Predictive value of baseline serum carbohydrate antigen 19-9 level on treatment effect of neoadjuvant chemoradiotherapy in patients with resectable and borderline resectable pancreatic cancer in two randomized trials.

BACKGROUND: Guidelines suggest that the serum carbohydrate antigen (CA19-9) level should be used when deciding on neoadjuvant treatment in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma (hereafter referred to as pancreatic cancer). In patients with resectable pancreatic cancer, neoadjuvant therapy is advised when the CA19-9 level is 'markedly elevated'. This study investigated the impact of baseline CA19-9 concentration on the treatment effect of neoadjuvant chemoradiotherapy (CRT) in patients with resectable and borderline resectable pancreatic cancers. METHODS: In this post hoc analysis, data were obtained from two RCTs that compared neoadjuvant CRT with upfront surgery in patients with resectable and borderline resectable pancreatic cancers. The effect of neoadjuvant treatment on overall survival was compared between patients with a serum CA19-9 level above or below 500 units/ml using the interaction test. RESULTS: Of 296 patients, 179 were eligible for analysis, 90 in the neoadjuvant CRT group and 89 in the upfront surgery group. Neoadjuvant CRT was associated with superior overall survival (HR 0.67, 95 per cent c.i. 0.48 to 0.94; P = 0.019). Among 127 patients (70, 9 per cent) with a low CA19-9 level, median overall survival was 23.5 months with neoadjuvant CRT and 16.3 months with upfront surgery (HR 0.63, 0.42 to 0.93). For 52 patients (29 per cent) with a high CA19-9 level, median overall survival was 15.5 months with neoadjuvant CRT and 12.9 months with upfront surgery (HR 0.82, 0.45 to 1.49). The interaction test for CA19-9 level exceeding 500 units/ml on the treatment effect of neoadjuvant CRT was not significant (P = 0.501). CONCLUSION: Baseline serum CA19-9 level defined as either high or low has prognostic value, but was not associated with the treatment effect of neoadjuvant CRT in patients with resectable and borderline resectable pancreatic cancers, in contrast with current guideline advice.

International assessment and validation of the prognostic role of lymph node ratio in patients with resected pancreatic head ductal adenocarcinoma.

Background: Lymph node ratio (LNR; positive/harvested lymph nodes) was identified as overall survival predictor in several cancers, including pancreatic adenocarcinoma. It remains unclear if LNR is predictive of overall survival in pancreatic adenocarcinoma patients staged pN2. This study assessed the prognostic overall survival role of LNR in pancreatic adenocarcinoma patients in relation with lymph node involvement. Methods: A retrospective international study in six different centers (Europe and United States) was performed. Pancreatic adenocarcinoma patients who underwent pancreatoduodenectomy from 2000 to 2017 were included. Patients with neoadjuvant treatment, metastases, R2 resections, or missing data regarding nodal status were excluded. Survival curves were calculated using Kaplan-Meier method and compared using log-rank test. Multivariable Cox regressions were performed to find independent overall survival predictors adjusted for potential confounders. Results: A total of 1,327 patients were included. Lymph node involvement (pN+) was found in 1,026 patients (77%), 561 pN1 (55%) and 465 pN2 (45%). Median LNR in pN+ patients was 0.214 [interquartile range (IQR): 0.105-0.364]. On multivariable analysis, LNR was the strongest overall survival predictor in the entire cohort [hazard ratio (HR) =5.5; 95% confidence interval (CI): 3.1-9.9; P<0.001] and pN+ patients (HR =3.8; 95% CI: 2.2-6.6; P<0.001). Median overall survival was better in patients with LNR <0.225 compared to patients with LNR ≥0.225 in the entire cohort and pN+ patients. Similar results were found in pN2 patients (worse overall survival when LNR ≥0.225). Conclusions: LNR appeared as an important prognostic factor in patients undergoing surgery for pancreatic adenocarcinoma and permitted to stratify overall survival in pN2 patients. LNR should be routinely used in complement to tumor-node-metastasis (TNM) stage to better predict patient prognosis.

Histopathological tumour response scoring in resected pancreatic cancer following neoadjuvant therapy: international interobserver study (ISGPP-1).

