusion, overall survival time and postoperative complications in LAPC patients who underwent curative resection following NACT showed similar results to those of BRPC patients who underwent curative resection following NACT. Further research is needed to identify specific subpopulations of LAPC patients who benefit most from conversion surgery and to minimize postoperative complications.

NOTES

Ethical Statement

All procedures in studies involving human participants were performed in accordance with the ethical standards of the Institutional Review Board of Asan Medical Center and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards (IRB approval number: 2016-0902). Patient consent was waived due to the retrospective nature of the study.

Author Contributions

Conceived and designed the analysis: Kim SC.

Collected the data: Lee YN, Hwang DW, Yoo C, Kim KP, Song KB, Lee JH, Lee W, Park Y, Kwak BJ, Chang HM, Ryoo BY, Kim SC.

Contributed data or analysis tools: Lee YN, Yoo C, Kim KP, Song KB, Lee JH, Lee W, Park Y, Kwak BJ, Chang HM, Ryoo BY, Kim SC.

Performed the analysis: Hwang DW, Yoo C.

Wrote the paper: Lee YN, Sung MK, Kim SC.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

Fig. 1.

Patient selection flow chart. NACT, neoadjuvant chemotherapy; PDAC, pancreatic ductal adenocarcinoma.

Fig. 2.

The overall survival (OS) curves were compared between locally advanced pancreatic cancer (LAPC) and borderline resectable pancreatic cancer (BRPC). The median OS of LAPC patients who underwent surgery after neoadjuvant chemotherapy (NACT) was 37.3 months (95% confidence interval [CI], 32.4 to 42.2) and the median OS of BRPC patients who underwent surgery after NACT was 37.0 months (95% CI, 32.6 to 41.3).

Fig. 3.

The relapse-free survival (RFS) curves were compared between locally advanced pancreatic cancer (LAPC) and borderline resectable pancreatic cancer (BRPC). The median RFS of LAPC patients who underwent surgery after neoadjuvant chemotherapy (NACT) was 22.7 months (95% confidence interval [CI], 17.9 to 27.5) and the median RFS of BRPC patients who underwent surgery after NACT was 26.0 months (95% CI, 21.7 to 30.3).

Fig. 4.

This figure shows the survival curves of patients who underwent upfront surgery with resectable pancreatic cancer (PC). It includes overall survival (OS) and recurrence-free survival (RFS) curves. The median OS of resectable pancreatic cancer was 38.4 months (95% confidence interval [CI], 36.6 to 40.2) and the median RFS of resectable pancreatic cancer was 32.3 months (95% CI, 30.2 to 34.4).

Fig. 5.

The overall survival curves were compared between locally advanced pancreatic cancer patients who underwent surgery after neoadjuvant chemotherapy (NACT) and those who received only chemotherapy without surgery, among those confirmed to have partial response (PR) and stable disease (SD). Overall survival was re-defined as the time from chemotherapy initiation to death from any cause in this analysis The median overall survival time for patients who underwent surgery after NACT was 43.2 months (95% confidence interval [CI], 38.4 to 48.1 months), while the median overall survival time for patients who received only chemotherapy was 21.5 months (95% CI, 19.7 to 23.3 months).

Table 1.

Demographic and clinical characteristics of patients undergoing surgery for pancreatic cancer

