Long-term survival analysis based on tumor location in patients with pancreatic ductal adenocarcinoma who underwent pancreatectomy following neoadjuvant chemoradiotherapy

Long-term survival analysis based on tumor location in patients with pancreatic ductal adenocarcinoma who underwent pancreatectomy following neoadjuvant chemoradiotherapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Long-term survival analysis based on tumor location in patients with pancreatic ductal adenocarcinoma who underwent pancreatectomy following neoadjuvant chemoradiotherapy Benson Kaluba, Naohisa Kuriyama, Tatsuya Sakamoto, Haruna Komatsubara, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5380534/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Jan, 2025 Read the published version in Langenbeck's Archives of Surgery → Version 1 posted 11 You are reading this latest preprint version Abstract Purpose The study aimed at assessing whether long-term survival outcomes were different based on tumor location in patients with pancreatic ductal adenocarcinoma who underwent pancreatectomy following neoadjuvant chemoradiotherapy (CRT). Methods 286 patients with localized PDAC were enrolled and divided as head (Ph = 218), body (Pb = 34) and tail (Pt = 34). 5-year survival analyses were performed and independent predictors of disease-free survival (DFS) and overall survival (OS) were identified. Results Ph patients exhibited a higher incidence of initial clinical stage 3 tumors (48.2%) compared to Pb (29.4%) and Pt (0%), p < 0.001 with more UR-LA cases (22.0%) compared to Pb (11.8%) and Pt (0%), p < 0.001. However, they demonstrated a better response to CRT; Evans grades 3/4 in 49.1% Ph vs. 23.5% Pb and 26.5% Pt, p = 0.015. 5-year DFS were; 26.4% (Ph) vs. 16.5% (Pb) vs. 33.1 (Pt), p = 0.691 and OS; 25.4% (Ph) vs. 27.7% (Pb) vs. 32.0% (Pt), p = 0.341. Significant predictors for both DFS and OS included CA19-9 levels, resection margins and pathological portal vein invasion, with tumor size and nodal invasion also influencing DFS, while pathological stage impacting OS. Conclusion Based on tumor location, long-term survival outcomes were comparable and was attributed to a better response to CRT by Ph than the Pb and Pt patients. Pancreatic ductal adenocarcinoma Tumor location Neoadjuvant chemoradiotherapy Survival outcomes Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid tumor with a high mortality rate as reported among new cases in the recent 2020 Global Cancer Statistics (94.0%; 466,003 / 495,773 deaths)[ 1 ] and 2024 United States Cancer Statistics (77.9%; 51,750 / 66,440 deaths) [ 2 ]. The challenge of treating PDAC is that 80–85% of patients present at initial diagnosis with advanced unresectable or metastasised (UR-M) disease making them unfit for pancreatectomy. Unfortunately, prognosis for the 15–20% cases undergoing surgery for either localised or resectable disease is still poor with overall survival (OS) rates of 24% in 1 year and 9% in 5 years [ 3 ]. There is still no consensus regarding survival outcomes based on tumor location in PDAC patients since previous studies indicate conflicting findings for both non-resected and resected pancreatic head (Ph), body (Pb) and tail (Pt) cases [ 4 – 6 ]. Moreover, it is still unclear whether survival outcomes are different for Ph, Pb and Pt PDAC patients undergoing surgical resection following neoadjuvant chemoradiotherapy (CRT). Embryologically, Ph, Pb and Pt originate differently leading to differences in histological structure, PDAC oncogenesis and eventually, response to neoadjuvant chemo/radiotherapy (CRT) [ 7 ]. Even though CRT is associated with improved PDAC patients’ survival [ 8 ], its role in resectable (R) cases is still a contentious issue since some reports have found no benefit of CRT and instead, advocate for upfront surgery (UFS) followed by adjuvant therapy [ 9 , 10 ]. While, others argue that PDAC is a systemic disease with a potential for microscopic positive surgical margins (R1) and have reported a better survival in CRT patients compared to UFS resectable cases [ 11 , 12 ]. In clinical practice, the treatment effect of CRT on PDAC can be assessed both radiologically and histologically. The latter is a better surrogate for assessing treatment efficacy as it characterizes the residual tumor load[ 13 ] but the former is dependent on the timing, technique, imaging used[ 14 , 15 ] and is also affected by peri-tumor edematous and fibrotic changes post CRT [ 16 ]. In 2016, the International consensus meeting on the definition and criteria of borderline resectable (BR) PDAC described the prognostic predictors of the disease as anatomical (A), biological (B) and conditional factors (C) factors[ 17 ]. In this definition, the anatomical factor involved the tumor interaction with such blood vessels as superior mesenteric artery (SMA) / celiac artery (CA), common hepatic artery (CHA), proper hepatic artery (PHA) or superior mesenteric vein/ portal vein (SMV/PV). Whereas, the biological factors included elevated serum carbohydrate antigen (CA) 19 − 9 level of more than 500 units/ml and presence of distant or regional lymph node metastases, while conditional factor was defined as pre-operative patients’ performance status of 2 or more according to the Eastern Cooperative Oncology Group (ECOG) classification [ 17 ]. As an addition to biological factors, several pathological predictors of survival such as arterial system invasion of SMA (Asm), portal venous system invasion of SMV (PVsm)[ 16 ], PV and splenic vein (SpV) invasion [ 18 ] have been reported in recent reports. The current study aimed at assessing whether long-term (5-year) survival outcomes were different for Ph, Pb and Pt PDAC patients who underwent pancreatectomy following CRT. The patients were recruited from our Institutional CRT protocol [ 8 ]. Additionally, independent prognostic predictors of disease-free (DFS) and overall survival (OS) were identified. Materials and methods Study population Among 468 patients with localized PDAC who underwent pancreatectomy from April, 2006 to August 2022, 286 (61.1%) post-CRT were enrolled in this study, while 182 (38.9%) non-CRT cases were excluded (Fig. 1 ). Clinicopathological and operative data were obtained from a prospectively maintained database at the Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Hospital and analyzed based on tumor location. This study was ethically conducted and approved by Mie University Hospital Institutional Review Board (H2020-118). Neoadjuvant chemo-radiotherapy The local Institutional gemcitabine-based CRT protocol (GEM-CRT) was launched in 2005 and switched to S-1/GEM-based (S-1/GEM-CRT) from 2011. Patients received 2 cycles of S-1 (60 mg/m 2 per day) administered orally for 21 days in a 28-day cycle combined with an infusion of gemcitabine (600 mg/m 2 ) on days 8, 22, 36 and 50. Furthermore, three-dimensional (3D) conformal radiotherapy was administered with a total radiation dose of 45 to 50.4 Gy divided into 25 to 28 fractions [ 17 , 19 ]. Upon completion, radiological re-evaluation was done after 4–6 weeks on dynamic CT-scan images as previously described [ 8 ]. Defining tumor location Tumor location was determined on dynamic CT-scan images as previously reported [ 20 ] and as shown in Fig. 1 ; the border between Ph and Pb was the left side of superior mesenteric / portal vein (SMV/PV), while the border between the Pb and Pt was the left side of the abdominal aorta. Ph included also both the uncinate process and pancreatic neck. Lastly, tumor location was assigned based on the part of the pancreas where the tumor was, but in cases where a tumor was located in two or more adjacent parts, location was assigned to the main site. Radiological evaluation Pre- and post-CRT dynamic CT-scan images were used to extract data regarding tumor size, clinical T- category and clinical N-category. Tumor resectability was also evaluated as previously reported [ 21 ] and classified as R, borderline resectable-portal vein (BR-PV), borderline resectable-arterial (BR-A) and unresectable-locally advanced (UR-LA) according to the National Comprehensive Cancer Network (NCCN) clinical practice guidelines [ 22 ]. Furthermore, clinical staging was evaluated according to the 8th TNM classification of the Union for International Cancer Control (UICC) [ 8 , 16 ]. The data were appropriately analyzed and compared based on tumor location as shown in Table 1 . Surgical outcomes Patients with Ph tumors underwent pancreatoduodenectomy (PD) using an anterior approach to superior mesenteric artery (SMA) as described by Mizuno et al.