Prognostic value of margin clearance in total and distal pancreatectomy specimens with pancreatic ductal adenocarcinoma in a Danish population-based nationwide study.

BACKGROUND: The prognostic role of resection margin status following total (TP) and distal (DP) pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) is insufficiently evaluated. In Denmark, pancreatic surgery, including the postoperative pathological examination of the resection specimens, is confined to four centres, all reporting to the Danish Pancreatic Cancer Database (DPCD). In this Danish population-based nationwide study on TP and DP for PDAC from 2015-2019, based on data from DPCD, we evaluated whether there is a prognostically relevant minimum margin clearance definition and whether certain margins hold independent prognostic information. METHODS: Clinical and pathological data were retrieved from DPCD and supplemented by review of pathology reports and re-microscopy, if needed. One of the study pathologists performed all re-microscopy. The prognostic significance of margin status was evaluated by dichotomisation of the TP cohort (n = 101) and the DP cohort (n = 90) into involved and uninvolved groups, using different clearance definitions (0.5 - ≥3.0 mm). RESULTS: Following TP, direct involvement of the superior mesenteric artery (SMA) margin had independent prognostic value. When using a clearance definition of ≥ 0.5 or ≥ 1.5 mm for SMA, median survival for R0 versus R1 was 19 (95% CI 14-26) versus 10 (95% CI 5-20) months (p = 0.010), and 21 (95% CI 15-30) versus 10 (95% CI 8-19) months (p = 0.011), respectively. Overall margin status was not of significant prognostic importance following neither DP nor TP. CONCLUSION: In this Danish population-based nationwide study, SMA margin involvement was a significant isolated prognostic factor following TP, whereas combined assessment of all circumferential margins did not hold statistically significant prognostic information. Following DP, resection margin status did not affect survival.

Prognostic importance of margin clearance in ampullary adenocarcinoma following pancreaticoduodenectomy in a Danish population-based nationwide study.

BACKGROUND: In this Danish nationwide population-based study, we evaluated the prognostically relevant minimum tumour-free margin width following pancreaticoduodenectomy (PD) for ampullary adenocarcinoma (AAC) and evaluated whether certain margins hold independent prognostic information. METHODS: We included 128 patients who underwent PD for AAC from 2015 to 2019. Clinical and pathological data including well-known prognostic factors were retrieved from the Danish Pancreatic Cancer Database. Missing data were obtained by review of pathology reports and re-microscopy of resection specimens. All PD specimens were examined using a standardised pathological protocol including multicolour inking, axial slicing and exact reporting of margin widths. The cohort was dichotomised into involved and uninvolved groups, using different margin clearance definitions (0.5-≥3.0 mm). RESULTS: Following PD for AAC, margin clearance of ≥1 mm was independently associated with improved chance of survival compared with <1 mm (HR: 0.30, 95 % CI: 0.14-0.64 (p = 0.002)). Posterior and anterior margin widths were narrower compared with superior mesenteric artery and vein margins. Posterior margin and anterior surface had isolated prognostic significance in multivariable analysis. CONCLUSION: Following PD for AAC, margin clearance of at least 1 mm is independently associated with improved survival. Our data further indicate that anterior surface and posterior margin hold particular prognostic value.

What is long-term survival in patients with peritoneal metastasis from gastric, pancreatic, or colorectal cancer? A study of patients treated with systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC).

Objectives: A definition of long-term survival (LTS) in patients with peritoneal metastasis (PM) from gastric cancer (GC), pancreatic cancer (PC) or colorectal cancer (CRC) treated with systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC) is lacking. We aimed to define LTS and investigate characteristics and treatment response in patients who reached LTS in data from two prospective trials. Methods: Retrospective study of patients with GC-, PC-, or CRC-PM from the prospective PIPAC-OPC1 and PIPAC-OPC2 studies. The definition of LTS was based on published systematic reviews and randomized controlled trials. LTS was defined at the time point where 25 % of the patients were alive in these studies. Histology based response was evaluated by the mean Peritoneal Regression Grading Score (PRGS) using biopsies obtained prior to PIPAC 3, and defined by a mean PRGS of ≤2.0 or a decrease of mean PRGS of ≥1, compared to baseline. Results: LTS was defined at 21 (GC), 15 (PC), and 24 (CRC) months. Fifty-one (47.2 %) patients (nine GC, 17 PC, 25 CRC) reached LTS calculated from the date of PM diagnosis. All but one received palliative chemotherapy before PIPAC, and 37 % received bidirectional treatment. More than 90 % of the LTS patients had response according to PRGS. The mOS from PIPAC 1 was 23.3, 12.4, and 28.5 months for GC, PC, and CRC LTS patients. Conclusions: Patients with PM from GC, PC, and CRC treated with systemic chemotherapy and PIPAC can reach LTS and most show histological response. Causality must be further investigated.