BACKGROUND: Most tumour response scoring systems for resected pancreatic cancer after neoadjuvant therapy score tumour regression. However, whether treatment-induced changes, including tumour regression, can be identified reliably on haematoxylin and eosin-stained slides remains unclear. Moreover, no large study of the interobserver agreement of current tumour response scoring systems for pancreatic cancer exists. This study aimed to investigate whether gastrointestinal/pancreatic pathologists can reliably identify treatment effect on tumour by histology, and to determine the interobserver agreement for current tumour response scoring systems. METHODS: Overall, 23 gastrointestinal/pancreatic pathologists reviewed digital haematoxylin and eosin-stained slides of pancreatic cancer or treated tumour bed. The accuracy in identifying the treatment effect was investigated in 60 patients (30 treatment-naive, 30 after neoadjuvant therapy (NAT)). The interobserver agreement for the College of American Pathologists (CAP) and MD Anderson Cancer Center (MDACC) tumour response scoring systems was assessed in 50 patients using intraclass correlation coefficients (ICCs). An ICC value below 0.50 indicated poor reliability, 0.50 or more and less than 0.75 indicated moderate reliability, 0.75 or more and below 0.90 indicated good reliability, and above 0.90 indicated excellent reliability. RESULTS: The sensitivity and specificity for identifying NAT effect were 76.2 and 49.0 per cent respectively. After NAT in 50 patients, ICC values for both tumour response scoring systems were moderate: 0.66 for CAP and 0.71 for MDACC. CONCLUSION: Identification of the effect of NAT in resected pancreatic cancer proved unreliable, and interobserver agreement for the current tumour response scoring systems was suboptimal. These findings support the recently published International Study Group of Pancreatic Pathologists recommendations to score residual tumour burden rather than tumour regression after NAT.

External validation of three lymph node ratio-based nomograms predicting survival using an international cohort of patients with resected pancreatic head ductal adenocarcinoma.

INTRODUCTION: Lymph node ratio (LNR) is an important prognostic factor of survival in patients with pancreatic ductal adenocarcinoma (PDAC). This study aimed to validate three LNR-based nomograms using an international cohort. MATERIALS AND METHODS: Consecutive PDAC patients who underwent upfront pancreatoduodenectomy from six centers (Europe/USA) were collected (2000-2017). Patients with metastases, R2 resection, missing LNR data, and who died within 90 postoperative days were excluded. The updated Amsterdam nomogram, the nomogram by Pu et al., and the nomogram by Li et al. were selected. For the validation, calibration, discrimination capacity, and clinical utility were assessed. RESULTS: After exclusion of 176 patients, 1'113 patients were included. Median overall survival (OS) of the cohort was 23 months (95% CI: 21-25). For the three nomograms, Kaplan-Meier curves showed significant OS diminution with increasing scores (p < 0.01). All nomograms showed good calibration (non-significant Hosmer-Lemeshow tests). For the Amsterdam nomogram, area under the ROC curve (AUROC) for 3-year OS was 0.64 and 0.67 for 5-year OS. Sensitivity and specificity for 3-year OS prediction were 65% and 59%. Regarding the nomogram by Pu et al., AUROC for 3- and 5-year OS were 0.66 and 0.70. Sensitivity and specificity for 3-year OS prediction were 68% and 53%. For the Li nomogram, AUROC for 3- and 5-year OS were 0.67 and 0.71, while sensitivity and specificity for 3-year OS prediction were 63% and 60%. CONCLUSION: The three nomograms were validated using an international cohort. Those nomograms can be used in clinical practice to evaluate survival after pancreatoduodenectomy for PDAC.

Nationwide Validation of the 8th American Joint Committee on Cancer TNM Staging System and Five Proposed Modifications for Resected Pancreatic Cancer.

