Predicting Long-term Disease-free Survival After Resection of Pancreatic Ductal Adenocarcinoma: A Nationwide Cohort Study.

OBJECTIVE: To develop a prediction model for long-term (≥5 years) disease-free survival (DFS) after the resection of pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Despite high recurrence rates, ~10% of patients have long-term DFS after PDAC resection. A model to predict long-term DFS may aid individualized prognostication and shared decision-making. METHODS: This nationwide cohort study included all consecutive patients who underwent PDAC resection in the Netherlands (2014-2016). The best-performing prognostic model was selected by Cox-proportional hazard analysis and Akaike's Information Criterion, presented by hazard ratios (HRs) with 95% confidence intervals (CIs). Internal validation was performed, and discrimination and calibration indices were assessed. RESULTS: In all, 836 patients with a median follow-up of 67 months (interquartile range 51-79) were analyzed. Long-term DFS was seen in 118 patients (14%). Factors predictive of long-term DFS were low preoperative carbohydrate antigen 19-9 (logarithmic; HR 1.21; 95% CI 1.10-1.32), no vascular resection (HR 1.33; 95% CI 1.12-1.58), T1 or T2 tumor stage (HR 1.52; 95% CI 1.14-2.04, and HR 1.17; 95% CI 0.98-1.39, respectively), well/moderate tumor differentiation (HR 1.44; 95% CI 1.22-1.68), absence of perineural and lymphovascular invasion (HR 1.42; 95% CI 1.11-1.81 and HR 1.14; 95% CI 0.96-1.36, respectively), N0 or N1 nodal status (HR 1.92; 95% CI 1.54-2.40, and HR 1.33; 95% CI 1.11-1.60, respectively), R0 resection margin status (HR 1.25; 95% CI 1.07-1.46), no major complications (HR 1.14; 95% CI 0.97-1.35) and adjuvant chemotherapy (HR 1.74; 95% CI 1.47-2.06). Moderate performance (concordance index 0.68) with adequate calibration (slope 0.99) was achieved. CONCLUSIONS: The developed prediction model, readily available at www.pancreascalculator.com, can be used to estimate the probability of long-term DFS after resection of pancreatic ductal adenocarcinoma.

Perineural Invasion is an Important Prognostic Factor in Patients With Radically Resected (R0) and Node-negative (pN0) Pancreatic Cancer.

OBJECTIVE: To investigate the association between perineural invasion (PNI) and overall survival (OS) in a nationwide cohort of patients with resected pancreatic ductal adenocarcinoma (PDAC), stratified for margin negative (R0) or positive (R1) resection and absence or presence of lymph node metastasis (pN0 or pN1-N2, respectively). BACKGROUND: Patients with R0 and pN0 resected PDAC have a relatively favorable prognosis. As PNI is associated with worse OS, this might be a useful factor to provide further prognostic information for patients counselling. METHODS: A nationwide observational cohort study was performed including all patients who underwent PDAC resection in the Netherlands (2014-2019) with complete information on relevant pathological features (PNI, R status, and N status). OS was assessed using Kaplan-Meier curves, and Cox-proportional hazard analyses were performed to calculate hazard ratio's (HR) with corresponding 95% confidence intervals (CI). RESULTS: In total, 1630 patients were included with a median follow-up of 43 (interquartile range 33-58) months. PNI was independently associated with worse OS in both R0 patients (HR 1.49 [95%CI 1.18-1.88]; P<0.001) and R1 patients (HR 1.39 [95% CI 1.06-1.83]; P=0.02), as well as in pN0 patients (HR 1.75 [95%CI 1.27-2.41]; P<0.001) and pN1-N2 patients (HR 1.35 [95% CI 1.10-1.67]; P<0.01). In 315 patients with R0N0, multivariable analysis showed that PNI was the strongest predictor of OS (HR 2.24 [95% CI 1.52-3.30]; P<0.001). CONCLUSION: PNI is strongly associated with worse survival in patients with resected PDAC, in particular in patients with relatively favorable pathological features. These findings may aid patient stratification and counselling and help guide treatment strategies.

The Value of Biological and Conditional Factors for Staging of Patients with Resectable Pancreatic Cancer Undergoing Upfront Resection: A Nationwide Analysis.