[ 23 ], while those with Pb and Pt tumors underwent distal pancretectomy (DP) with a radical antegrade modular pancreatosplenectomy (RAMPS) procedure as recently reported by Kuriyama et al. [ 24 ]. Assessment of pathological outcomes The pathological data in this study were similar to our recent report [ 16 ] and apart from tumor size, stage, tumor differentiation, resection margins, nodal and portal vein invasion, data on histological response to CRT were also retrieved based on the Evans tumor grading ; 1 (< 10 or no tumor cell destruction), 2a (destruction of 10%-50% of tumor cells), 2b (destruction of 51% – 90% of tumor cells), 3 (< 10% tumor cells present) and 4 (no viable tumor cells present) [ 25 ]. Data on histological treatment response to CRT that were recorded according to the General Rules for the Study of Pancreatic Cancer (7th Edition) by the Japan Pancreas Society (7th JPS) were re-classified to the Evans grading as guided by the 7th JPS [ 26 ]. Adjuvant chemotherapy Following surgical resection, from 2006 to 2013, all patients received GEM (800 mg/m 2 ) biweekly as adjuvant chemotherapy, while from 2013, oral S-1 (60 mg/m 2 per day) was administered on days 1–14 in a 21-day cycle. However, depending on how a patient tolerated any of these drugs, the two regimens were switched as previously described [ 18 , 27 ]. Survival analyses The Kaplan-Meier method with a log-rank test was used to analyze DFS and OS based on tumor location (Fig. 2 A-B), pathological T-category (Fig. 3 A-F) and N- category (Fig. 4 A-D) according to tumor location, respectively. Identifying significant prognostic predictors of disease-free and overall survival To determine significant independent prognostic predictors of both DFS and OS, univariate analyses for the clinicopathological variables were first performed. Then those variables which had p < 0.05 in the univariate analyses, were respectively included in a multivariate stepwise forward Cox logistic regression analyses, Table 2 . Statistics analyses Five-year DFS and OS were the primary end-points. DFS was calculated in months from the date of surgery to the date of recurrence, last visit (for the alive patients) or death, while OS was calculated from date of surgery to date of death or last visit for the alive patients. Continuous variables were expressed as median (range) and appropriately compared based on tumor location using either the Mann–Whitney U test or Kruskal–Wallis test. Categorical variables were compared using either Pearson's chi-squared or Fisher's exact test. The Kaplan-Meier method with log-rank test was used to analyze DFS and OS based on tumor location, pathological T- and N-categories according to tumor location. To determine predictors of both DFS and OS, multivariate stepwise forward Cox logistic regression analyses were conducted for variables which had p < 0.05 in the univariate analyses, respectively. Statistical package SPSS version 23 (IBM SPSS Statistics for Windows, v. 23.0; IBM, Armonk, NY, USA) was used for all analyses, and p < 0.05 was considered statistically significant. Results Clinical outcomes before and after neoadjuvant chemo-radiotherapy As shown in Table 1 , among the 286 patients, 218 (76.2%) had Ph, 34 (11.9%) had Pb and 34 (11.9%) had Pt PDAC tumors, respectively. There was no difference among the patients based on carbohydrate antigen 19 − 9 (CA19-9; U/mL), carcinoembryonic antigen (CEA; ng/mL), radiological tumor size (mm) and N-category (N0 / N1/N2). However, there was a significant difference based on tumor resectability ( p < 0.001), T-category ( p < 0.001) and clinical stage ( p < 0.001). Most importantly, Ph patients exhibited more advanced tumors; clinical T3/T4; 54.6% (Ph) / 38.3% (Pb) / 44.1% (Pt), respectively before CRT ( p < 0.001) and 55.5% (Ph) / 23.2% (Pb) / 35.3% (Pt), respectively after CRT ( p < 0.001). Secondly, clinical stage 3 tumors were; 48.2% (Ph) / 29.4% (Pb) vs. 0% (Pt), respectively before CRT ( p < 0.001) and 53.2% (Ph) / 20.6% (Pb) / 0% (Pt), respectively after CRT ( p < 0.001). Then lastly, Ph patients had more UR-LA cases; 22.0% for Ph vs. 11.8% for Pb vs. 0 for Pt cases, respectively ( p < 0.001). Surgical and pathological outcomes Surgical outcomes Pancreatoduodenectomy (PD) was performed in 100% and 32.4% of Ph and Pb patients, respectively. While, DP was done in 67.6% (Pb) and 100% (Pt) cases, respectively ( p < 0.001). Ph patients (78.0%) underwent significantly more combined SMV/PV resection and reconstruction than the Pb (41.2%) and Pt (0%), p < 0.001.However, arterial resection ( celiac axis, common hepatic or proper hepatic arteries) and reconstruction were similar between the Ph (5.5%) and Pb (8.8%) patients as no Pt patient had arterial resection, p = 0.248 (Table 1 ) . Pathological outcomes As shown in Table 1 , patients were similar based on pathological tumor size (mm), resection margins (R0/R1), N-category, portal venous system (pPV) invasion, neural (pne) invasion, lymphatics (ply) invasion, venous system (pve) invasion, serosal side of the anterior pancreatic tissue (pS) invasion and retropancreatic tissue (pRP) invasion and pathological stage. However, the three groups were different based on tumor differentiation ( p = 0.014), T-category ( p = 0.008), arterial system invasion (pA; p = 0.004) and histological treatment effect ( p = 0.015). According to the Evans grading, Ph cases had a better treatment response to CRT than Pb and Pt cases; Evans 3 /4 grade (< 10% to no viable tumor cells present in surgical specimens): 84 (38.5%) / 23 (10.6%) for Ph vs. 6 (17.6%) / 2 (5.9%) for Pb vs. 7 (20.8%) / 2 (5.9%) for Pt cases, respectively ( p = 0.015). Survival analyses based on tumor location Long-term survival outcomes were statistically comparable among the three groups. Five-year DFS were; 26.4% (Ph) vs. 16.5% (Pb) vs. 33.1% (Pt), respectively ( p = 0.691), Fig. 2 A. Whereas OS were; 25.4% (Ph) vs. 27.7% (Pb) vs. 32.0% (Pt), respectively ( p = 0.341), Fig. 2 B. Survival analyses based on pathological T- and N-categories according to tumor location When we compared survival outcomes based on pT-category, 5-year survival outcomes were statistically similar among the less advanced tumors; pT1 (n = 84), Fig. 3 A-B and pT2 (n = 72), Fig. 3 C-D but different among the advanced tumors (pT3/T4) with regards to tumor location. For the pT3/T4 (n = 130) subgroup, 5-year DFS was significantly better for Ph patients; 18.5% (Ph) / N/A (Pb) / N/A (Pt), respectively ( p = 0.026), yet OS was favorable in Pt patients but worse for the Pb cases; 13.3% (Ph) / N/A (Pb) / 25.0% (Pt) months, respectively ( p = 0.008), Fig. 3 E-F. Additionally, analyses based on pN-category according to tumor location revealed similar long-term survival outcomes for both the pN0 (n = 200) and pN1/N2 (n = 86) patients as shown in Fig. 4 A-D. Significant independent predictors of disease-free and overall survival In univariate and multivariate analyses, tumor location was not an independent predictor of both DFS and OS. Instead, predictors of DFS were CA19-9 (HR; 1.001, p < 0.001), pathological tumor size (HR; 1.020, p = 0.001), pathological lymph node invasion (HR; 0.796, p = 0.004), resection margins (HR; 0.777, p = 0.004) and pPV system invasion (HR; 0.633, p = 0.009). Whereas, CA19-9 (HR; 1.001, p = 0.003), resection margins (HR; 0.756, p = 0.001), pPV system invasion (HR; 0.620, p = 0.004) and pathological tumor stage (HR; 1.069, p < 0.001) were predictors of OS, Table 2 . Discussion In this single-center retrospective study, we observed that even though Ph patients clinically presented with significantly more advanced and aggressive initial tumors than Pb and Pt ones, following CRT, 5-year survival outcomes were statistically comparable among the three groups. This was attributed to Ph patients demonstrating a better histological treatment response to CRT than the Pb and Pt cases (Table 1 ). Firstly, our findings reflects the effectiveness of CRT in treating PDAC, including patients with more advanced tumors. Secondly, considering the differences in histological treatment response based on tumor location, it can be suggested that tumors of the Ph might be more receptive to the effects of CRT compared to those of the Pb and Pt. In multivariate analyses, significant independent predictor of both DFS and OS were CA19-9, resection margins and pPV system invasion. Additionally, pathological tumor size and lymph node invasion were predictors of DFS, while pathological stage was also a predictor of OS (Table 2 ). The positive impact of CRT in PDAC has widely been reported [ 8 , 16 , 17 ], but its role in R cases is still debatable as some favor UFS followed by adjuvant therapy and have found no superiority of CRT over UFS [ 9 , 10 ], yet others report the opposite [ 11 , 12 ]. Nonetheless, long-term survival outcomes for Ph, Pb and Pt PDAC patients undergoing pancreatectomy following CRT still remain unclear. In view of the above, this study recruited post-CRT PDAC patients that underwent surgical resection and aimed at assessing whether long-term (5-year) survival rates were different based on tumor location, especially considering that most of previous studies which assessed survival outcomes based on tumor location involved mainly UFS patients. Artinyan et.al. [ 4 ] did not indicate whether their participants received CRT or not, but similar to us, their Ph patients had more T3 / T4 tumors than the Pb/Pt cases, yet OS was much better for their Ph patients which was attributed to the more number of harvested lymph nodes compared to the Pb/Pt patients. However, van Erning et al.[ 28 ] only had 67 / 2311 (3%) Ph vs. 11 / 104 (11%) Pb vs. 5 / 206 (2%) Pt patients who received neoadjuvant chemotherapy (NAC) alone and OS was comparable even though Pt cases had significantly more large-sized tumors (> 40 mm); 21% (Ph) / 40% (Pb) / 51% (Pt), but no cause was cited for these findings. In contrast, tumor size was similar among our patients. Lastly, Winer et al.[ 6 ] had 1,673 / 32,990 (5.1%) Ph vs. 186 (6.4%) Pb vs. 88 / 5078 (1.7%) Pt patients who received CRT and contrary to us, besides their Ph cases having more earlier-stage tumors (1/2); 39.2 (Ph) vs. 19.7% (Pb) vs. 16.0% (Pt), they had the worst OS due to having more pathologically advanced tumors. For us though, Ph patients had significantly more initial stage 3 and UR-LA tumors, yet except for tumor differentiation, almost all the pathological characteristics were similar among the three groups. Moreover, Ph patients demonstrated a better response to CRT than the other 2 groups (Table 1 ). This in itself could explain why long-term survival rates were similar based on tumor location (Fig. 2 ). Subgroup analyses based on pathological T-category showed that for less advanced tumors; pT1 (n = 84) and T2 (n = 72) cases, long-term survival rates were comparable among the Ph, Pb and Pt patients (Fig. 3 A-D), but among patients with advanced tumors (pT3/ T4, n = 130), Pb patients had the least favorable long-term survival (Fig. 3 E-F). However, as a study limitation, Pb and Pt patients were fewer compared to the Ph cases across these sub-cohorts. Nonetheless, the poor OS among the Pb cases for the pT3/T4 cases can be attributed to them having more prevalent R1 cases as shown in Table 1 ; 19 .3% (Ph) vs. 29.4% (Pb) vs. 14.7% (Pt) and possibly, the presence of intra-abdominal occult metastatic disease which is estimated to be present at surgical exploration in 11–24% of PDAC patients [ 29 ]. In previous reports, Lee et al.