BACKGROUND: The prognostic value of four proposed modifications to the 8th American Joint Committee on Cancer (AJCC) TNM staging system has yet to be evaluated. This study aimed to validate five proposed modifications. METHODS: Patients who underwent pancreatic ductal adenocarcinoma resection (2014-2016), as registered in the prospective Dutch Pancreatic Cancer Audit, were included. Stratification and prognostication of TNM staging systems were assessed using Kaplan-Meier curves, Cox proportional hazard analyses, and C-indices. A new modification was composed based on overall survival (OS). RESULTS: Overall, 750 patients with a median OS of 18 months (interquartile range 10-32) were included. The 8th edition had an increased discriminative ability compared with the 7th edition {C-index 0.59 (95% confidence interval [CI] 0.56-0.61) vs. 0.56 (95% CI 0.54-0.58)}. Although the 8th edition showed a stepwise decrease in OS with increasing stage, no differences could be demonstrated between all substages; stage IIA vs. IB (hazard ratio [HR] 1.30, 95% CI 0.80-2.09; p  = 0.29) and stage IIB vs. IIA (HR 1.17, 95% CI 0.75-1.83; p  = 0.48). The four modifications showed comparable prognostic accuracy (C-index 0.59-0.60); however, OS did not differ between all modified TNM stages (ns). The new modification, migrating T3N1 patients to stage III, showed a C-index of 0.59, but did detect significant survival differences between all TNM stages (p  < 0.05). CONCLUSIONS: The 8th TNM staging system still lacks prognostic value for some categories of patients, which was not clearly improved by four previously proposed modifications. The modification suggested in this study allows for better prognostication in patients with all stages of disease.

Development and external validation of a prediction model for overall survival after resection of distal cholangiocarcinoma.

BACKGROUND: Various prognostic factors are associated with overall survival (OS) after resection of distal cholangiocarcinoma (dCCA). The objective of this study was to develop and validate a prediction model for 3-year OS after pancreatoduodenectomy for dCCA. METHODS: The derivation cohort consisted of all patients who underwent pancreatoduodenectomy for dCCA in the Netherlands (2009-2016). Clinically relevant variables were selected based on the Akaike information criterion using a multivariate Cox proportional hazards regression model, with model performance being assessed by concordance index (C-index) and calibration plots. External validation was performed using patients from the Belgium Cancer Registry (2008-2016), and patients from two university hospitals of Southampton (U.K.) and Verona (Italy). RESULTS: Independent prognostic factors for OS in the derivation cohort of 454 patients after pancreatoduodenectomy for dCCA were age (HR 1.02, 95% CI 1.01-1.03), pT (HR 1.43, 95% CI 1.07-1.90) and pN category (pN1: HR 1.78, 95% CI 1.37-2.32; pN2: HR 2.21, 95% CI 1.63-3.01), resection margin status (HR 1.79, 95% CI 1.39-2.29) and tumour differentiation (HR 2.02, 95% CI 1.62-2.53). The prediction model was based on these prognostic factors. The optimism-adjusted C-indices were similar in the derivation cohort (0.69), and in the Belgian (0.66) and Southampton-Verona (0.68) validation cohorts. Calibration was accurate in the Belgian validation cohort (slope = 0.93, intercept = 0.12), but slightly less optimal in the Southampton-Verona validation cohort (slope = 0.88, intercept = 0.32). Based on this model, three risk groups with different prognoses were identified (3-year OS of 65.4%, 33.2% and 11.8%). CONCLUSIONS: The prediction model for 3-year OS after resection of dCCA had reasonable performance in both the derivation and geographically external validation cohort. Calibration slightly differed between validation cohorts. The model is readily available via www. pancreascalculator.com to inform patients from Western European countries on their prognosis, and may be used to stratify patients for clinical trials.

International Validation of a Nomogram to Predict Recurrence after Resection of Grade 1 and 2 Nonfunctioning Pancreatic Neuroendocrine Tumors.

BACKGROUND: Despite the low recurrence rate of resected nonfunctional pancreatic neuroendocrine tumors (NF-pNETs), nearly all patients undergo long-term surveillance. A prediction model for recurrence may help select patients for less intensive surveillance or identify patients for adjuvant therapy. The objective of this study was to assess the external validity of a recently published model predicting recurrence within 5 years after surgery for NF-pNET in an international cohort. This prediction model includes tumor grade, lymph node status and perineural invasion as predictors. METHODS: Retrospectively, data were collected from 7 international referral centers on patients who underwent resection for a grade 1-2 NF-pNET between 1992 and 2018. Model performance was evaluated by calibration statistics, Harrel's C-statistic, and area under the curve (AUC) of the receiver operating characteristic curve for 5-year recurrence-free survival (RFS). A sub-analysis was performed in pNETs >2 cm. The model was improved to stratify patients into 3 risk groups (low, medium, high) for recurrence. RESULTS: Overall, 342 patients were included in the validation cohort with a 5-year RFS of 83% (95% confidence interval [CI]: 78-88%). Fifty-eight patients (17%) developed a recurrence. Calibration showed an intercept of 0 and a slope of 0.74. The C-statistic was 0.77 (95% CI: 0.70-0.83), and the AUC for the prediction of 5-year RFS was 0.74. The prediction model had a better performance in tumors >2 cm (C-statistic 0.80). CONCLUSIONS: External validity of this prediction model for recurrence after curative surgery for grade 1-2 NF-pNET showed accurate overall performance using 3 easily accessible parameters. This model is available via www.pancreascalculator.com.