BACKGROUND: Novel definitions suggest that resectability status for pancreatic ductal adenocarcinoma (PDAC) should be assessed beyond anatomical criteria, considering both biological and conditional factors. This has, however, yet to be validated on a nationwide scale. This study evaluated the prognostic value of biological and conditional factors for staging of patients with resectable PDAC. PATIENTS AND METHODS: A nationwide observational cohort study was performed, including all consecutive patients who underwent upfront resection of National Comprehensive Cancer Network resectable PDAC in the Netherlands (2014-2019) with complete information on preoperative carbohydrate antigen (CA) 19-9 and Eastern Cooperative Oncology Group (ECOG) performance status. PDAC was considered biologically unfavorable (RB+) if CA19-9 ≥ 500 U/mL and favorable (RB-) otherwise. ECOG ≥ 2 was considered conditionally unfavorable (RC+) and favorable otherwise (RC-). Overall survival (OS) was assessed using Kaplan-Meier and Cox-proportional hazard analysis, presented as hazard ratios (HRs) with 95% confidence interval (CI). RESULTS: Overall, 688 patients were analyzed with a median overall survival (OS) of 20 months (95% CI 19-23). OS was 14 months (95% CI 10 months-median not reached) in 20 RB+C+ patients (3%; HR 1.61, 95% CI 0.86-2.70), 13 months (95% CI 11-15) in 156 RB+C- patients (23%; HR 1.86, 95% CI 1.50-2.31), and 21 months (95% CI 12-41) in 47 RB-C+ patients (7%; HR 1.14, 95% CI 0.80-1.62) compared with 24 months (95% CI 22-27) in 465 patients with RB-C- PDAC (68%; reference). CONCLUSIONS: Survival after upfront resection of anatomically resectable PDAC is worse in patients with CA19-9 ≥ 500 U/mL, while performance status had no impact. This supports consideration of CA19-9 in preoperative staging of resectable PDAC.

Improving diagnosis of early complications (<1 week) through continuous vital sign monitoring following oncological gastrointestinal surgical procedures.

BACKGROUND: Patients undergoing major oncological abdominal surgery are prone to postoperative complications, making early recognition crucial. Clinical deterioration is often preceded by changes in vital signs, which are typically measured thrice a day by a nurse. However, intermittent measurements may delay recognizing clinical deterioration. Continuous vital parameter monitoring may lead to earlier recognition and management of complications and reduce nursing workload. OBJECTIVE: To compare vital parameter measurements between ward nurses and a wireless continuous monitoring system (Sensium® wireless patch) and assess whether this patch can detect clinical deterioration earlier in patients with complications in the first postoperative week. METHODS: Vital parameters (heart rate, respiratory rate, and temperature) were collected in patients undergoing an oncological resection of the liver, colorectal, or pancreas. Sensium® patch measurements were compared to nurses' measurements to assess the percentages of discordant measurements. In patients with complications in the first postoperative week, time discrepancies between nurses and Sensium® patch measurements were identified in cases of clinical deterioration (respiratory rate ≥15/min, heart rate ≥100/min, and temperature ≥38°C). RESULTS: Among 227 patients, 22% of the patients experienced complications. Nurse and Sensium® measurements were discrepant in 586/2272 measurements (26%). In 506/586 discrepancies (86%), this was due to the respiratory rate (difference ≥4/min). Compared to nurses, the Sensium® patch detected an elevated respiratory rate 14 h earlier and heart rate 2 h earlier within complications in the first postoperative week. For temperature, no difference was observed. CONCLUSION: Continuous monitoring with the Sensium® wireless patch holds promise for earlier recognition of complications in patients who underwent major oncological abdominal surgery.

Risk Models for Developing Pancreatic Fistula After Pancreatoduodenectomy: Validation in a Nationwide Prospective Cohort.