[ 30 ] observed comparable OS rates among 646 Ph and Pb / Pt UFS patients in cT1 (n = 96), cT3 (n = 103) and cT4 (n = 11) cases which they attributed to smaller sub-groups, but Pb / Pt cases had a better OS than Ph ones among the cT2 (n = 426) patients. Additionally, survival rates were comparable among their nodal-involvement sub-group which was similar to our results (Fig. 4 A-D), Lastly, Meng et al.[ 5 ] also did not indicate whether their participants received CRT or not, but observed that tumor location was a predictor of survival only in early (T1) tumors. However, our findings indicate that CRT was equally effective in treating early (T1/T2) tumors as both DFS and OS rates were similar among the Ph, Pb and Pt patients, Fig. 3 A-D. Several anatomical, biological and conditional prognostic factors of PDAC have been reported recently [ 6 , 8 , 16 , 17 ]. Similar to us, both Lee et al.[ 30 ] and Malleo et al.[ 31 ] observed that tumor location was not a predictor of survival, but CA19-9, N-category, T-category, tumor grade,[ 30 ] lymphatic invasion, resection margins and tumor stage [ 31 ] were. However, in some reports, tumor location was identified as an independent predictor of survival [ 4 , 6 ]. We, however, identified CA 19 − 9, resection margins (R0 / R1) and PV system invasion as predictors of both DFS and OS (Table 2 ). The International consensus meeting on definition and criteria of borderline resectable PDAC [ 17 ] reported that a pre-operative CA 19 − 9 > 500 U /mL was linked to poor survival, while Kobayashi et al.[ 32 ] noticed that a > 50% CA 19 − 9 reduction post-CRT was prognostic for a better survival. Interestingly, our Ph patients had the best CA 19 − 9 reduction rate; 77.0% (Ph) vs. 52.6% (Pb) vs. 3.6% (increment for Pt) which might indicate a better response to CRT by the Ph patients than both the Pb and Pt ones, Table 1 . Following CRT, R0 is linked to a better survival than R1, [ 33 ] and unfortunately, our Pb cases had more R1 cases with worst survival among the subgroup of advanced tumors (pT3/T4 patients), Fig. 3 E-F. Portal vein system invasion is a significant indicator of survival in PDAC [ 34 ] and similarly, Kuriyama et al.[ 18 ] found that splenic vein involvement in PDAC was associated with poor survival. Furthermore, our results indicate that PV system invasion is a better predictor of survival than arterial system invasion (Table 2 ) and since veins have thinner walls than arteries [ 35 ], we can postulate that PDAC might easily invade the thin walls of the PV than the arterial system, thereby directly introducing tumor cells into the blood stream. We also identified pathological tumor size, nodal status as predictors of DFS and pathological stage for OS whose predictive significance have previously been described [ 30 , 31 ]. The impact of CRT on Ph, Pb and Pt tumors is unclear as there are limited studies which focused on this. However, these pancreatic sites originate differently leading to differences in tumor oncogenesis, invasiveness and chemo /radiotherapy resistance [ 7 ]. Chemoradiotherapy causes tumor cell apoptosis, remodels the complex and dense tumor microenviroment (TME) filled with immunosuppressive cells; cancer-associated fibroblasts, myeloid-derived suppressor cells and regulatory T cells [ 36 ]. The TME modulation results in increased density of tumor-infiltrating lymphocytes which enhances antitumoral immune response [ 37 ]. In clinical practice, as mentioned earlier, this effect can be assessed both radiologically and pathologically. For pathological assessment, surgical specimens are used to assess present viable tumor cell load based on the Evans [ 25 ] Japan Pancreas Society [ 26 ] and College of American pathologists [ 38 ] systems. Among 525 PDAC patients, Maeda et al.[ 39 ] found that histological treatment response was better for CRT (377; 71.8%) than NAC alone (148; 28.2%) patients. We, however, excluded the NAC cases and included only CRT ones (Fig. 1 ). In other reports, both Wittman et al.[ 40 ] and Chuong et al.[ 41 ] observed that improved histological response to CRT was associated with improved survival for PDAC patients. Since our Ph patients had a better histological response to CRT than the Pb and Pt patients based on the Evans grade and if we consider the possibility that Ph tumors respond much better to CRT than those of Pb and Pt, it might be as result of them having a microenviroment that is more favorable and receptive to the effects of CRT than that of the Pb and Pt tumors. However, further studies are needed to verify this fact. For the current study though, the better response to CRT can explain how the Ph patients were able to overcome the burden of having significantly more advanced initial tumors than the Pb and Pt patients and result in comparable pathological and survival outcomes. However, the current study has some limitations. Firstly, it was a single-center retrospective study and secondly, they were few Pb and Pt patients for better analyses among the pT sub-groups (Fig. 3 A-E). Consequently, further multicenter prospective studies are needed to validate our findings. Conclusion Even though Ph patients clinically presented with significantly more advanced initial tumors than the Pb and Pt cases, they had the best histological treatment response to CRT and consequently, long-term survival outcomes were comparable among the 3 groups. Declarations Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of Interest The authors declare that they have no competing interests. Author Contribution Study conception and design: Benson Kaluba, Naohisa Kuriyama, Masashi Kishiwada, and Shugo Mizuno. Acquisition of data: Benson Kaluba, Naohisa Kuriyama, Tatsuya Sakamoto, Haruna Komatsubara, Koki Maeda, Daisuke Noguchi, Kazuyuki Gyoten, Takahiro Ito, Aoi Hayasaki, Takehiro Fujii, Yusuke Iizawa, Yasuhiro Murata, and Akihiro Tanemura. Analysis and interpretation of data: All the authors participated in the critical revision of the manuscript for important intellectual content. All the authors approved the final version to be published and agreed to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved. Drafting of the manuscript and critical revision of the manuscript: Benson Kaluba, Naohisa Kuriyama and Masashi Kishiwada. All authors have read and approved the manuscript. Ethics approval and consent to participate: The study was performed in accordance with the ethical principles stipulated in the Declaration of Helsinki. Ethics approval was sought and granted by the Ethics Committee of Mie University Graduate School of Medicine (H2020-118). All participants provided informed consent for participation and for the use of their medical records through an optout form. Consent for publication: Not applicable Availability of data and materials: The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. 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Pancreas 48(2):281–291 Imamura T, Yamamoto Y, Sugiura T, Okamura Y, Ito T, Ashida R et al (2021) Reconsidering the Optimal Regional Lymph Node Station According to Tumor Location for Pancreatic Cancer. Ann Surg Oncol 28(3):1602–1611 Wittel UA, Lubgan D, Ghadimi M, Belyaev O, Uhl W, Bechstein WO et al (2019) Consensus in determining the resectability of locally progressed pancreatic ductal adenocarcinoma - results of the Conko-007 multicenter trial. BMC Cancer 19(1):979 Guideline NCCN, V2.2022 [internet] (2022) Pancreatic Adenocarcinoma. https://www.nccn.org/guidlines/ categ ory_1, 2022 Mizuno S, Isaji S, Tanemura A, Kishiwada M, Murata Y, Azumi Y et al (2014) Anterior approach to the superior mesenteric artery by using nerve plexus hanging maneuver for borderline resectable pancreatic head carcinoma. J Gastrointest surgery: official J Soc Surg Aliment Tract 18(6):1209–1215 Kuriyama N, Maeda K, Shinkai T, Ito T, Gyoten K, Hayasaki A et al (2023) Anterior versus posterior radical antegrade modular pancreatosplenectomy for pancreatic body and tail cancer: an inverse probability of treatment weighting with survival analysis. Surg Today 53(8):917–929 Evans DB, Rich TA, Byrd DR, Cleary KR, Connelly JH, Levin B et al (1992) Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg 127(11):1335–1339 Society JP (2016) Classification of Pancreatic Carcinoma, 4th edn. Kanehara & Co., Ltd.: Tokyo, Japan,. Ichikawa K, Mizuno S, Hayasaki A, Kishiwada M, Fujii T, Iizawa Y et al (2019) Prognostic Nutritional Index After Chemoradiotherapy Was the Strongest Prognostic Predictor Among Biological and Conditional Factors in Localized Pancreatic Ductal Adenocarcinoma Patients. Cancers. ;11(4) van Erning FN, Mackay TM, van der Geest LGM, Groot Koerkamp B, van Laarhoven HWM, Bonsing BA et al (2018) Association of the location of pancreatic ductal adenocarcinoma (head, body, tail) with tumor stage, treatment, and survival: a population-based analysis. Acta Oncol 57(12):1655–1662 Satoi S, Yanagimoto H, Toyokawa H, Inoue K, Wada K, Yamamoto T et al (2011) Selective use of staging laparoscopy based on carbohydrate antigen 19 – 9 level and tumor size in patients with radiographically defined potentially or borderline resectable pancreatic cancer. Pancreas 40(3):426–432 Lee M, Kwon W, Kim H, Byun Y, Han Y, Kang JS et al (2020) The Role of Location of Tumor in the Prognosis of the Pancreatic Cancer. Cancers. ;12(8) Malleo G, Maggino L, Ferrone CR, Marchegiani G, Luchini