Prognostic significance of margin clearance in pancreaticoduodenectomy specimens with pancreatic ductal adenocarcinoma in a Danish population-based nationwide study.

BACKGROUND: In this nationwide population-based cohort study, we investigated the overall minimum margin width that is independently associated with improved survival following pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) and evaluated whether certain margins or surfaces hold independent prognostic significance. METHODS: Data from 367 patients who underwent PD for PDAC in the period 2015-2019 were retrieved from the Danish Pancreatic Cancer Database. Missing data were obtained by review of pathology reports and re-microscopy of resection specimens. Surgical specimens were evaluated using a standardised pathological protocol involving multicolour inking, axial slicing and exact reporting of circumferential margin clearances in 0.5 mm increments. RESULTS: When categorised according to margin widths of <0.5, <1.0, <1.5, <2.0, <2.5 and <3.0 mm, R1 resections were detected in 34%, 57%, 75%, 78%, 86% and 87% of cases, respectively. In multivariable analyses, an overall margin clearance of ≥1.5 mm was associated with improved survival compared with a clearance of <1.5 mm (HR 0.70 95% CI 0.51-0.97 (p = 0.031)). When evaluating the margins separately, no margin had independent prognostic significance. CONCLUSION: Margin clearance of at least 1.5 mm was independently associated with improved survival following PD for PDAC.

Importance of biopsy site selection for peritoneal regression grading score (PRGS) in peritoneal metastasis treated with repeated pressurized intraperitoneal aerosol chemotherapy (PIPAC).

Objectives: The four-tiered peritoneal regression grading score (PRGS) is used for histological response evaluation in patients with peritoneal metastasis (PM) treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC). Four quadrant biopsies (QBs) from the parietal peritoneum should be assessed by PRGS, but consensus on biopsy site strategy for follow-up biopsies during repeated PIPACs is lacking. We aimed to evaluate whether there is a difference between PRGS in QBs from clips marked PM (QB-CM) compared to biopsies from PM with the visually most malignant features (worst biopsy, WB). Methods: Prospective, descriptive study. During the first PIPAC, index QBs sites were marked with metal clips. During the second PIPAC, an independent surgical oncologist selected biopsy site for WB and biopsies were taken from QB-CM and WB. One blinded pathologist evaluated all biopsies according to PRGS. From each biopsy, three step sections were stained H&E, followed by an immunostained section, and another three step sections stained H&E. Results: Thirty-four patients were included from March 2020 to May 2021. Median age 64 years. Maximum mean PRGS in QB-CM at PIPAC 1 was 3.3 (SD 1.2). Maximum mean PRGS in QB-CM at PIPAC 2 was 2.6 (SD 1.2), whereas mean PRGS in WB at PIPAC 2 was 2.4 (SD 1.3). At PIPAC 2, there was agreement between maximum PRGS from QB-CM and PRGS from WB in 21 patients. Maximum PRGS from QB-CM was higher in nine and lower in four patients, compared to PRGS from WB. Conclusions: Biopsies from QB-CM did not overestimate treatment response compared to biopsies from WB.

Healthcare use in the year preceding a diagnosis of pancreatic cancer: a register-based cohort study in Denmark.