OBJECTIVE: To evaluate the performance of published fistula risk models by external validation, and to identify independent risk factors for postoperative pancreatic fistula (POPF). BACKGROUND: Multiple risk models have been developed to predict POPF after pancreatoduodenectomy. External validation in high-quality prospective cohorts is, however, lacking or only performed for individual models. METHODS: A post hoc analysis of data from the stepped-wedge cluster cluster-randomized Care After Pancreatic Resection According to an Algorithm for Early Detection and Minimally Invasive Management of Pancreatic Fistula versus Current Practice (PORSCH) trial was performed. Included were all patients undergoing pancreatoduodenectomy in the Netherlands (January 2018-November 2019). Risk models on POPF were identified by a systematic literature search. Model performance was evaluated by calculating the area under the receiver operating curves (AUC) and calibration plots. Multivariable logistic regression was performed to identify independent risk factors associated with clinically relevant POPF. RESULTS: Overall, 1358 patients undergoing pancreatoduodenectomy were included, of whom 341 patients (25%) developed clinically relevant POPF. Fourteen risk models for POPF were evaluated, with AUCs ranging from 0.62 to 0.70. The updated alternative fistula risk score had an AUC of 0.70 (95% confidence intervals [CI]: 0.69-0.72). The alternative fistula risk score demonstrated an AUC of 0.70 (95% CI: 0.689-0.71), whilst an AUC of 0.70 (95% CI: 0.699-0.71) was also found for the model by Petrova and colleagues. Soft pancreatic texture, pathology other than pancreatic ductal adenocarcinoma or chronic pancreatitis, small pancreatic duct diameter, higher body mass index, minimally invasive resection and male sex were identified as independent predictors of POPF. CONCLUSION: Published risk models predicting clinically relevant POPF after pancreatoduodenectomy have a moderate predictive accuracy. Their clinical applicability to identify high-risk patients and guide treatment strategies is therefore questionable.

The Feasibility, Proficiency, and Mastery Learning Curves in 635 Robotic Pancreatoduodenectomies Following a Multicenter Training Program: "Standing on the Shoulders of Giants".

OBJECTIVE: To assess the feasibility, proficiency, and mastery learning curves for robotic pancreatoduodenectomy (RPD) in "second-generation" RPD centers following a multicenter training program adhering to the IDEAL framework. BACKGROUND: The long learning curves for RPD reported from "pioneering" expert centers may discourage centers interested in starting an RPD program. However, the feasibility, proficiency, and mastery learning curves may be shorter in "second-generation" centers that participated in dedicated RPD training programs, although data are lacking. We report on the learning curves for RPD in "second-generation" centers trained in a dedicated nationwide program. METHODS: Post hoc analysis of all consecutive patients undergoing RPD in 7 centers that participated in the LAELAPS-3 training program, each with a minimum annual volume of 50 pancreatoduodenectomies, using the mandatory Dutch Pancreatic Cancer Audit (March 2016-December 2021). Cumulative sum analysis determined cutoffs for the 3 learning curves: operative time for the feasibility (1) risk-adjusted major complication (Clavien-Dindo grade ≥III) for the proficiency, (2) and textbook outcome for the mastery, (3) learning curve. Outcomes before and after the cutoffs were compared for the proficiency and mastery learning curves. A survey was used to assess changes in practice and the most valued "lessons learned." RESULTS: Overall, 635 RPD were performed by 17 trained surgeons, with a conversion rate of 6.6% (n=42). The median annual volume of RPD per center was 22.5±6.8. From 2016 to 2021, the nationwide annual use of RPD increased from 0% to 23% whereas the use of laparoscopic pancreatoduodenectomy decreased from 15% to 0%. The rate of major complications was 36.9% (n=234), surgical site infection 6.3% (n=40), postoperative pancreatic fistula (grade B/C) 26.9% (n=171), and 30-day/in-hospital mortality 3.5% (n=22). Cutoffs for the feasibility, proficiency, and mastery learning curves were reached at 15, 62, and 84 RPD. Major morbidity and 30-day/in-hospital mortality did not differ significantly before and after the cutoffs for the proficiency and mastery learning curves. Previous experience in laparoscopic pancreatoduodenectomy shortened the feasibility (-12 RPDs, -44%), proficiency (-32 RPDs, -34%), and mastery phase learning curve (-34 RPDs, -23%), but did not improve clinical outcome. CONCLUSIONS: The feasibility, proficiency, and mastery learning curves for RPD at 15, 62, and 84 procedures in "second-generation" centers after a multicenter training program were considerably shorter than previously reported from "pioneering" expert centers. The learning curve cutoffs and prior laparoscopic experience did not impact major morbidity and mortality. These findings demonstrate the safety and value of a nationwide training program for RPD in centers with sufficient volume.

Algorithm-based care versus usual care for the early recognition and management of complications after pancreatic resection in the Netherlands: an open-label, nationwide, stepped-wedge cluster-randomised trial.