Venous wedge and segment resection during pancreatoduodenectomy for pancreatic cancer: impact on short- and long-term outcomes in a nationwide cohort analysis.

BACKGROUND: Venous resection of the superior mesenteric or portal vein is increasingly performed in pancreatic cancer surgery, whereas results of studies on short- and long-term outcomes are contradictory. The aim of this study was to evaluate the impact of the type of venous resection in pancreatoduodenectomy for pancreatic cancer on postoperative morbidity and overall survival. METHODS: This nationwide retrospective cohort study included all patients who underwent pancreatoduodenectomy for pancreatic cancer in 18 centres (2013-2017). RESULTS: A total of 1311 patients were included, of whom 17 per cent underwent wedge resection and 10 per cent segmental resection. Patients with segmental resection had higher rates of major morbidity (39 versus 20 versus 23 per cent, respectively; P < 0.001) and portal or superior mesenteric vein thrombosis (18 versus 5 versus 1 per cent, respectively; P < 0.001) and worse overall survival (median 12 versus 16 versus 20 months, respectively; P < 0.001), compared to patients with wedge resection and those without venous resection. Multivariable analysis showed patients with segmental resection, but not those who had wedge resection, had higher rates of major morbidity (odds ratio = 1.93, 95 per cent c.i. 1.20 to 3.11) and worse overall survival (hazard ratio = 1.40, 95 per cent c.i. 1.10 to 1.78), compared to patients without venous resection. Among patients who received neoadjuvant therapy, there was no difference in overall survival among patients with segmental and wedge resection and those without venous resection (median 32 versus 25 versus 33 months, respectively; P = 0.470), although there was a difference in major morbidity rates (52 versus 19 versus 21 per cent, respectively; P = 0.012). CONCLUSION: In pancreatic surgery, the short- and long-term outcomes are worse in patients with venous segmental resection, compared to patients with wedge resection and those without venous resection.

Artificial Intelligence-Based Segmentation of Residual Tumor in Histopathology of Pancreatic Cancer after Neoadjuvant Treatment.

BACKGROUND: Histologic examination of resected pancreatic cancer after neoadjuvant therapy (NAT) is used to assess the effect of NAT and may guide the choice for adjuvant treatment. However, evaluating residual tumor burden in pancreatic cancer is challenging given tumor response heterogeneity and challenging histomorphology. Artificial intelligence techniques may offer a more reproducible approach. METHODS: From 64 patients, one H&E-stained slide of resected pancreatic cancer after NAT was digitized. Three separate classes were manually outlined in each slide (i.e., tumor, normal ducts, and remaining epithelium). Corresponding segmentation masks and patches were generated and distributed over training, validation, and test sets. Modified U-nets with varying encoders were trained, and F1 scores were obtained to express segmentation accuracy. RESULTS: The highest mean segmentation accuracy was obtained using modified U-nets with a DenseNet161 encoder. Tumor tissue was segmented with a high mean F1 score of 0.86, while the overall multiclass average F1 score was 0.82. CONCLUSIONS: This study shows that artificial intelligence-based assessment of residual tumor burden is feasible given the promising obtained F1 scores for tumor segmentation. This model could be developed into a tool for the objective evaluation of the response to NAT and may potentially guide the choice for adjuvant treatment.

Resection of the Portal-Superior Mesenteric Vein in Pancreatic Cancer: Pathological Assessment and Recurrence Patterns.