OBJECTIVE: To describe the use of healthcare prior to a diagnosis of pancreatic cancer in Denmark. DESIGN: A population-based cohort study using prospectively recorded data from Danish National Health Registries. SETTING: Danish general practice and hospitals. SUBJECTS: A total of 5926 patients diagnosed with pancreatic cancer in 2012-2018 and 59,260 matched references without pancreatic cancer from the Danish general population. MAIN OUTCOME MEASURES: The monthly frequency of healthcare use (contacts and tests in general practice and contacts and diagnostic investigations in hospitals) during the 12 months preceding the pancreatic cancer diagnosis and a corresponding index date assigned to the references. RESULTS: Compared to the references, the patients had increased contacts and diagnostic tests, especially blood glucose testing, in general practice from 7 to 12 months before diagnosis. Hospital contacts and diagnostic imaging increased from 5 months before the diagnosis. CONCLUSIONS: The pattern of increasing healthcare contacts before a diagnosis of pancreatic cancer may represent a window of opportunity to diagnose pancreatic cancer earlier. The increased use of blood glucose test in general practice may represent an important sign of an underlying disease. Key pointsPancreatic cancer is a rapidly progressing and highly lethal disease. Focus on early diagnosis is essential to improve the prognosis.Patients with pancreatic cancer had increased number of healthcare contacts from 7 months before the diagnosis.Patients with pancreatic cancer had increased number of blood glucose tests taken throughout almost the entire year before the diagnosis.The results may indicate that a window of opportunity exists to diagnose pancreatic cancer earlier.

Patterns of Palliative Chemotherapy and Survival in Patients With Pancreatic Cancer Focusing on Age: A Nationwide Real-World Danish Registry Study.

OBJECTIVES: The aim of this study was to identify patterns of palliative chemotherapy (CTh) and the associated overall survival (OS) in patients with pancreatic cancer, with specific focus on age. METHODS: Between May 1, 2011, and April 30, 2016, 4260 patients were registered in the Danish Pancreatic Cancer Database. The 1715 patients receiving palliative CTh were retrieved. Age was grouped into less than 70, 70 to less than 75, and 75 years or more. RESULTS: Of the 1715 patients receiving first-line CTh, 586 (34%) underwent second-line CTh and 151 (9%) third-line CTh. First-line gemcitabine resulted in a significant worse survival compared with combination CTh, hazard ratio 1.51. For combination CTh, OS differed between the age groups, P < 0.01. The median OS in the less than 70 years (n = 547), 70 to less than 75 years (n = 163), and 75 years or more (n = 67) groups were 9.3, 9.6, and 7.2 months, respectively. No differences in survival were observed among patients receiving first-line gemcitabine (P = 0.35). CONCLUSIONS: Our findings are useful in treatment-related decision making in patients with pancreatic cancer. A significant survival benefit was observed for all patients after first-line combination CTh. The effect of combination CTh was most prominent among patients aged less than 75 years. By age, no differences in survival were observed in those receiving gemcitabine.

Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC)-directed treatment of peritoneal metastasis in end-stage colo-rectal cancer patients.

BACKGROUND: Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) represents a novel approach to intraperitoneal chemotherapy. Hereby results, obtained with PIPAC in patients with advanced peritoneal metastasis (PM) from colorectal cancer (CRC), are presented. METHODS: Data from CRC patients (n = 24) included in the prospective PIPAC-OPC1 and PIPAC-OPC2 trials are reported. Oxaliplatin 92 mg/m2 was administered at 4-6-week intervals. A CE certified nebulizer was used to aerosolize the chemotherapeutics. Outcome criteria were objective tumor response, survival and adverse events. RESULTS: Retrospective analysis of 74 PIPAC procedures carried out in 24 consecutive patients with PM from CRC included from October 2015 to February 2019. Five patients had still the primary tumor in situ, and 22 patients had received palliative systemic chemotherapy. Nineteen patients completed more than two PIPAC procedures, and objective tumor response according to the histological Peritoneal Regression Grading Score (PRGS) was observed in 67% of the patients, while 21% had stable disease. Four patients (21%) had complete response (mean PRGS = 1 and negative cytology). We recorded a median survival of 37.6 (range 7.3-48.9) months from the time of PM diagnosis, whereas it was 20.5 (range 0.13-34.7) months following the first PIPAC session. Minor postoperative complications were noted, and few were considered causally related to the PIPAC treatment. However, two cases of severe postoperative complications were recorded (urosepsis and iatrogenic bowel perforation). CONCLUSIONS: PIPAC with low-dose oxaliplatin can induce objective tumor regression in selected patients with advanced PM from colorectal cancer.

Initial treatment and survival in 4163 Danish patients with pancreatic cancer: A nationwide unselected real-world register study.