C, Mino-Kenudson M et al (2020) Does Site Matter? Impact of Tumor Location on Pathologic Characteristics, Recurrence, and Survival of Resected Pancreatic Ductal Adenocarcinoma. Ann Surg Oncol 27(10):3898–3912 Kobayashi M, Mizuno S, Murata Y, Kishiwada M, Usui M, Sakurai H et al (2014) Gemcitabine-based chemoradiotherapy followed by surgery for borderline resectable and locally unresectable pancreatic ductal adenocarcinoma: significance of the CA19-9 reduction rate and intratumoral human equilibrative nucleoside transporter 1 expression. Pancreas 43(3):350–360 Maeda S, Moore AM, Yohanathan L, Hata T, Truty MJ, Smoot RL et al (2020) Impact of resection margin status on survival in pancreatic cancer patients after neoadjuvant treatment and pancreatoduodenectomy. Surgery 167(5):803–811 Roch AM, House MG, Cioffi J, Ceppa EP, Zyromski NJ, Nakeeb A et al (2016) Significance of Portal Vein Invasion and Extent of Invasion in Patients Undergoing Pancreatoduodenectomy for Pancreatic Adenocarcinoma. J Gastrointest surgery: official J Soc Surg Aliment Tract 20(3):479–487 discussion 87 Vekilov DP, Grande-Allen KJ (2018) Mechanical Properties of Diseased Veins. Methodist Debakey Cardiovasc J 14(3):182–187 Mota Reyes C, Teller S, Muckenhuber A, Konukiewitz B, Safak O, Weichert W et al (2020) Neoadjuvant Therapy Remodels the Pancreatic Cancer Microenvironment via Depletion of Protumorigenic Immune Cells. Clin cancer research: official J Am Association Cancer Res 26(1):220–231 Katz MHG, Petroni GR, Bauer T, Reilley MJ, Wolpin BM, Stucky CC et al (2023) Multicenter randomized controlled trial of neoadjuvant chemoradiotherapy alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic adenocarcinoma. J Immunother Cancer. ;11(12) Sanjay Kakar MCS, PhD*; MD, Volkan Adsay N, Patrick Fitzgibbons MD, Wendy MD, Frankel L, David MD, Klimstra S, Mari MAMKMD, Mino-Kenudson MD, Mary PDJ-NVMD (2017) Timothy Pawlik, MD, MPH, K. Washington, MD, PhD. Protocol for the Examination of Specimens From Patients With Carcinoma of the Pancreas College of American Pathologists;Version: PancreasExocrine 4001 Maeda S, Mederos MA, Chawla A, Moore AM, Shoucair S, Yin L et al (2022) Pathological treatment response has different prognostic implications for pancreatic cancer patients treated with neoadjuvant chemotherapy or chemoradiotherapy. Surgery 171(5):1379–1387 Wittmann D, Hall WA, Christians KK, Barnes CA, Jariwalla NR, Aldakkak M et al (2020) Impact of Neoadjuvant Chemoradiation on Pathologic Response in Patients With Localized Pancreatic Cancer. Front Oncol 10:460 Chuong MD, Frakes JM, Figura N, Hoffe SE, Shridhar R, Mellon EA et al (2016) Histopathologic tumor response after induction chemotherapy and stereotactic body radiation therapy for borderline resectable pancreatic cancer. J Gastrointest Oncol 7(2):221–227 Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1Characteristicsbasedontumorlocation.pptx Table2UniMultivariateanalyseseforindependentpredictorsofDFSandOS.pptx Cite Share Download PDF Status: Published Journal Publication published 22 Jan, 2025 Read the published version in Langenbeck's Archives of Surgery → Version 1 posted Editorial decision: Revision requested 14 Dec, 2024 Reviews received at journal 08 Dec, 2024 Reviews received at journal 03 Dec, 2024 Reviewers agreed at journal 01 Dec, 2024 Reviews received at journal 26 Nov, 2024 Reviewers agreed at journal 25 Nov, 2024 Reviewers agreed at journal 25 Nov, 2024 Reviewers invited by journal 25 Nov, 2024 Editor assigned by journal 05 Nov, 2024 Submission checks completed at journal 04 Nov, 2024 First submitted to journal 03 Nov, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5380534","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":374899837,"identity":"5cf647f6-51bd-450e-8b7b-24029d361725","order_by":0,"name":"Benson Kaluba","email":"","orcid":"","institution":"Mie University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Benson","middleName":"","lastName":"Kaluba","suffix":""},{"id":374899839,"identity":"b0c1e7b6-6acf-44ea-a3af-03fdfe3065b5","order_by":1,"name":"Naohisa Kuriyama","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIiWNgGAWjYHACZiC2AeIEMIIACcJa0kjXcpgBST0BYM5++LAx747z0fzsCawbHlQwJDawH37AYLkDtxbLnrTkZN4zt3Nn9jxgu5FwBqiFJ82AQfIMbi0GB3KMD/O23c7dcCOB7UZi2//EBoYcBgbJNjxazr8BaTmXux+s5R/QFv43BLTcyDFO5m07kLtBAqSlAahFgpAtN54lG85tS86dceZh242EYwzGbRLPDA7g9cv55MMSb9vscvvbk4/d/FHDINvPn/zwsSSeEEMCjA1gig2ID0s2EKUFWfdHkrWMglEwCkbBMAYAuIlTfgrxJvwAAAAASUVORK5CYII=","orcid":"","institution":"Mie University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Naohisa","middleName":"","lastName":"Kuriyama","suffix":""},{"id":374899840,"identity":"2870bbe2-38c7-4f06-9ea2-b81c32f5ba06","order_by":2,"name":"Tatsuya Sakamoto","email":"","orcid":"","institution":"Mie 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University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yasuhiro","middleName":"","lastName":"Murata","suffix":""},{"id":374899865,"identity":"f95b68b6-c065-46a6-ae3a-5bda0f08f03a","order_by":12,"name":"Akihiro Tanemura","email":"","orcid":"","institution":"Mie University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Akihiro","middleName":"","lastName":"Tanemura","suffix":""},{"id":374899866,"identity":"1deec27c-8fea-4889-9f07-e387ff96b77c","order_by":13,"name":"Masashi Kishiwada","email":"","orcid":"","institution":"Mie University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Masashi","middleName":"","lastName":"Kishiwada","suffix":""},{"id":374899867,"identity":"82636d94-8725-44fe-9c66-0e3d0f6f7fb4","order_by":14,"name":"Shugo Mizuno","email":"","orcid":"","institution":"Mie University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shugo","middleName":"","lastName":"Mizuno","suffix":""}],"badges":[],"createdAt":"2024-11-03 04:53:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5380534/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5380534/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00423-025-03609-8","type":"published","date":"2025-01-22T15:57:03+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":70402550,"identity":"da4c6f71-161e-4989-b517-db5dd8d6e199","added_by":"auto","created_at":"2024-12-02 22:36:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":175512,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patient selection\u003c/p\u003e\n\u003cp\u003eAmong 468 consecutive PDAC patients who underwent pancreatectomy from April, 2006 to August, 2022, 286 post- NARCT cases were enrolled while 182 non-NACRT were excluded. 218 had pancreatic head, 34 had pancreatic body and 34 had pancreatic tail tumors. The border between pancreatic head (Ph) and body (Pb) was the left side of superior mesenteric and portal vein (SMV/PV), while the border between the Pb and tail (Pt) was the left side of the abdominal aorta.\u003c/p\u003e\n\u003cp\u003ePDAC: Pancreatic ductal adenocarcinoma, NARCT: Neoadjuvant chemoradiotherapy, Ph: Pancreatic head, Pb: Pancreatic body, Pt: Pancreatic tail, PV: Portal vein, DU: Duodenum, SMV: Superior mesenteric vein, SpV: Splenic vein, SMA: Superior mesenteric artery\u003c/p\u003e","description":"","filename":"Fig1Flowchartofpatientselection1.png","url":"https://assets-eu.researchsquare.com/files/rs-5380534/v1/dc28727b3ed6c51219693e6a.png"},{"id":70402545,"identity":"49899995-2312-4b61-8800-796292d49784","added_by":"auto","created_at":"2024-12-02 22:36:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":50321,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curves based on tumor location in 286 pancreatic ductal adenocarcinoma patients\u003c/p\u003e\n\u003cp\u003eDisease-free (\u003cstrong\u003eA\u003c/strong\u003e) and overall survival (\u003cstrong\u003eB\u003c/strong\u003e) based on tumor location in 286 patients.\u003c/p\u003e\n\u003cp\u003ePh: Pancreatic head, Pb: Pancreatic body, Pt: Pancreatic tail, MST: Median survival time\u003c/p\u003e","description":"","filename":"Fig2Survivalcurvesbasedonlocation1.png","url":"https://assets-eu.researchsquare.com/files/rs-5380534/v1/4780e39e544bdc02795cbb49.png"},{"id":70402549,"identity":"4d278b3f-ac15-4f6b-83d1-3a43e22d0e96","added_by":"auto","created_at":"2024-12-02 22:36:28","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":86041,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curves based on pathological T-category according to tumor location\u003c/p\u003e\n\u003cp\u003eDisease-free and overall survival in pT1 (\u003cstrong\u003eA-B\u003c/strong\u003e; n=84), pT2 (\u003cstrong\u003eC-D\u003c/strong\u003e; n=72) and pT3/4 (\u003cstrong\u003eE-F\u003c/strong\u003e; n=130) sub-groups.\u003c/p\u003e\n\u003cp\u003ePh: Pancreatic head, Pb: Pancreatic body, Pt: Pancreatic tail, MST: Median survival time\u003c/p\u003e","description":"","filename":"Fig3SurvivalcurvesbasedonpTcategory1.png","url":"https://assets-eu.researchsquare.com/files/rs-5380534/v1/bfc503fea0e6deadea62debb.png"},{"id":70402546,"identity":"ef4f631e-b033-467f-90f7-8bbfb4dd106e","added_by":"auto","created_at":"2024-12-02 22:36:27","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":62001,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curves based on pathological N-category according to tumor location\u003c/p\u003e\n\u003cp\u003eDisease-free and overall survival in pN0 (\u003cstrong\u003eA-B\u003c/strong\u003e; n=200) and pN1/2 (\u003cstrong\u003eC-D\u003c/strong\u003e; n=86) sub-groups.