	LAPC (n=98)		BRPC (n=147)		Resectable (n=569)
	No. (%)	p-value	No. (%)	p-value	No. (%)
Age (yr)
< 65	66 (67.3)	< 0.001	90 (61.2)	0.001	262 (46.0)
≥ 65	32 (32.7)		57 (38.8)		307 (54.0)
Sex
Male	52 (53.1)	0.721	73 (49.7)	0.311	313 (55.0)
Female	46 (46.9)		74 (50.3)		256 (45.0)
BMI (kg/m²)
< 25	68 (70.1)	0.647	109 (74.1)	0.642	411 (72.4)
≥ 25	29 (29.9)		38 (25.9)		157 (27.6)
Baseline serum CA 19-9 level
Mean±SD (U/mL)	1,409.6±370.6		1,581.43±734.2		1,037.74±638.8
Within normal range	36 (36.7)	0.387	49 (33.6)	0.085	233 (41.4)
Elevated	62 (63.3)		97 (66.4)		330 (58.6)
Baseline serum CEA level^a)
Mean±SD (ng/mL)	8.1±1.8		3.8±0.2		4.3±0.3
Within normal range	67 (69.8)	0.004	112 (78.9)	0.343	461 (82.3)
Elevated	29 (30.2)		30 (21.1)		99 (17.7)
Initial tumor size (cm)
Mean±SD	3.70±1.4	0.218	3.17±1.1	0.234	3.11±1.3
Tumor location
Head	52 (53.1)	< 0.001	119 (81.0)	< 0.001	304 (53.4)
Body	40 (40.8)		23 (15.6)		126 (22.1)
Tail	5 (5.1)		4 (2.7)		137 (24.1)
Multicentric	1 (1.0)		1 (0.7)		2 (0.4)
NACT regimen
FOLFIRINOX	78 (80.8)	0.337	124 (84.4)
Others	20 (17.2)		23 (15.6)
NACT duration
Mean±SD (mo)	4.71±2.07	< 0.001	2.97±3.31
Response to NACT (clinical)
Partial response	57 (58.2)	0.814	74 (50.3)
Stable disease	39 (39.8)		70 (47.6)
Progressive disease	2 (2.0)		3 (2.0)
Adjuvant
No	6 (6.1)	0.012	4 (2.7)	< 0.001	90 (15.8)
CTx	83 (84.7)		137 (93.2)		436 (76.6)
CCRTx	9 (9.2)		6 (4.1)		43 (7.6)
Adjuvant CTx regimen^a)
GEM based	14 (15.2)	< 0.001	22 (15.4)	< 0.001	334 (69.7)
FOLFIRINOX	53 (57.6)		67 (46.9)		81 (16.9)
Others	25 (27.2)		54 (37.8)		64 (13.4)

BMI, body mass index; BRPC, borderline resectable pancreatic cancer; CA 19-9, carbohydrate antigen 19-9; CCRTx, chemoradiation treatment; CEA, carcinoembryonic antigen; CTx, chemotherapy; FOLFIRINOX, fluorouracil, leucovorin, irinotecan, oxaliplatin; GEM, gemcitabine; LAPC, locally advanced pancreatic cancer; NACT, neoadjuvant chemotherapy; SD, standard deviation.

^a) Some data are missing.

Table 2.

Operative characteristics of patients undergoing surgery for pancreatic cancer

	LAPC (n=98)		BRPC (n=147)		Resectable (n=569)
	No. (%)	p-value	No. (%)	p-value	No. (%)
OP procedure
PD	49 (50.0)	< 0.001	118 (80.3)	< 0.001	336 (59.1)
DP	41 (41.8)		24 (16.3)		226 (39.7)
TP	8 (8.2)		5 (3.4)		7 (1.2)
OP method
Open	89 (90.8)	< 0.001	137 (93.2)	< 0.001	363 (63.8)
Lap/Robot	9 (9.2)		10 (6.8)		206 (36.2)
Vein resection
No	70 (71.4)	< 0.001	75 (51.0)	< 0.001	546 (96.0)
Yes	28 (28.6)		72 (49.0)		23 (4.0)
Artery resection
No	68 (69.4)	< 0.001	137 (93.2)	< 0.001	566 (99.5)
Yes	30 (30.6)		10 (6.8)		3 (0.5)
Operative time (min)
Mean±SD	305.5±100.4	0.094	294.3±80.6	0.017	256.4±92.2
EBL (mL)
Mean±SD	260.5±488.4	< 0.001	213.1±30.9	< 0.001	70.4±236.0
Complication
No	69 (70.4)	0.090	111 (75.5)	0.484	445 (78.2)
I-II	16 (16.3)		24 (16.3)		76 (13.3)
III-IV	12 (12.2)		12 (8.1)		46 (8.1)
V	1 (1.0)		0		2 (0.4)
Vascular complication	3 (3.1)	0.090	2 (1.4)	0.143	3 (0.5)
Hospital stays
Mean±SD	12.9±10.8	0.480	12.7±6.7	0.729	11.6±8.1
≤ 14	81 (82.7)		111 (75.5)		486 (85.4)
> 14	17 (17.3)		36 (24.5)		83 (14.6)
Readmission
No	95 (96.9)	0.643	138 (93.9)	0.277	546 (96.0)
Yes	3 (3.1)		9 (6.1)		23 (4.0)
POPF
No	90 (91.8)	0.737	139 (94.6)	0.450	528 (92.8)
A	1 (1.0)		0		8 (1.4)
B or C	7 (7.1)		8 (5.4)		33 (5.8)