BACKGROUND: Early recognition and management of postoperative complications, before they become clinically relevant, can improve postoperative outcomes for patients, especially for high-risk procedures such as pancreatic resection. METHODS: We did an open-label, nationwide, stepped-wedge cluster-randomised trial that included all patients having pancreatic resection during a 22-month period in the Netherlands. In this trial design, all 17 centres that did pancreatic surgery were randomly allocated for the timing of the crossover from usual care (the control group) to treatment given in accordance with a multimodal, multidisciplinary algorithm for the early recognition and minimally invasive management of postoperative complications (the intervention group). Randomisation was done by an independent statistician using a computer-generated scheme, stratified to ensure that low-medium-volume centres alternated with high-volume centres. Patients and investigators were not masked to treatment. A smartphone app was designed that incorporated the algorithm and included the daily evaluation of clinical and biochemical markers. The algorithm determined when to do abdominal CT, radiological drainage, start antibiotic treatment, and remove abdominal drains. After crossover, clinicians were trained in how to use the algorithm during a 4-week wash-in period; analyses comparing outcomes between the control group and the intervention group included all patients other than those having pancreatic resection during this wash-in period. The primary outcome was a composite of bleeding that required invasive intervention, organ failure, and 90-day mortality, and was assessed by a masked adjudication committee. This trial was registered in the Netherlands Trial Register, NL6671. FINDINGS: From Jan 8, 2018, to Nov 9, 2019, all 1805 patients who had pancreatic resection in the Netherlands were eligible for and included in this study. 57 patients who underwent resection during the wash-in phase were excluded from the primary analysis. 1748 patients (885 receiving usual care and 863 receiving algorithm-centred care) were included. The primary outcome occurred in fewer patients in the algorithm-centred care group than in the usual care group (73 [8%] of 863 patients vs 124 [14%] of 885 patients; adjusted risk ratio [RR] 0·48, 95% CI 0·38-0·61; p<0·0001). Among patients treated according to the algorithm, compared with patients who received usual care there was a decrease in bleeding that required intervention (47 [5%] patients vs 51 [6%] patients; RR 0·65, 0·42-0·99; p=0·046), organ failure (39 [5%] patients vs 92 [10%] patients; 0·35, 0·20-0·60; p=0·0001), and 90-day mortality (23 [3%] patients vs 44 [5%] patients; 0·42, 0·19-0·92; p=0·029). INTERPRETATION: The algorithm for the early recognition and minimally invasive management of complications after pancreatic resection considerably improved clinical outcomes compared with usual care. This difference included an approximate 50% reduction in mortality at 90 days. FUNDING: The Dutch Cancer Society and UMC Utrecht.

Preoptimisation in patients with acute obstructive colon cancer (PREOCC) - a prospective registration study protocol.

BACKGROUND: Postoperative mortality and morbidity rates are high in patients with obstructing colon cancer (OCC). Different treatment options have been evaluated over the years, mainly for left sided OCC. Optimising the preoperative health condition in elective colorectal cancer (CRC) treatment shows promising results. The aim of this study is to determine whether preoptimisation is feasible in patients with OCC, with a special interest/focus on right-sided OCC, and if, ultimately, optimisation reduces mortality and morbidity (stoma rates, major and minor complications) rates in OCC. METHODS: This is a prospective registration study including all patients presenting with OCC in our hospital. Patients with OCC, treated with curative intent, will be screened for eligibility to receive preoptimisation before surgery. The preoptimisation protocol includes; decompression of the small bowel with a NG-tube for right sided obstruction and SEMS or decompressing ileostomy or colostomy, proximal to the site of obstruction, for left sided colonic obstructions. For the additional work-up, additional nutrition by means of parenteral feeding (for patients who are dependent on a NG tube) or oral/enteral nutrition (in case the obstruction is relieved) is provided. Physiotherapy with attention to both cardio and muscle training prior surgical resection is provided. The primary endpoint is complication-free survival (CFS) at the 90 day period after hospitalisation. Secondary outcomes include pre- and postoperative complications, patient- and tumour characteristics, surgical procedures, total in hospital stay, creation of decompressing and/or permanent ileo- or colostomy and long-term (oncological) outcomes. DISCUSSION: Preoptimisation is expected to improve the preoperative health condition of patients and thereby reduce postoperative complications. TRIAL REGISTRATION: Trial Registry: NL8266 date of registration: 06-jan-2020. STUDY STATUS: Open for inclusion.