\u003c/p\u003e\n\u003cp\u003ePh: Pancreatic head, Pb: Pancreatic body, Pt: Pancreatic tail, MST: Median survival time\u003c/p\u003e","description":"","filename":"Fig4SurvivalcurvesbasedonpNcategory1.png","url":"https://assets-eu.researchsquare.com/files/rs-5380534/v1/871122299885a39f03e20c55.png"},{"id":74858454,"identity":"23c357a1-1288-43e7-aad4-30c4ebe2f64a","added_by":"auto","created_at":"2025-01-27 16:09:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1299729,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5380534/v1/67b98290-7383-4577-b2cd-98cf4ebd0f37.pdf"},{"id":70403274,"identity":"e27611c8-a0dc-4299-a9c5-7683d5297576","added_by":"auto","created_at":"2024-12-02 22:44:27","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":56978,"visible":true,"origin":"","legend":"","description":"","filename":"Table1Characteristicsbasedontumorlocation.pptx","url":"https://assets-eu.researchsquare.com/files/rs-5380534/v1/455f36e02e9df047194e250a.pptx"},{"id":70402548,"identity":"4838a70f-2978-4948-a0a6-abc8e4ed614f","added_by":"auto","created_at":"2024-12-02 22:36:28","extension":"pptx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":54444,"visible":true,"origin":"","legend":"","description":"","filename":"Table2UniMultivariateanalyseseforindependentpredictorsofDFSandOS.pptx","url":"https://assets-eu.researchsquare.com/files/rs-5380534/v1/bb18dcb46e5a8cb6817e87bd.pptx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Long-term survival analysis based on tumor location in patients with pancreatic ductal adenocarcinoma who underwent pancreatectomy following neoadjuvant chemoradiotherapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePancreatic ductal adenocarcinoma (PDAC) is an aggressive solid tumor with a high mortality rate as reported among new cases in the recent 2020 Global Cancer Statistics (94.0%; 466,003 / 495,773 deaths)[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] and 2024 United States Cancer Statistics (77.9%; 51,750 / 66,440 deaths) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The challenge of treating PDAC is that 80\u0026ndash;85% of patients present at initial diagnosis with advanced unresectable or metastasised (UR-M) disease making them unfit for pancreatectomy. Unfortunately, prognosis for the 15\u0026ndash;20% cases undergoing surgery for either localised or resectable disease is still poor with overall survival (OS) rates of 24% in 1 year and 9% in 5 years [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere is still no consensus regarding survival outcomes based on tumor location in PDAC patients since previous studies indicate conflicting findings for both non-resected and resected pancreatic head (Ph), body (Pb) and tail (Pt) cases [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Moreover, it is still unclear whether survival outcomes are different for Ph, Pb and Pt PDAC patients undergoing surgical resection following neoadjuvant chemoradiotherapy (CRT). Embryologically, Ph, Pb and Pt originate differently leading to differences in histological structure, PDAC oncogenesis and eventually, response to neoadjuvant chemo/radiotherapy (CRT) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Even though CRT is associated with improved PDAC patients\u0026rsquo; survival [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], its role in resectable (R) cases is still a contentious issue since some reports have found no benefit of CRT and instead, advocate for upfront surgery (UFS) followed by adjuvant therapy [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. While, others argue that PDAC is a systemic disease with a potential for microscopic positive surgical margins (R1) and have reported a better survival in CRT patients compared to UFS resectable cases [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In clinical practice, the treatment effect of CRT on PDAC can be assessed both radiologically and histologically. The latter is a better surrogate for assessing treatment efficacy as it characterizes the residual tumor load[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] but the former is dependent on the timing, technique, imaging used[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and is also affected by peri-tumor edematous and fibrotic changes post CRT [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn 2016, the International consensus meeting on the definition and criteria of borderline resectable (BR) PDAC described the prognostic predictors of the disease as anatomical (A), biological (B) and conditional factors (C) factors[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In this definition, the anatomical factor involved the tumor interaction with such blood vessels as superior mesenteric artery (SMA) / celiac artery (CA), common hepatic artery (CHA), proper hepatic artery (PHA) or superior mesenteric vein/ portal vein (SMV/PV). Whereas, the biological factors included elevated serum carbohydrate antigen (CA) 19\u0026thinsp;\u0026minus;\u0026thinsp;9 level of more than 500 units/ml and presence of distant or regional lymph node metastases, while conditional factor was defined as pre-operative patients\u0026rsquo; performance status of 2 or more according to the Eastern Cooperative Oncology Group (ECOG) classification [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. As an addition to biological factors, several pathological predictors of survival such as arterial system invasion of SMA (Asm), portal venous system invasion of SMV (PVsm)[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], PV and splenic vein (SpV) invasion [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] have been reported in recent reports.\u003c/p\u003e \u003cp\u003eThe current study aimed at assessing whether long-term (5-year) survival outcomes were different for Ph, Pb and Pt PDAC patients who underwent pancreatectomy following CRT. The patients were recruited from our Institutional CRT protocol [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Additionally, independent prognostic predictors of disease-free (DFS) and overall survival (OS) were identified.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy population\u003c/h2\u003e\n \u003cp\u003eAmong 468 patients with localized PDAC who underwent pancreatectomy from April, 2006 to August 2022, 286 (61.1%) post-CRT were enrolled in this study, while 182 (38.9%) non-CRT cases were excluded (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Clinicopathological and operative data were obtained from a prospectively maintained database at the Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Hospital and analyzed based on tumor location. This study was ethically conducted and approved by Mie University Hospital Institutional Review Board (H2020-118).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eNeoadjuvant chemo-radiotherapy\u003c/h3\u003e\n\u003cp\u003eThe local Institutional gemcitabine-based CRT protocol (GEM-CRT) was launched in 2005 and switched to S-1/GEM-based (S-1/GEM-CRT) from 2011. Patients received 2 cycles of S-1 (60 mg/m\u003csup\u003e2\u003c/sup\u003e per day) administered orally for 21 days in a 28-day cycle combined with an infusion of gemcitabine (600 mg/m\u003csup\u003e2\u003c/sup\u003e) on days 8, 22, 36 and 50. Furthermore, three-dimensional (3D) conformal radiotherapy was administered with a total radiation dose of 45 to 50.4 Gy divided into 25 to 28 fractions [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]. Upon completion, radiological re-evaluation was done after 4\u0026ndash;6 weeks on dynamic CT-scan images as previously described [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eDefining tumor location\u003c/h3\u003e\n\u003cp\u003eTumor location was determined on dynamic CT-scan images as previously reported [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e] and as shown in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e; the border between Ph and Pb was the left side of superior mesenteric / portal vein (SMV/PV), while the border between the Pb and Pt was the left side of the abdominal aorta. Ph included also both the uncinate process and pancreatic neck. Lastly, tumor location was assigned based on the part of the pancreas where the tumor was, but in cases where a tumor was located in two or more adjacent parts, location was assigned to the main site.\u003c/p\u003e\n\u003ch3\u003eRadiological evaluation\u003c/h3\u003e\n\u003cp\u003ePre- and post-CRT dynamic CT-scan images were used to extract data regarding tumor size, clinical T- category and clinical N-category. Tumor resectability was also evaluated as previously reported [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e] and classified as R, borderline resectable-portal vein (BR-PV), borderline resectable-arterial (BR-A) and unresectable-locally advanced (UR-LA) according to the National Comprehensive Cancer Network (NCCN) clinical practice guidelines [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. Furthermore, clinical staging was evaluated according to the 8th TNM classification of the Union for International Cancer Control (UICC) [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]. The data were appropriately analyzed and compared based on tumor location as shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003ch3\u003eSurgical outcomes\u003c/h3\u003e\n\u003cp\u003ePatients with Ph tumors underwent pancreatoduodenectomy (PD) using an anterior approach to superior mesenteric artery (SMA) as described by Mizuno et al.