Postoperative complication was classified according to the Clavien-Dindo classification. Vascular complications were included that occur in the vein and artery, thrombus, stenosis, and occlusion of vessel. POPF was graded according to the guidelines of the International Study Group on Pancreatic Fistula (ISGPF). BRPC, borderline resectable pancreatic cancer; DP, distal pancreatectomy; EBL, estimated blood loss; LAPC, locally advanced pancreatic cancer; PD, pancreaticoduodenectomy; POPF, postoperative pancreatic fistula; SD, standard deviation; TP, total pancreatectomy.

Table 3.

Pathologic characteristics of patients undergoing surgery for pancreatic cancer

	LAPC (n=98)		BRPC (n=147)		Resectable (n=569)
	No. (%)	p-value	No. (%)	p-value	No. (%)
Tumor size (cm)
Mean±SD	2.4±1.6	0.01	2.6±1.2	0.293	3.0±1.3
T category
T1	35 (35.7)	< 0.001	45 (30.6)	0.041	125 (22.0)
T2	41 (41.8)		89 (60.5)		362 (63.6)
T3	13 (13.3)		12 (8.2)		81 (14.2)
T4	3 (3.1)		1 (0.7)		1 (0.2)
N/A	6 (6.1)		0		0
N category
N0	62 (63.3)	0.034	76 (51.7)	0.688	279 (49.0)
N1	29 (29.6)		59 (40.1)		231 (40.6)
N2	7 (7.1)		12 (8.2)		59 (10.4)
Staging
I	49 (50.0)	< 0.001	73 (49.7)	0.018	250 (43.9)
II	33 (33.7)		61 (41.5)		259 (45.5)
III	9 (9.2)		11 (7.5)		60 (10.5)
IV	1 (1.0)		2 (1.4)		0
N/A	6 (6.1)		0		0
LVI
No	69 (70.4)	< 0.001	84 (57.1)	< 0.001	232 (40.8)
Yes	29 (29.6)		63 (42.9)		337 (50.2)
PNI
No	37 (37.8)	0.028	48 (32.7)	0.166	153 (26.9)
Yes	61 (62.2)		99 (67.3)		416 (73.1)
RM
R0	83 (84.7)	0.670	128 (87.1)	0.227	472 (83.0)
R1	15 (15.3)		19 (12.9)		97 (17.0)

BRPC, borderline resectable pancreatic cancer; LAPC, borderline resectable pancreatic cancer; LVI, lymphovascular invasion; PNI, perineural invasion; RM, resection margin; SD, standard deviation.

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Clinical Outcomes of Surgery after Neoadjuvant Chemotherapy in Locally Advanced Pancreatic Ductal Adenocarcinoma

Cancer Res Treat. 2024;56(4):1240-1251. Published online June 19, 2024

DOI: https://doi.org/10.4143/crt.2023.977

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Abstract
Introduction
Materials and Methods
Results
Discussion
NOTES
REFERENCES

Clinical Outcomes of Surgery after Neoadjuvant Chemotherapy in Locally Advanced Pancreatic Ductal Adenocarcinoma

Fig. 1. Patient selection flow chart. NACT, neoadjuvant chemotherapy; PDAC, pancreatic ductal adenocarcinoma.

Fig. 2. The overall survival (OS) curves were compared between locally advanced pancreatic cancer (LAPC) and borderline resectable pancreatic cancer (BRPC). The median OS of LAPC patients who underwent surgery after neoadjuvant chemotherapy (NACT) was 37.3 months (95% confidence interval [CI], 32.4 to 42.2) and the median OS of BRPC patients who underwent surgery after NACT was 37.0 months (95% CI, 32.6 to 41.3).

Fig. 3. The relapse-free survival (RFS) curves were compared between locally advanced pancreatic cancer (LAPC) and borderline resectable pancreatic cancer (BRPC). The median RFS of LAPC patients who underwent surgery after neoadjuvant chemotherapy (NACT) was 22.7 months (95% confidence interval [CI], 17.9 to 27.5) and the median RFS of BRPC patients who underwent surgery after NACT was 26.0 months (95% CI, 21.7 to 30.3).