Surgical treatment and overall survival in patients with right-sided obstructing colon cancer-a nationwide retrospective cohort study.

PURPOSE: The aim of this study was to compare baseline characteristics, 90-day mortality and overall survival (OS) between patients with obstructing and non-obstructing right-sided colon cancer at a national level. METHODS: All patients who underwent resection for right-sided colon cancer between January 2015 and December 2016 were selected from the Netherlands Cancer Registry and stratified for obstruction. Primary outcome was 5-year OS after excluding 90-day mortality as assessed by the Kaplan-Meier and multivariable Cox regression analysis. RESULTS: A total of 525 patients (7%) with obstructing and 6891 patients (93%) with non-obstructing right-sided colon cancer were included. Patients with right-sided obstructing colon cancer (OCC) were older and had more often transverse tumour location, and the pathological T and N stage was more advanced than in those without obstruction (p < 0.001). The 90-day mortality in patients with right-sided OCC was higher compared to that in patients with non-obstructing colon cancer: 10% versus 3%, respectively (p < 0.001). The 5-year OS of those surviving 90 days postoperatively was 42% in patients with OCC versus 73% in patients with non-obstructing colon cancer, respectively (p < 0.001). Worse 5-year OS was found in patients with right-sided OCC for all stages. Obstruction was an independent risk factor for decreased OS in right-sided colon cancer (HR 1.79, 95% CI 1.57-2.03). CONCLUSION: In addition to increased risk of postoperative mortality, a stage-independent worse 5-year OS after excluding 90-day mortality was found in patients with right-sided OCC compared to patients without obstruction.

Detection, Treatment, and Survival of Pancreatic Cancer Recurrence in the Netherlands: A Nationwide Analysis.

OBJECTIVE: To evaluate whether detection of recurrent pancreatic ductal adenocarcinoma (PDAC) in an early, asymptomatic stage increases the number of patients receiving additional treatment, subsequently improving survival. SUMMARY OF BACKGROUND DATA: International guidelines disagree on the value of standardized postoperative surveillance for early detection and treatment of PDAC recurrence. METHODS: A nationwide, observational cohort study was performed including all patients who underwent PDAC resection (2014-2016). Prospective baseline and perioperative data were retrieved from the Dutch Pancreatic Cancer Audit. Data on follow-up, treatment, and survival were collected retrospectively. Overall survival (OS) was evaluated using multivariable Cox regression analysis, before and after propensity-score matching, stratified for patients with symptomatic and asymptomatic recurrence. RESULTS: Eight hundred thirty-six patients with a median follow-up of 37 months (interquartile range 30-48) were analyzed. Of those, 670 patients (80%) developed PDAC recurrence after a median follow-up of 10 months (interquartile range 5-17). Additional treatment was performed in 159/511 patients (31%) with symptomatic recurrence versus 77/159 (48%) asymptomatic patients (P < 0.001). After propensity-score matching on lymph node ratio, adjuvant therapy, disease-free survival, and recurrence site, additional treatment was independently associated with improved OS for both symptomatic patients [hazard ratio 0.53 (95% confidence interval 0.42-0.67); P < 0.001] and asymptomatic patients [hazard ratio 0.45 (95% confidence interval 0.29-0.70); P < 0.001]. CONCLUSIONS: Additional treatment of PDAC recurrence was independently associated with improved OS, with asymptomatic patients having a higher probability to receive recurrence treatment. Therefore, standardized postoperative surveillance aiming to detect PDAC recurrence before the onset of symptoms has the potential to improve survival. This provides a rationale for prospective studies on standardized surveillance after PDAC resection.

Impact of Complications After Pancreatoduodenectomy on Mortality, Organ Failure, Hospital Stay, and Readmission: Analysis of a Nationwide Audit.