OBJECTIVES: The portal vein (PV)-superior mesenteric vein (SMV) margin is the most affected margin in pancreatic cancer. This study investigates the association between venous resection, tumor invasion in the resected PV-SMV, recurrence patterns, and overall survival (OS). METHODS: This multicenter cohort study included patients who underwent pancreatoduodenectomy for pancreatic cancer (2010-2017). In addition, a systematic literature search was performed. RESULTS: In total, 531 patients were included, of which 149 (28%) underwent venous resection of whom 53% had tumor invasion in the resected PV-SMV. Patients with venous resection had a significant higher rate of R1 margins (69% vs 37%) and had more often multiple R1 margins (43% vs 16%). Patient with venous resection had a significant shorter time to locoregional recurrence and a shorter OS (15 vs 19 months). At multivariable analyses, venous resection and tumor invasion in the resected PV-SMV were not predictive for time to recurrence and OS. The literature overview showed that pathological assessment of the resected PV-SMV is not adequately standardized. CONCLUSIONS: Only half of patients with venous resection had pathology confirmed tumor invasion in the resected PV-SMV, and both are not independently associated with time to recurrence and OS. The pathological assessment of the resected PV-SMV needs to be standardized.

Hospital costs of delayed gastric emptying following pancreatoduodenectomy and the financial headroom for novel prophylactic treatment strategies.

BACKGROUND: Delayed gastric emptying (DGE) is one of the most common complications following pancreatoduodenectomy (PD). In-hospital costs of DGE are unknown as well as the financial headroom for novel prophylactic treatments. This retrospective study aims to estimate the hospital costs of DGE and model the financial headroom per patient for new prophylactic treatment strategies within budget. METHODS: Retrospective analysis of a single-center prospective database including patients after PD (2010-2017). In-hospital costs for clinically relevant DGE (ISGPS grade B/C) were calculated by comparing patient groups with and without DGE or other complications. The financial headroom per patient was modelled for potential reductions (0-100%) of empirical DGE baseline risks (15-30%). RESULTS: Overall, DGE was present in 156 (26.9%) of 581 patients after PD. Costs for patients with isolated DGE (n = 90) were €10,295 higher than for patients without complications (n = 333). Costs for patients with other complications including DGE (n = 66) were €9008 higher than for patients with other complications without DGE (n = 92). The financial headroom for a novel prophylactic treatment per patient undergoing PD was €975 per 10% absolute decrease of DGE risk. CONCLUSION: Hospital costs of DGE after PD are substantial. The financial headroom per patient for new DGE prophylactic treatments can be easily calculated via www.pancreascalculator.com.

Predicting overall survival and resection in patients with locally advanced pancreatic cancer treated with FOLFIRINOX: Development and internal validation of two nomograms.

BACKGROUND AND OBJECTIVES: Patients with locally advanced pancreatic cancer (LAPC) are increasingly treated with FOLFIRINOX, resulting in improved survival and resection of tumors that were initially unresectable. It remains unclear, however, which specific patients benefit from FOLFIRINOX. Two nomograms were developed predicting overall survival (OS) and resection at the start of FOLFIRINOX for LAPC. METHODS: From our multicenter, prospective LAPC registry in 14 Dutch hospitals, LAPC patients starting first-line FOLFIRINOX (April 2015-December 2017) were included. Stepwise backward selection according to the Akaike Information Criterion was used to identify independent baseline predictors for OS and resection. Two prognostic nomograms were generated. RESULTS: A total of 252 patients were included, with a median OS of 14 months. Thirty-two patients (13%) underwent resection, with a median OS of 23 months. Older age, female sex, Charlson Comorbidity Index ≤1, and CA 19.9 < 274 were independent factors predicting a better OS (c-index: 0.61). WHO ps >1, involvement of the superior mesenteric artery, celiac trunk, and superior mesenteric vein ≥ 270° were independent factors decreasing the probability of resection (c-index: 0.79). CONCLUSIONS: Two nomograms were developed to predict OS and resection in patients with LAPC before starting treatment with FOLFIRINOX. These nomograms could be beneficial in the shared decision-making process and counseling of these patients.

Preoperative misdiagnosis of pancreatic and periampullary cancer in patients undergoing pancreatoduodenectomy: A multicentre retrospective cohort study.