Fig. 4. This figure shows the survival curves of patients who underwent upfront surgery with resectable pancreatic cancer (PC). It includes overall survival (OS) and recurrence-free survival (RFS) curves. The median OS of resectable pancreatic cancer was 38.4 months (95% confidence interval [CI], 36.6 to 40.2) and the median RFS of resectable pancreatic cancer was 32.3 months (95% CI, 30.2 to 34.4).

Fig. 5. The overall survival curves were compared between locally advanced pancreatic cancer patients who underwent surgery after neoadjuvant chemotherapy (NACT) and those who received only chemotherapy without surgery, among those confirmed to have partial response (PR) and stable disease (SD). Overall survival was re-defined as the time from chemotherapy initiation to death from any cause in this analysis The median overall survival time for patients who underwent surgery after NACT was 43.2 months (95% confidence interval [CI], 38.4 to 48.1 months), while the median overall survival time for patients who received only chemotherapy was 21.5 months (95% CI, 19.7 to 23.3 months).

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

Clinical Outcomes of Surgery after Neoadjuvant Chemotherapy in Locally Advanced Pancreatic Ductal Adenocarcinoma

	LAPC (n=98)		BRPC (n=147)		Resectable (n=569)
	No. (%)	p-value	No. (%)	p-value	No. (%)
Age (yr)
< 65	66 (67.3)	< 0.001	90 (61.2)	0.001	262 (46.0)
≥ 65	32 (32.7)		57 (38.8)		307 (54.0)
Sex
Male	52 (53.1)	0.721	73 (49.7)	0.311	313 (55.0)
Female	46 (46.9)		74 (50.3)		256 (45.0)
BMI (kg/m²)
< 25	68 (70.1)	0.647	109 (74.1)	0.642	411 (72.4)
≥ 25	29 (29.9)		38 (25.9)		157 (27.6)
Baseline serum CA 19-9 level
Mean±SD (U/mL)	1,409.6±370.6		1,581.43±734.2		1,037.74±638.8
Within normal range	36 (36.7)	0.387	49 (33.6)	0.085	233 (41.4)
Elevated	62 (63.3)		97 (66.4)		330 (58.6)
Baseline serum CEA level^a)
Mean±SD (ng/mL)	8.1±1.8		3.8±0.2		4.3±0.3
Within normal range	67 (69.8)	0.004	112 (78.9)	0.343	461 (82.3)
Elevated	29 (30.2)		30 (21.1)		99 (17.7)
Initial tumor size (cm)
Mean±SD	3.70±1.4	0.218	3.17±1.1	0.234	3.11±1.3
Tumor location
Head	52 (53.1)	< 0.001	119 (81.0)	< 0.001	304 (53.4)
Body	40 (40.8)		23 (15.6)		126 (22.1)
Tail	5 (5.1)		4 (2.7)		137 (24.1)
Multicentric	1 (1.0)		1 (0.7)		2 (0.4)
NACT regimen
FOLFIRINOX	78 (80.8)	0.337	124 (84.4)
Others	20 (17.2)		23 (15.6)
NACT duration
Mean±SD (mo)	4.71±2.07	< 0.001	2.97±3.31
Response to NACT (clinical)
Partial response	57 (58.2)	0.814	74 (50.3)
Stable disease	39 (39.8)		70 (47.6)
Progressive disease	2 (2.0)		3 (2.0)
Adjuvant
No	6 (6.1)	0.012	4 (2.7)	< 0.001	90 (15.8)
CTx	83 (84.7)		137 (93.2)		436 (76.6)
CCRTx	9 (9.2)		6 (4.1)		43 (7.6)
Adjuvant CTx regimen^a)
GEM based	14 (15.2)	< 0.001	22 (15.4)	< 0.001	334 (69.7)
FOLFIRINOX	53 (57.6)		67 (46.9)		81 (16.9)
Others	25 (27.2)		54 (37.8)		64 (13.4)