OBJECTIVE: To quantify the impact of individual complications on mortality, organ failure, hospital stay, and readmission after pancreatoduodenectomy. SUMMARY OF BACKGROUND DATA: An initial complication may provoke a sequence of adverse events potentially leading to mortality after pancreatoduodenectomy. This study was conducted to aid prioritization of quality improvement initiatives. METHODS: Data from consecutive patients undergoing pancreatoduodenectomy (2014-2017) were extracted from the Dutch Pancreatic Cancer Audit. Population attributable fractions (PAF) were calculated for the association of each complication (ie, postoperative pancreatic fistula, postpancreatectomy hemorrhage, bile leakage, delayed gastric emptying, wound infection, and pneumonia) with each unfavorable outcome [ie, in-hospital mortality, organ failure, prolonged hospital stay (>75th percentile), and unplanned readmission), whereas adjusting for confounders and other complications. The PAF represents the proportion of an outcome that could be prevented if a complication would be eliminated completely. RESULTS: Overall, 2620 patients were analyzed. In-hospital mortality occurred in 95 patients (3.6%), organ failure in 198 patients (7.6%), and readmission in 427 patients (16.2%). Postoperative pancreatic fistula and postpancreatectomy hemorrhage had the greatest independent impact on mortality [PAF 25.7% (95% CI 13.4-37.9) and 32.8% (21.9-43.8), respectively] and organ failure [PAF 21.8% (95% CI 12.9-30.6) and 22.1% (15.0-29.1), respectively]. Delayed gastric emptying had the greatest independent impact on prolonged hospital stay [PAF 27.6% (95% CI 23.5-31.8)]. The impact of individual complications on unplanned readmission was smaller than 11%. CONCLUSION: Interventions focusing on postoperative pancreatic fistula and postpancreatectomy hemorrhage may have the greatest impact on in-hospital mortality and organ failure. To prevent prolonged hospital stay, initiatives should in addition focus on delayed gastric emptying.

Outcomes of a Multicenter Training Program in Robotic Pancreatoduodenectomy (LAELAPS-3).

OBJECTIVE: To assess feasibility and safety of a multicenter training program in robotic pancreatoduodenectomy (RPD) adhering to the IDEAL framework for implementation of surgical innovation. BACKGROUND: Good results for RPD have been reported from single center studies. However, data on feasibility and safety of implementation through a multicenter training program in RPD are lacking. METHODS: A multicenter training program in RPD was designed together with the University of Pittsburgh Medical Center, including an online video bank, robot simulation exercises, biotissue drills, and on-site proctoring. Benchmark patients were based on the criteria of Clavien. Outcomes were collected prospectively (March 2016-October 2019). Cumulative sum analysis of operative time was performed to distinguish the first and second phase of the learning curve. Outcomes were compared between both phases of the learning curve. Trends in nationwide use of robotic and laparoscopic PD were assessed in the Dutch Pancreatic Cancer Audit. RESULTS: Overall, 275 RPD procedures were performed in seven centers by 15 trained surgeons. The recent benchmark criteria for low-risk PD were met by 125 (45.5%) patients. The conversion rate was 6.5% (n = 18) and median blood loss 250ml [interquartile range (IQR) 150-500]. The rate of Clavien-Dindo grade ≥III complications was 44.4% (n = 122), postoperative pancreatic fistula (grade B/C) rate 23.6% (n = 65), 90-day complication-related mortality 2.5% (n = 7) and 90-day cancer-related mortality 2.2.% (n = 6). Median postoperative hospital stay was 12 days (IQR 8-20). In the subgroup of patients with pancreatic cancer (n = 80), the major complication rate was 31.3% and POPF rate was 10%. Cumulative sum analysis for operative time found a learning curve inflection point at 22 RPDs (IQR 10-35) with similar rates of Clavien-Dindo grade ≥III complications in the first and second phase (43.4% vs 43.8%, P = 0.956, respectively). During the study period the nationwide use of laparoscopic PD reduced from 15% to 1%, whereas the use of RPD increased from 0% to 25%. CONCLUSIONS: This multicenter RPD training program in centers with sufficient surgical volume was found to be feasible without a negative impact of the learning curve on clinical outcomes.

Short- and Long-Term Outcomes of Pancreatic Cancer Resection in Elderly Patients: A Nationwide Analysis.