[\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e], while those with Pb and Pt tumors underwent distal pancretectomy (DP) with a radical antegrade modular pancreatosplenectomy (RAMPS) procedure as recently reported by Kuriyama et al. [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eAssessment of pathological outcomes\u003c/h2\u003e\n \u003cp\u003eThe pathological data in this study were similar to our recent report [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e] and apart from tumor size, stage, tumor differentiation, resection margins, nodal and portal vein invasion, data on histological response to CRT were also retrieved based on the Evans tumor grading ; 1 (\u0026lt;\u0026thinsp;10 or no tumor cell destruction), 2a (destruction of 10%-50% of tumor cells), 2b (destruction of 51% \u0026ndash; 90% of tumor cells), 3 (\u0026lt;\u0026thinsp;10% tumor cells present) and 4 (no viable tumor cells present) [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e]. Data on histological treatment response to CRT that were recorded according to the General Rules for the Study of Pancreatic Cancer (7th Edition) by the Japan Pancreas Society (7th JPS) were re-classified to the Evans grading as guided by the 7th JPS [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eAdjuvant chemotherapy\u003c/h3\u003e\n\u003cp\u003eFollowing surgical resection, from 2006 to 2013, all patients received GEM (800 mg/m\u003csup\u003e2\u003c/sup\u003e) biweekly as adjuvant chemotherapy, while from 2013, oral S-1 (60 mg/m\u003csup\u003e2\u003c/sup\u003e per day) was administered on days 1\u0026ndash;14 in a 21-day cycle. However, depending on how a patient tolerated any of these drugs, the two regimens were switched as previously described [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eSurvival analyses\u003c/h3\u003e\n\u003cp\u003eThe Kaplan-Meier method with a log-rank test was used to analyze DFS and OS based on tumor location (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA-B), pathological T-category (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA-F) and N- category (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eA-D) according to tumor location, respectively.\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eIdentifying significant prognostic predictors of disease-free and overall survival\u003c/h2\u003e\n \u003cp\u003eTo determine significant independent prognostic predictors of both DFS and OS, univariate analyses for the clinicopathological variables were first performed. Then those variables which had \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in the univariate analyses, were respectively included in a multivariate stepwise forward Cox logistic regression analyses, Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ch2 align=\"left\" class=\"colspec\"\u003eStatistics analyses\u003c/h2\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003cp\u003eFive-year DFS and OS were the primary end-points. DFS was calculated in months from the date of surgery to the date of recurrence, last visit (for the alive patients) or death, while OS was calculated from date of surgery to date of death or last visit for the alive patients. Continuous variables were expressed as median (range) and appropriately compared based on tumor location using either the Mann\u0026ndash;Whitney \u003cem\u003eU\u003c/em\u003e test or Kruskal\u0026ndash;Wallis test. Categorical variables were compared using either Pearson\u0026apos;s chi-squared or Fisher\u0026apos;s exact test. The Kaplan-Meier method with log-rank test was used to analyze DFS and OS based on tumor location, pathological T- and N-categories according to tumor location. To determine predictors of both DFS and OS, multivariate stepwise forward Cox logistic regression analyses were conducted for variables which had \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in the univariate analyses, respectively. Statistical package SPSS version 23 (IBM SPSS Statistics for Windows, v. 23.0; IBM, Armonk, NY, USA) was used for all analyses, and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eClinical outcomes before and after neoadjuvant chemo-radiotherapy\u003c/h2\u003e \u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, among the 286 patients, 218 (76.2%) had Ph, 34 (11.9%) had Pb and 34 (11.9%) had Pt PDAC tumors, respectively. There was no difference among the patients based on carbohydrate antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9 (CA19-9; U/mL), carcinoembryonic antigen (CEA; ng/mL), radiological tumor size (mm) and N-category (N0 / N1/N2). However, there was a significant difference based on tumor resectability (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), T-category (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and clinical stage (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Most importantly, Ph patients exhibited more advanced tumors; clinical T3/T4; 54.6% (Ph) / 38.3% (Pb) / 44.1% (Pt), respectively before CRT (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and 55.5% (Ph) / 23.2% (Pb) / 35.3% (Pt), respectively after CRT (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Secondly, clinical stage 3 tumors were; 48.2% (Ph) / 29.4% (Pb) vs. 0% (Pt), respectively before CRT (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and 53.2% (Ph) / 20.6% (Pb) / 0% (Pt), respectively after CRT (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Then lastly, Ph patients had more UR-LA cases; 22.0% for Ph vs. 11.8% for Pb vs. 0 for Pt cases, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSurgical and pathological outcomes\u003c/h2\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003eSurgical outcomes\u003c/h2\u003e \u003cp\u003ePancreatoduodenectomy (PD) was performed in 100% and 32.4% of Ph and Pb patients, respectively. While, DP was done in 67.6% (Pb) and 100% (Pt) cases, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Ph patients (78.0%) underwent significantly more combined SMV/PV resection and reconstruction than the Pb (41.2%) and Pt (0%), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001.However, arterial resection ( celiac axis, common hepatic or proper hepatic arteries) and reconstruction were similar between the Ph (5.5%) and Pb (8.8%) patients as no Pt patient had arterial resection, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.248 (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003ePathological outcomes\u003c/h2\u003e \u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, patients were similar based on pathological tumor size (mm), resection margins (R0/R1), N-category, portal venous system (pPV) invasion, neural (pne) invasion, lymphatics (ply) invasion, venous system (pve) invasion, serosal side of the anterior pancreatic tissue (pS) invasion and retropancreatic tissue (pRP) invasion and pathological stage. However, the three groups were different based on tumor differentiation (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014), T-category (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008), arterial system invasion (pA; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004) and histological treatment effect (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015). According to the Evans grading, Ph cases had a better treatment response to CRT than Pb and Pt cases; Evans 3 /4 grade (\u0026lt;\u0026thinsp;10% to no viable tumor cells present in surgical specimens): 84 (38.5%) / 23 (10.6%) for Ph vs. 6 (17.6%) / 2 (5.9%) for Pb vs. 7 (20.8%) / 2 (5.9%) for Pt cases, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eSurvival analyses based on tumor location\u003c/h2\u003e \u003cp\u003eLong-term survival outcomes were statistically comparable among the three groups. Five-year DFS were; 26.4% (Ph) vs. 16.5% (Pb) vs. 33.1% (Pt), respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.691), Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA. Whereas OS were; 25.4% (Ph) vs. 27.7% (Pb) vs. 32.0% (Pt), respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.341), Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eSurvival analyses based on pathological T- and N-categories according to tumor location\u003c/h2\u003e \u003cp\u003eWhen we compared survival outcomes based on pT-category, 5-year survival outcomes were statistically similar among the less advanced tumors; pT1 (n\u0026thinsp;=\u0026thinsp;84), Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-B and pT2 (n\u0026thinsp;=\u0026thinsp;72), Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC-D but different among the advanced tumors (pT3/T4) with regards to tumor location. For the pT3/T4 (n\u0026thinsp;=\u0026thinsp;130) subgroup, 5-year DFS was significantly better for Ph patients; 18.5% (Ph) / N/A (Pb) / N/A (Pt), respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026), yet OS was favorable in Pt patients but worse for the Pb cases; 13.3% (Ph) / N/A (Pb) / 25.0% (Pt) months, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008), Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eE-F. Additionally, analyses based on pN-category according to tumor location revealed similar long-term survival outcomes for both the pN0 (n\u0026thinsp;=\u0026thinsp;200) and pN1/N2 (n\u0026thinsp;=\u0026thinsp;86) patients as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA-D.