INTRODUCTION: Whereas neoadjuvant chemo(radio)therapy is increasingly used in pancreatic cancer, it is currently not recommended for other periampullary (non-pancreatic) cancers. This has important implications for the relevance of the preoperative diagnosis for pancreatoduodenectomy. This retrospective multicentre cohort study aimed to determine the frequency of clinically relevant misdiagnoses in patients undergoing pancreatoduodenectomy for pancreatic or other periampullary cancer. METHODS: Data from all consecutive patients who underwent a pancreatoduodenectomy between 2014 and 2018 were obtained from the prospective Dutch Pancreatic Cancer Audit. The preoperative diagnosis as concluded by the multidisciplinary team (MDT) meeting was compared with the final postoperative diagnosis at pathology to determine the rate of clinically relevant misdiagnosis (defined as missed pancreatic cancer or incorrect diagnosis of pancreatic cancer). RESULTS: In total, 1244 patients underwent pancreatoduodenectomy of whom 203 (16%) had a clinically relevant misdiagnosis preoperatively. Of all patients with a final diagnosis of pancreatic cancer, 13% (87/679) were preoperatively misdiagnosed as distal cholangiocarcinoma (n = 41, 6.0%), ampullary cancer (n = 27, 4.0%) duodenal cancer (n = 16, 2.4%), or other (n = 3, 0.4%). Of all patients with a final diagnosis of periampullary (non-pancreatic) cancer, 21% (116/565) were preoperatively incorrectly diagnosed as pancreatic cancer. Accuracy of preoperative diagnosis was 84% for pancreatic cancer, 71% for distal cholangiocarcinoma, 73% for ampullary cancer and 73% for duodenal cancer. A prediction model for the preoperative likelihood of pancreatic cancer (versus other periampullary cancer) prior to pancreatoduodenectomy demonstrated an AUC of 0.88. DISCUSSION: This retrospective multicentre cohort study showed that 16% of patients have a clinically relevant misdiagnosis that could result in either missing the opportunity of neoadjuvant chemotherapy in patients with pancreatic cancer or inappropriate administration of neoadjuvant chemotherapy in patients with non-pancreatic periampullary cancer. A preoperative prediction model is available on www.pancreascalculator.com.

Axial slicing versus bivalving in the pathological examination of pancreatoduodenectomy specimens (APOLLO): a multicentre randomized controlled trial.

BACKGROUND: In pancreatoduodenectomy specimens, dissection method may affect the assessment of primary tumour origin (i.e. pancreatic, distal bile duct or ampullary adenocarcinoma), which is primarily determined macroscopically. This is the first study to prospectively compare the two commonly used techniques, i.e. axial slicing and bivalving. METHODS: In four centres, a randomized controlled trial was performed in specimens of patients with a suspected (pre)malignant tumour in the pancreatic head. Primary outcome measure was the level of certainty (scale 0-100) regarding tumour origin by four independent gastrointestinal pathologists based on macroscopic assessment. Secondary outcomes were inter-observer agreement and R1 rate. RESULTS: In total, 128 pancreatoduodenectomy specimens were randomized. The level of certainty in determining the primary tumour origin did not differ between axial slicing and bivalving (mean score 72 [sd 13] vs. 68 [sd 16], p = 0.21), nor did inter-observer agreement, both being moderate (kappa 0.45 vs. 0.47). In pancreatic cancer specimens, R1 rate (60% vs. 55%, p = 0.71) and the number of harvested lymph nodes (median 16 vs. 17, p = 0.58) were similar. CONCLUSION: This study demonstrated no differences in determining the tumour origin between axial slicing and bivalving. Both techniques performed similarly regarding inter-observer agreement, R1 rate, and lymph node harvest.

Using Textbook Outcomes to benchmark practice in pancreatic surgery.

BACKGROUND: Textbook Outcome (TO) is a novel composite measure of clinical outcomes that can be used to measure the quality of surgical outcomes. TOs for pancreatic surgery were published by the Dutch Pancreatic Cancer Group (DPCG) in 2020. The aim of this study was to explore how a medium volume hepatopancreaticobiliary unit could use TO to benchmark local outcomes following pancreatic surgery. METHODS: Retrospective analysis of prospectively collected data from patients who underwent pancreaticoduodenectomy (PD) or distal pancreatectomy (DP) for all indications between March 2005 and February 2020 at Christchurch Hospital (CH). Analysis of TO items as defined by the DPCG was performed and compared to nationwide Dutch outcomes (2014-2017), including cumulative analysis using CuSum. RESULTS: In total, 273 patients were included (median age 63 years; 51% female) of which 182 (67%) underwent PD and 91 (33%) underwent DP (median annual volume 12 PDs/6 DPs). Overall, 58% of patients undergoing PD and 74% of patients undergoing DP achieved TO, compared with 58% and 67%, P = 0.944 and P = 0.231, respectively, for the Netherlands (median annual volume 33 PDs/8 DPs per hospital). CONCLUSIONS: TO offers a useful quality measure to benchmark local outcomes following pancreatic surgery against an external nationwide analysis. The results show that as a medium volume centre performance was comparable to previously published Dutch results, which included high volume centres. Applying CuSum methodology to the TO metric allows a continuous measure of performance. This offers the potential to provide feedback for quality improvement strategies.