BACKGROUND: Nationwide register data on the effect of primary treatment on survival in an unselected population of patients with pancreatic cancer (PC) have not been reported before. The study aim was to investigate the overall survival (OS) related to initial treatment with resection, chemotherapy, or best supportive care (BSC) in all patients diagnosed with PC in Denmark from 2011 to 2016. METHODS: From 1 May 2011 to 30 April 2016, 4260 patients with PC were identified in the Danish Pancreatic Cancer Database. Ninety-seven patients (2%) were excluded, 56 because of treatment with preoperative chemotherapy, 39 because of incorrect registration of diagnosis or treatment, and 2 because of loss to follow-up; thus, 4163 patients were included. RESULTS: The 718 patients (17%) receiving resection had a median overall survival (mOS) of 21.9 months (range 20.0-24.2). In the chemotherapy group of 1746 patients (42%), those treated with FOLFIRINOX had the longest mOS of 10.0 months (9.2-11.0), whereas those treated with gemcitabine had the shortest mOS of 5.1 months (4.8-5.6). The 1697 patients (41%) receiving BSC had a mOS of only 1.6 months (1.5-1.7). CONCLUSIONS: The resected PC cohort had an OS comparable with that reported in randomised controlled trials (RCTs). The mOS of the chemotherapy-treated patients was slightly shorter compared with the results from RCTs and reflects the unselected population in this study. During the last decade, a larger fraction of patients received anticancer treatment, but the BSC group was still large and showed extremely poor OS.

Reproducibility of the peritoneal regression grading score for assessment of response to therapy in peritoneal metastasis.

AIMS: The four-tiered peritoneal regression grading score (PRGS) assesses the response to chemotherapy in peritoneal metastasis (PM). The PRGS is used, for example, to assess the response to pressurised intraperitoneal aerosol chemotherapy (PIPAC). However, the reproducibility of the PRGS is currently unknown. We aimed to evaluate the inter- and intraobserver variability of the PRGS. METHODS AND RESULTS: Thirty-three patients who underwent at least three PIPAC treatments as part of the PIPAC-OPC1 or PIPAC-OPC2 clinical trials at Odense University Hospital, Denmark, were included. Prior to each therapy cycle, peritoneal quadrant biopsies were obtained and three haematoxylin and eosin (H&E)-stained step sections were scanned and uploaded to a pseudonymised web library. For determining interobserver variability, eight pathologists assessed the PRGS for each quadrant biopsy, and Krippendorff's alpha and intraclass correlation coefficients (ICCs) were calculated. For determining intraobserver variability, three pathologists repeated their own assessments and Cohen's kappa and ICCs were calculated. A total of 331 peritoneal biopsies were analysed. Interobserver variability for PRGS of each biopsy and for the mean and maximum PRGS per biopsy set was moderate to good/substantial. The intraobserver variability for PRGS of each biopsy and for the mean and maximum PRGS per biopsy set was good to excellent/almost perfect. CONCLUSIONS: Our data support the PRGS as a reproducible and useful tool to assess response to intraperitoneal chemotherapy in PM. Future studies should evaluate the prognostic and predictive role of the PRGS.

Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations.

OBJECTIVE: Resection can potentially cure resectable pancreatic cancer (PaC) and significantly prolong survival in some patients. This large-scale international study aimed to investigate variations in resection for PaC in Europe and USA and determinants for its utilisation. DESIGN: Data from six European population-based cancer registries and the US Surveillance, Epidemiology, and End Results Program database during 2003-2016 were analysed. Age-standardised resection rates for overall and stage I-II PaCs were computed. Associations between resection and demographic and clinical parameters were assessed using multivariable logistic regression models. RESULTS: A total of 153 698 records were analysed. In population-based registries in 2012-2014, resection rates ranged from 13.2% (Estonia) to 21.2% (Slovenia) overall and from 34.8% (Norway) to 68.7% (Denmark) for stage I-II tumours, with great international variations. During 2003-2014, resection rates only increased in USA, the Netherlands and Denmark. Resection was significantly less frequently performed with more advanced tumour stage (ORs for stage III and IV versus stage I-II tumours: 0.05-0.18 and 0.01-0.06 across countries) and increasing age (ORs for patients 70-79 and ≥80 versus those <60 years: 0.37-0.63 and 0.03-0.16 across countries). Patients with advanced-stage tumours (stage III-IV: 63.8%-81.2%) and at older ages (≥70 years: 52.6%-59.5%) receiving less frequently resection comprised the majority of diagnosed cases. Patient performance status, tumour location and size were also associated with resection application. CONCLUSION: Rates of PaC resection remain low in Europe and USA with great international variations. Further studies are warranted to explore reasons for these variations.