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eSignificant independent predictors of disease-free and overall survival\u003c/h2\u003e \u003cp\u003eIn univariate and multivariate analyses, tumor location was not an independent predictor of both DFS and OS. Instead, predictors of DFS were CA19-9 (HR; 1.001, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), pathological tumor size (HR; 1.020, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), pathological lymph node invasion (HR; 0.796, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004), resection margins (HR; 0.777, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004) and pPV system invasion (HR; 0.633, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009). Whereas, CA19-9 (HR; 1.001, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), resection margins (HR; 0.756, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), pPV system invasion (HR; 0.620, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004) and pathological tumor stage (HR; 1.069, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were predictors of OS, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this single-center retrospective study, we observed that even though Ph patients clinically presented with significantly more advanced and aggressive initial tumors than Pb and Pt ones, following CRT, 5-year survival outcomes were statistically comparable among the three groups. This was attributed to Ph patients demonstrating a better histological treatment response to CRT than the Pb and Pt cases (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Firstly, our findings reflects the effectiveness of CRT in treating PDAC, including patients with more advanced tumors. Secondly, considering the differences in histological treatment response based on tumor location, it can be suggested that tumors of the Ph might be more receptive to the effects of CRT compared to those of the Pb and Pt. In multivariate analyses, significant independent predictor of both DFS and OS were CA19-9, resection margins and pPV system invasion. Additionally, pathological tumor size and lymph node invasion were predictors of DFS, while pathological stage was also a predictor of OS (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe positive impact of CRT in PDAC has widely been reported [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], but its role in R cases is still debatable as some favor UFS followed by adjuvant therapy and have found no superiority of CRT over UFS [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], yet others report the opposite [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Nonetheless, long-term survival outcomes for Ph, Pb and Pt PDAC patients undergoing pancreatectomy following CRT still remain unclear.\u003c/p\u003e \u003cp\u003eIn view of the above, this study recruited post-CRT PDAC patients that underwent surgical resection and aimed at assessing whether long-term (5-year) survival rates were different based on tumor location, especially considering that most of previous studies which assessed survival outcomes based on tumor location involved mainly UFS patients. Artinyan et.al. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] did not indicate whether their participants received CRT or not, but similar to us, their Ph patients had more T3 / T4 tumors than the Pb/Pt cases, yet OS was much better for their Ph patients which was attributed to the more number of harvested lymph nodes compared to the Pb/Pt patients. However, van Erning et al.[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] only had 67 / 2311 (3%) Ph vs. 11 / 104 (11%) Pb vs. 5 / 206 (2%) Pt patients who received neoadjuvant chemotherapy (NAC) alone and OS was comparable even though Pt cases had significantly more large-sized tumors (\u0026gt;\u0026thinsp;40 mm); 21% (Ph) / 40% (Pb) / 51% (Pt), but no cause was cited for these findings. In contrast, tumor size was similar among our patients. Lastly, Winer et al.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] had 1,673 / 32,990 (5.1%) Ph vs. 186 (6.4%) Pb vs. 88 / 5078 (1.7%) Pt patients who received CRT and contrary to us, besides their Ph cases having more earlier-stage tumors (1/2); 39.2 (Ph) vs. 19.7% (Pb) vs. 16.0% (Pt), they had the worst OS due to having more pathologically advanced tumors. For us though, Ph patients had significantly more initial stage 3 and UR-LA tumors, yet except for tumor differentiation, almost all the pathological characteristics were similar among the three groups. Moreover, Ph patients demonstrated a better response to CRT than the other 2 groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e This in itself could explain why long-term survival rates were similar based on tumor location (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSubgroup analyses based on pathological T-category showed that for less advanced tumors; pT1 (n\u0026thinsp;=\u0026thinsp;84) and T2 (n\u0026thinsp;=\u0026thinsp;72) cases, long-term survival rates were comparable among the Ph, Pb and Pt patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-D), but among patients with advanced tumors (pT3/ T4, n\u0026thinsp;=\u0026thinsp;130), Pb patients had the least favorable long-term survival (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eE-F). However, as a study limitation, Pb and Pt patients were fewer compared to the Ph cases across these sub-cohorts. Nonetheless, the poor OS among the Pb cases for the pT3/T4 cases can be attributed to them having more prevalent R1 cases as shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; \u003cb\u003e19\u003c/b\u003e.3% (Ph) vs. 29.4% (Pb) vs. 14.7% (Pt) and possibly, the presence of intra-abdominal occult metastatic disease which is estimated to be present at surgical exploration in 11\u0026ndash;24% of PDAC patients [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In previous reports, Lee et al.[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] observed comparable OS rates among 646 Ph and Pb / Pt UFS patients in cT1 (n\u0026thinsp;=\u0026thinsp;96), cT3 (n\u0026thinsp;=\u0026thinsp;103) and cT4 (n\u0026thinsp;=\u0026thinsp;11) cases which they attributed to smaller sub-groups, but Pb / Pt cases had a better OS than Ph ones among the cT2 (n\u0026thinsp;=\u0026thinsp;426) patients. Additionally, survival rates were comparable among their nodal-involvement sub-group which was similar to our results (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA-D), Lastly, Meng et al.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] also did not indicate whether their participants received CRT or not, but observed that tumor location was a predictor of survival only in early (T1) tumors. However, our findings indicate that CRT was equally effective in treating early (T1/T2) tumors as both DFS and OS rates were similar among the Ph, Pb and Pt patients, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-D.\u003c/p\u003e \u003cp\u003eSeveral anatomical, biological and conditional prognostic factors of PDAC have been reported recently [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Similar to us, both Lee et al.[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] and Malleo et al.[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] observed that tumor location was not a predictor of survival, but CA19-9, N-category, T-category, tumor grade,[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] lymphatic invasion, resection margins and tumor stage [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] were. However, in some reports, tumor location was identified as an independent predictor of survival [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. We, however, identified CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9, resection margins (R0 / R1) and PV system invasion as predictors of both DFS and OS (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The International consensus meeting on definition and criteria of borderline resectable PDAC [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] reported that a pre-operative CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9\u0026thinsp;\u0026gt;\u0026thinsp;500 U /mL was linked to poor survival, while Kobayashi et al.[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] noticed that a\u0026thinsp;\u0026gt;\u0026thinsp;50% CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 reduction post-CRT was prognostic for a better survival. Interestingly, our Ph patients had the best CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 reduction rate; 77.0% (Ph) vs. 52.6% (Pb) vs. 3.6% (increment for Pt) which might indicate a better response to CRT by the Ph patients than both the Pb and Pt ones, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Following CRT, R0 is linked to a better survival than R1, [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] and unfortunately, our Pb cases had more R1 cases with worst survival among the subgroup of advanced tumors (pT3/T4 patients), Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eE-F. Portal vein system invasion is a significant indicator of survival in PDAC [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] and similarly, Kuriyama et al.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] found that splenic vein involvement in PDAC was associated with poor survival. Furthermore, our results indicate that PV system invasion is a better predictor of survival than arterial system invasion (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e ) and since veins have thinner walls than arteries [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], we can postulate that PDAC might easily invade the thin walls of the PV than the arterial system, thereby directly introducing tumor cells into the blood stream. We also identified pathological tumor size, nodal status as predictors of DFS and pathological stage for OS whose predictive significance have previously been described [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe impact of CRT on Ph, Pb and Pt tumors is unclear as there are limited studies which focused on this. However, these pancreatic sites originate differently leading to differences in tumor oncogenesis, invasiveness and chemo /radiotherapy resistance [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Chemoradiotherapy causes tumor cell apoptosis, remodels the complex and dense tumor microenviroment (TME) filled with immunosuppressive cells; cancer-associated fibroblasts, myeloid-derived suppressor cells and regulatory T cells [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. The TME modulation results in increased density of tumor-infiltrating lymphocytes which enhances antitumoral immune response [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. In clinical practice, as mentioned earlier, this effect can be assessed both radiologically and pathologically. For pathological assessment, surgical specimens are used to assess present viable tumor cell load based on the Evans [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] Japan Pancreas Society [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] and College of American pathologists [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] systems. Among 525 PDAC patients, Maeda et al.