Amsterdam International Consensus Meeting: tumor response scoring in the pathology assessment of resected pancreatic cancer after neoadjuvant therapy.

Histopathologically scoring the response of pancreatic ductal adenocarcinoma (PDAC) to neoadjuvant treatment can guide the selection of adjuvant therapy and improve prognostic stratification. However, several tumor response scoring (TRS) systems exist, and consensus is lacking as to which system represents best practice. An international consensus meeting on TRS took place in November 2019 in Amsterdam, The Netherlands. Here, we provide an overview of the outcomes and consensus statements that originated from this meeting. Consensus (≥80% agreement) was reached on a total of seven statements: (1) TRS is important because it provides information about the effect of neoadjuvant treatment that is not provided by other histopathology-based descriptors. (2) TRS for resected PDAC following neoadjuvant therapy should assess residual (viable) tumor burden instead of tumor regression. (3) The CAP scoring system is considered the most adequate scoring system to date because it is based on the presence and amount of residual cancer cells instead of tumor regression. (4) The defining criteria of the categories in the CAP scoring system should be improved by replacing subjective terms including "minimal" or "extensive" with objective criteria to evaluate the extent of viable tumor. (5) The improved, consensus-based system should be validated retrospectively and prospectively. (6) Prospective studies should determine the extent of tissue sampling that is required to ensure adequate assessment of the residual cancer burden, taking into account the heterogeneity of tumor response. (7) In future scientific publications, the extent of tissue sampling should be described in detail in the "Materials and methods" section.

Evaluation of Adjuvant Chemotherapy in Patients With Resected Pancreatic Cancer After Neoadjuvant FOLFIRINOX Treatment.

IMPORTANCE: The benefit of adjuvant chemotherapy after resection of pancreatic cancer following neoadjuvant combination treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) is unclear. OBJECTIVE: To assess the association of adjuvant chemotherapy with overall survival (OS) in patients after pancreatic cancer resection and neoadjuvant FOLFIRINOX treatment. DESIGN, SETTING, AND PARTICIPANTS: This international, multicenter, retrospective cohort study was conducted from January 1, 2012, to December 31, 2018. An existing cohort of patients undergoing resection of pancreatic cancer after FOLFIRINOX was updated and expanded for the purpose of this study. All consecutive patients who underwent pancreatic surgery after at least 2 cycles of neoadjuvant FOLFIRINOX chemotherapy for nonmetastatic pancreatic cancer were retrospectively identified from institutional databases. Patients with resectable pancreatic cancer, borderline resectable pancreatic cancer, and locally advanced pancreatic cancer were eligible for this study. Patients with in-hospital mortality or who died within 3 months after surgery were excluded. EXPOSURES: The association of adjuvant chemotherapy with OS was evaluated in different subgroups including interaction terms for clinicopathological parameters with adjuvant treatment in a multivariable Cox model. Overall survival was defined as the time starting from surgery plus 3 months (moment eligible for adjuvant therapy), unless mentioned otherwise. RESULTS: We included 520 patients (median [interquartile range] age, 61 [53-66] years; 279 [53.7%] men) from 31 centers in 19 countries. The median number of neoadjuvant cycles of FOLFIRINOX was 6 (interquartile range, 5-8). Overall, 343 patients (66.0%) received adjuvant chemotherapy, of whom 68 (19.8%) received FOLFIRINOX, 201 (58.6%) received gemcitabine-based chemotherapy, 14 (4.1%) received capecitabine, 45 (13.1%) received a combination or other agents, and 15 (4.4%) received an unknown type of adjuvant chemotherapy. Median OS was 38 months (95% CI, 36-46 months) after diagnosis and 31 months (95% CI, 29-37 months) after surgery. No survival difference was found for patients who received adjuvant chemotherapy vs those who did not (median OS, 29 vs 29 months, univariable hazard ratio [HR], 0.99; 95% CI, 0.77-1.28; P = .93). In multivariable analysis, only the interaction term for lymph node stage with adjuvant therapy was statistically significant: In patients with pathology-proven node-positive disease, adjuvant chemotherapy was associated with improved survival (median OS, 26 vs 13 months; multivariable HR, 0.41 [95% CI, 0.22-0.75]; P = .004). In patients with node-negative disease, adjuvant chemotherapy was not associated with improved survival (median OS, 38 vs 54 months; multivariable HR, 0.85; 95% CI, 0.35-2.10; P = .73). CONCLUSIONS AND RELEVANCE: These results suggest that adjuvant chemotherapy after neoadjuvant FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease. Future randomized studies should be conducted to confirm this finding.