BACKGROUND: The number of elderly patients with pancreatic cancer is growing, however clinical data on the short-term outcomes, rate of adjuvant chemotherapy, and survival in these patients are limited and we therefore performed a nationwide analysis. METHODS: Data from the prospective Dutch Pancreatic Cancer Audit were analyzed, including all patients undergoing pancreatic cancer resection between January 2014 and December 2016. Patients were classified into two age groups: <75 and ≥75 years. Major complications (Clavien-Dindo grade 3 or higher), 90-day mortality, rates of adjuvant chemotherapy, and survival were compared between age groups. Factors associated with start of adjuvant chemotherapy and survival were evaluated with logistic regression and multivariable Cox regression analysis. RESULTS: Of 836 patients, 198 were aged ≥75 years (24%) and 638 were aged <75 years (76%). Median follow-up was 38 months (interquartile range [IQR] 31-47). Major complications (31% vs. 28%; p = 0.43) and 90-day mortality (8% vs. 5%; p = 0.18) did not differ. Adjuvant chemotherapy was started in 37% of patients aged ≥75 years versus 69% of patients aged <75 years (p < 0.001). Median overall survival (OS) was 15 months (95% confidence interval [CI] 14-18) versus 21 months (95% CI 19-24; p < 0.001). Age ≥75 years was not independently associated with OS (hazard ratio 0.96, 95% CI 0.79-1.17; p = 0.71), but was associated with a lower rate of adjuvant chemotherapy (odds ratio 0.27, 95% CI 0.18-0.40; p < 0.001). CONCLUSIONS: The rate of major complications and 90-day mortality after pancreatic resection did not differ between elderly and younger patients; however, elderly patients were less often treated with adjuvant chemotherapy and their OS was shorter.

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.

The impact of cancer treatment on quality of life in patients with pancreatic and periampullary cancer: a propensity score matched analysis.

BACKGROUND: The impact of pancreatic and periampullary cancer treatment on health-related quality of life (HRQoL) is unclear. METHODS: This study merged data from the Netherlands Cancer Registry with EORTC QLQ-C30 and -PAN26 questionnaires at baseline and three-months follow-up of pancreatic and periampullary cancer patients (2015-2018). Propensity score matching (1:3) of group without to group with treatment was performed. Linear mixed model regression analyses were performed to investigate the association between cancer treatment and HRQoL at follow-up. RESULTS: After matching, 247 of 629 available patients remained (68 (27.5%) no treatment, 179 (72.5%) treatment). Treatment consisted of resection (n = 68 (27.5%)), chemotherapy only (n = 111 (44.9%)), or both (n = 40 (16.2%)). At follow-up, cancer treatment was associated with better global health status (Beta-coefficient 4.8, 95% confidence-interval 0.0-9.5) and less constipation (Beta-coefficient -7.6, 95% confidence-interval -13.8-1.4) compared to no cancer treatment. Median overall survival was longer for the cancer treatment group compared to the no treatment group (15.4 vs. 6.2 months, p < 0.001). CONCLUSION: Patients undergoing treatment for pancreatic and periampullary cancer reported slight improvement in global HRQoL and less constipation at three months-follow up compared to patients without cancer treatment, while overall survival was also improved.

Preoperative predictors for early and very early disease recurrence in patients undergoing resection of pancreatic ductal adenocarcinoma.

BACKGROUND: This study aimed to identify predictors for early and very early disease recurrence in patients undergoing resection of pancreatic ductal adenocarcinoma (PDAC) resection with and without neoadjuvant therapy. METHODS: Included were patients who underwent PDAC resection (2014-2016). Multivariable multinomial regression was performed to identify preoperative predictors for manifestation of recurrence within 3, 6 and 12 months after PDAC resection. RESULTS: 836 patients with a median follow-up of 37 (interquartile range [IQR] 30-48) months and overall survival of 18 (IQR 10-32) months were analyzed. 670 patients (80%) developed recurrence: 82 patients (10%) <3 months, 96 patients (11%) within 3-6 months and 226 patients (27%) within 6-12 months. LogCA 19-9 (OR 1.25 [95% CI 1.10-1.41]; P < 0.001) and neoadjuvant treatment (OR 0.09 [95% CI 0.01-0.68]; P = 0.02) were associated with recurrence <3 months. LogCA 19-9 (OR 1.23 [95% CI 1.10-1.38]; P < 0.001) and 0-90° venous involvement on CT imaging (OR 2.93 [95% CI 1.60-5.37]; P < 0.001) were associated with recurrence within 3-6 months. A Charlson Age Comorbidity Index ≥4 (OR 1.53 [95% CI 1.09-2.16]; P = 0.02) and logCA 19-9 (OR 1.24 [95% CI 1.14-1.35]; P < 0.001) were related to recurrence within 6-12 months. CONCLUSION: This study demonstrates preoperative predictors that are associated with the manifestation of early and very early recurrence after PDAC resection. Knowledge of these predictors can be used to guide individualized surveillance and treatment strategies.