[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] found that histological treatment response was better for CRT (377; 71.8%) than NAC alone (148; 28.2%) patients. We, however, excluded the NAC cases and included only CRT ones (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In other reports, both Wittman et al.[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] and Chuong et al.[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] observed that improved histological response to CRT was associated with improved survival for PDAC patients. Since our Ph patients had a better histological response to CRT than the Pb and Pt patients based on the Evans grade and if we consider the possibility that Ph tumors respond much better to CRT than those of Pb and Pt, it might be as result of them having a microenviroment that is more favorable and receptive to the effects of CRT than that of the Pb and Pt tumors. However, further studies are needed to verify this fact. For the current study though, the better response to CRT can explain how the Ph patients were able to overcome the burden of having significantly more advanced initial tumors than the Pb and Pt patients and result in comparable pathological and survival outcomes.\u003c/p\u003e \u003cp\u003eHowever, the current study has some limitations. Firstly, it was a single-center retrospective study and secondly, they were few Pb and Pt patients for better analyses among the pT sub-groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-E). Consequently, further multicenter prospective studies are needed to validate our findings.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eEven though Ph patients clinically presented with significantly more advanced initial tumors than the Pb and Pt cases, they had the best histological treatment response to CRT and consequently, long-term survival outcomes were comparable among the 3 groups.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003e \u003cb\u003eConflict of Interest\u003c/b\u003e\u003c/strong\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eStudy conception and design: Benson Kaluba, Naohisa Kuriyama, Masashi Kishiwada, and Shugo Mizuno. Acquisition of data: Benson Kaluba, Naohisa Kuriyama, Tatsuya Sakamoto, Haruna Komatsubara, Koki Maeda, Daisuke Noguchi, Kazuyuki Gyoten, Takahiro Ito, Aoi Hayasaki, Takehiro Fujii, Yusuke Iizawa, Yasuhiro Murata, and Akihiro Tanemura. Analysis and interpretation of data: All the authors participated in the critical revision of the manuscript for important intellectual content. All the authors approved the final version to be published and agreed to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved. Drafting of the manuscript and critical revision of the manuscript: Benson Kaluba, Naohisa Kuriyama and Masashi Kishiwada. All authors have read and approved the manuscript.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eThe study was performed in accordance with the ethical principles stipulated in the Declaration of Helsinki. Ethics approval was sought and granted by the Ethics Committee of Mie University Graduate School of Medicine (H2020-118). All participants provided informed consent for participation and for the use of their medical records through an optout form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eORCID ID\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBenson Kaluba: https://orcid.org/0000-0003-1057-3251\u003c/p\u003e\n\u003cp\u003eNaohisa Kuriyama: https://orcid.org/0000-0002-9668-0500\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. 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Protocol for the Examination of Specimens From Patients With Carcinoma of the Pancreas College of American Pathologists;Version: PancreasExocrine 4001\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaeda S, Mederos MA, Chawla A, Moore AM, Shoucair S, Yin L et al (2022) Pathological treatment response has different prognostic implications for pancreatic cancer patients treated with neoadjuvant chemotherapy or chemoradiotherapy. Surgery 171(5):1379\u0026ndash;1387\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWittmann D, Hall WA, Christians KK, Barnes CA, Jariwalla NR, Aldakkak M et al (2020) Impact of Neoadjuvant Chemoradiation on Pathologic Response in Patients With Localized Pancreatic Cancer. Front Oncol 10:460\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChuong MD, Frakes JM, Figura N, Hoffe SE, Shridhar R, Mellon EA et al (2016) Histopathologic tumor response after induction chemotherapy and stereotactic body radiation therapy for borderline resectable pancreatic cancer. J Gastrointest Oncol 7(2):221\u0026ndash;227\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"langenbecks-archives-of-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"laos","sideBox":"Learn more about [Langenbeck's Archives of Surgery](http://link.springer.com/journal/423)","snPcode":"423","submissionUrl":"https://submission.nature.com/new-submission/423/3","title":"Langenbeck's Archives of Surgery","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Pancreatic ductal adenocarcinoma, Tumor location, Neoadjuvant chemoradiotherapy, Survival outcomes","lastPublishedDoi":"10.21203/rs.3.rs-5380534/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5380534/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThe study aimed at assessing whether long-term survival outcomes were different based on tumor location in patients with pancreatic ductal adenocarcinoma who underwent pancreatectomy following neoadjuvant chemoradiotherapy (CRT).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e286 patients with localized PDAC were enrolled and divided as head (Ph\u0026thinsp;=\u0026thinsp;218), body (Pb\u0026thinsp;=\u0026thinsp;34) and tail (Pt\u0026thinsp;=\u0026thinsp;34). 5-year survival analyses were performed and independent predictors of disease-free survival (DFS) and overall survival (OS) were identified.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePh patients exhibited a higher incidence of initial clinical stage 3 tumors (48.2%) compared to Pb (29.4%) and Pt (0%), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 with more UR-LA cases (22.0%) compared to Pb (11.8%) and Pt (0%), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001. However, they demonstrated a better response to CRT; Evans grades 3/4 in 49.1% Ph vs. 23.5% Pb and 26.5% Pt, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015. 5-year DFS were; 26.4% (Ph) vs. 16.5% (Pb) vs. 33.1 (Pt), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.691 and OS; 25.4% (Ph) vs. 27.7% (Pb) vs. 32.0% (Pt), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.341. Significant predictors for both DFS and OS included CA19-9 levels, resection margins and pathological portal vein invasion, with tumor size and nodal invasion also influencing DFS, while pathological stage impacting OS.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eBased on tumor location, long-term survival outcomes were comparable and was attributed to a better response to CRT by Ph than the Pb and Pt patients.\u003c/p\u003e","manuscriptTitle":"Long-term survival analysis based on tumor location in patients with pancreatic ductal adenocarcinoma who underwent pancreatectomy following neoadjuvant chemoradiotherapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-02 22:36:23","doi":"10.21203/rs.3.rs-5380534/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-15T04:32:37+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-08T11:39:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-03T15:04:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"165215355875875191857456840823062434496","date":"2024-12-01T22:09:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-26T23:46:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"29209210559097753088474209215517275676","date":"2024-11-25T20:01:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"35318193775825066421562274600973817297","date":"2024-11-25T14:02:11+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-25T13:28:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-05T05:31:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-05T00:21:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"Langenbeck's Archives of Surgery","date":"2024-11-03T04:41:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"langenbecks-archives-of-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"laos","sideBox":"Learn more about [Langenbeck's Archives of Surgery](http://link.springer.com/journal/423)","snPcode":"423","submissionUrl":"https://submission.nature.com/new-submission/423/3","title":"Langenbeck's Archives of Surgery","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"61a1caa0-2e58-411a-a33c-9b1fb2689f05","owner":[],"postedDate":"December 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-27T16:03:13+00:00","versionOfRecord":{"articleIdentity":"rs-5380534","link":"https://doi.org/10.1007/s00423-025-03609-8","journal":{"identity":"langenbecks-archives-of-surgery","isVorOnly":false,"title":"Langenbeck's Archives of Surgery"},"publishedOn":"2025-01-22 15:57:03","publishedOnDateReadable":"January 22nd, 2025"},"versionCreatedAt":"2024-12-02 22:36:23","video":"","vorDoi":"10.1007/s00423-025-03609-8","vorDoiUrl":"https://doi.org/10.1007/s00423-025-03609-8","workflowStages":[]},"version":"v1","identity":"rs-5380534","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5380534","identity":"rs-5380534","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}