Development and external validation of a prediction model for survival in patients with resected ampullary adenocarcinoma.

INTRODUCTION: Ampullary adenocarcinoma (AAC) is a rare malignancy with great morphological heterogeneity, which complicates the prediction of survival and, therefore, clinical decision-making. The aim of this study was to develop and externally validate a prediction model for survival after resection of AAC. MATERIALS AND METHODS: An international multicenter cohort study was conducted, including patients who underwent pancreatoduodenectomy for AAC (2006-2017) from 27 centers in 10 countries spanning three continents. A derivation and validation cohort were separately collected. Predictors were selected from the derivation cohort using a LASSO Cox proportional hazards model. A nomogram was created based on shrunk coefficients. Model performance was assessed in the derivation cohort and subsequently in the validation cohort, by calibration plots and Uno's C-statistic. Four risk groups were created based on quartiles of the nomogram score. RESULTS: Overall, 1007 patients were available for development of the model. Predictors in the final Cox model included age, resection margin, tumor differentiation, pathological T stage and N stage (8th AJCC edition). Internal cross-validation demonstrated a C-statistic of 0.75 (95% CI 0.73-0.77). External validation in a cohort of 462 patients demonstrated a C-statistic of 0.77 (95% CI 0.73-0.81). A nomogram for the prediction of 3- and 5-year survival was created. The four risk groups showed significantly different 5-year survival rates (81%, 57%, 22% and 14%, p < 0.001). Only in the very-high risk group was adjuvant chemotherapy associated with an improved overall survival. CONCLUSION: A prediction model for survival after curative resection of AAC was developed and externally validated. The model is easily available online via www.pancreascalculator.com.

Conditional Survival After Resection for Pancreatic Cancer: A Population-Based Study and Prediction Model.

BACKGROUND: Conditional survival is the survival probability after already surviving a predefined time period. This may be informative during follow-up, especially when adjusted for tumor characteristics. Such prediction models for patients with resected pancreatic cancer are lacking and therefore conditional survival was assessed and a nomogram predicting 5-year survival at a predefined period after resection of pancreatic cancer was developed. METHODS: This population-based study included patients with resected pancreatic ductal adenocarcinoma from the Netherlands Cancer Registry (2005-2016). Conditional survival was calculated as the median, and the probability of surviving up to 8 years in patients who already survived 0-5 years after resection was calculated using the Kaplan-Meier method. A prediction model was constructed. RESULTS: Overall, 3082 patients were included, with a median age of 67 years. Median overall survival was 18 months (95% confidence interval 17-18 months), with a 5-year survival of 15%. The 1-year conditional survival (i.e. probability of surviving the next year) increased from 55 to 74 to 86% at 1, 3, and 5 years after surgery, respectively, while the median overall survival increased from 15 to 40 to 64 months at 1, 3, and 5 years after surgery, respectively. The prediction model demonstrated that the probability of achieving 5-year survival at 1 year after surgery varied from 1 to 58% depending on patient and tumor characteristics. CONCLUSIONS: This population-based study showed that 1-year conditional survival was 55% 1 year after resection and 74% 3 years after resection in patients with pancreatic cancer. The prediction model is available via www.pancreascalculator.com to inform patients and caregivers.