	LAPC (n=98)		BRPC (n=147)		Resectable (n=569)
	No. (%)	p-value	No. (%)	p-value	No. (%)
OP procedure
PD	49 (50.0)	< 0.001	118 (80.3)	< 0.001	336 (59.1)
DP	41 (41.8)		24 (16.3)		226 (39.7)
TP	8 (8.2)		5 (3.4)		7 (1.2)
OP method
Open	89 (90.8)	< 0.001	137 (93.2)	< 0.001	363 (63.8)
Lap/Robot	9 (9.2)		10 (6.8)		206 (36.2)
Vein resection
No	70 (71.4)	< 0.001	75 (51.0)	< 0.001	546 (96.0)
Yes	28 (28.6)		72 (49.0)		23 (4.0)
Artery resection
No	68 (69.4)	< 0.001	137 (93.2)	< 0.001	566 (99.5)
Yes	30 (30.6)		10 (6.8)		3 (0.5)
Operative time (min)
Mean±SD	305.5±100.4	0.094	294.3±80.6	0.017	256.4±92.2
EBL (mL)
Mean±SD	260.5±488.4	< 0.001	213.1±30.9	< 0.001	70.4±236.0
Complication
No	69 (70.4)	0.090	111 (75.5)	0.484	445 (78.2)
I-II	16 (16.3)		24 (16.3)		76 (13.3)
III-IV	12 (12.2)		12 (8.1)		46 (8.1)
V	1 (1.0)		0		2 (0.4)
Vascular complication	3 (3.1)	0.090	2 (1.4)	0.143	3 (0.5)
Hospital stays
Mean±SD	12.9±10.8	0.480	12.7±6.7	0.729	11.6±8.1
≤ 14	81 (82.7)		111 (75.5)		486 (85.4)
> 14	17 (17.3)		36 (24.5)		83 (14.6)
Readmission
No	95 (96.9)	0.643	138 (93.9)	0.277	546 (96.0)
Yes	3 (3.1)		9 (6.1)		23 (4.0)
POPF
No	90 (91.8)	0.737	139 (94.6)	0.450	528 (92.8)
A	1 (1.0)		0		8 (1.4)
B or C	7 (7.1)		8 (5.4)		33 (5.8)

	LAPC (n=98)		BRPC (n=147)		Resectable (n=569)
	No. (%)	p-value	No. (%)	p-value	No. (%)
Tumor size (cm)
Mean±SD	2.4±1.6	0.01	2.6±1.2	0.293	3.0±1.3
T category
T1	35 (35.7)	< 0.001	45 (30.6)	0.041	125 (22.0)
T2	41 (41.8)		89 (60.5)		362 (63.6)
T3	13 (13.3)		12 (8.2)		81 (14.2)
T4	3 (3.1)		1 (0.7)		1 (0.2)
N/A	6 (6.1)		0		0
N category
N0	62 (63.3)	0.034	76 (51.7)	0.688	279 (49.0)
N1	29 (29.6)		59 (40.1)		231 (40.6)
N2	7 (7.1)		12 (8.2)		59 (10.4)
Staging
I	49 (50.0)	< 0.001	73 (49.7)	0.018	250 (43.9)
II	33 (33.7)		61 (41.5)		259 (45.5)
III	9 (9.2)		11 (7.5)		60 (10.5)
IV	1 (1.0)		2 (1.4)		0
N/A	6 (6.1)		0		0
LVI
No	69 (70.4)	< 0.001	84 (57.1)	< 0.001	232 (40.8)
Yes	29 (29.6)		63 (42.9)		337 (50.2)
PNI
No	37 (37.8)	0.028	48 (32.7)	0.166	153 (26.9)
Yes	61 (62.2)		99 (67.3)		416 (73.1)
RM
R0	83 (84.7)	0.670	128 (87.1)	0.227	472 (83.0)
R1	15 (15.3)		19 (12.9)		97 (17.0)

Table 1. Demographic and clinical characteristics of patients undergoing surgery for pancreatic cancer

Some data are missing.

Table 2. Operative characteristics of patients undergoing surgery for pancreatic cancer

Table 3. Pathologic characteristics of patients undergoing surgery for pancreatic cancer

BRPC, borderline resectable pancreatic cancer; LAPC, borderline resectable pancreatic cancer; LVI, lymphovascular invasion; PNI, perineural invasion; RM, resection margin; SD, standard deviation.