A Systematic Review Comparing Emergency Resection and Staged Treatment for Curable Obstructing Right-Sided Colon Cancer.

BACKGROUND: Treatment for obstructing colon cancer (OCC) is controversial because the outcome of acute resection is less favorable than for patients without obstruction. Few studies have investigated curable right-sided OCC, and patients with OCC usually undergo acute resection. This study aimed to better understand the outcome and best management of potentially curable right-sided OCC. METHODS: A systematic review of studies was performed with a focus on differences in mortality and morbidity between emergency resection and staged treatment for patients with potentially curable right-sided OCC. In March 2019, the study searched Embase, Medline, Web of Science, Cochrane, and Google scholar databases according to PRISMA guidelines using search terms related to "colon tumour," "stenosis or obstruction and surgery," and "decompression or stents." All English-language studies reporting emergency or staged treatment for potentially curable right-sided OCC were included in the review. Emergency resection and staged resection were compared for mortality, morbidity, complications, and survival. RESULTS: Nine studies were found to be eligible and comprised 600 patients treated with curative intent for their right-sided OCC by emergency resection or staged resection. The mean overall complication rate was 42% (range 19-54%) after emergency resection, and 30% (range 7-44%) after staged treatment. The average mortality rate was 7.2% (range 0-14.5%) after emergency resection and 1.2% (range 0-6.3%) after staged treatment. The 5-year disease-free and overall survival rates were comparable for the two treatments. CONCLUSIONS: The patients who received staged treatment for right-sided OCC had lower mortality rates, fewer complications, and fewer anastomotic leaks and stoma creations than the patients who had emergency resection.

Differences in Metastatic Pattern in Patients Presenting With or Without Obstructing Colorectal Cancer: A Retrospective Observational Study of 2595 Patients.

BACKGROUND: Little is known about metastatic patterns in patients with obstructing colorectal cancer (CRC). OBJECTIVE: The aim of this study was to determine if metastatic patterns in patients with CRC differ between patients with or without obstruction. METHODS: This single-center, observational, retrospective cohort study includes patients who underwent surgery for CRC between 2004 and 2015 in our hospital. Patients were divided into two groups-patients with or without obstructing CRC. All anatomic sites of distant metastases were reported. Differences in synchronous and metachronous metastases were compared between both groups. RESULTS: A total of 2595 patients were included for analysis, of whom 315 (12%) presented with obstructing CRC. Synchronous metastases were diagnosed in 483 patients (19%). Patients with obstructing CRC and synchronous metastases, were diagnosed with peritoneal metastases more often than patients without obstruction (37% vs. 16%; p < 0.01). With regard to the location of the tumor, obstructing right-sided CRC patients were diagnosed with peritoneal metastases more often than patients without obstruction (52% vs. 21%; p < 0.01). Additionally, metachronous metastases were found significantly more often in patients with obstructing CRC (27%) compared with patients without obstruction (15%; p < 0.01). CONCLUSIONS: Patients with obstructing CRC have more advanced tumor stage compared with patients without obstructing CRC. Synchronous peritoneal metastases are more often encountered in patients with obstructing CRC compared with patients without obstruction. This difference is due to the raised presence of synchronous peritoneal metastases in patients with obstructed right-sided colonic cancer. Furthermore, metachronous metastases are more often found in patients with obstructing CRC.

Neoadjuvant Chemotherapy for Locally Advanced T4 Colon Cancer: A Nationwide Propensity-Score Matched Cohort Analysis.

INTRODUCTION: Neoadjuvant chemotherapy (CT) for locally advanced colon cancer (LACC) could potentially lead to tumor shrinkage, eradication of micrometastases, and prevention of tumor cell shedding during surgery. This retrospective study investigates the surgical and oncological outcomes of preoperative CT for LACC. METHODS: Using the Netherlands Cancer Registry, data of patients with stage II or III colon cancer, diagnosed between 2008 and 2016 was collected. A propensity score matching (PSM; 1:2) was performed and compared patients with clinical tumor (cT) 4 colon cancer who were treated with neoadjuvant CT to patients with cT4 colon cancer treated with adjuvant CT (Fig. 1). RESULTS: A total of 192 patients treated with neoadjuvant CT were compared to 1,954 patients that received adjuvant CT. After PSM, 149 patients in the neoadjuvant group were compared to 298 patients in the control group. No significant differences were found in baseline characteristics after PSM. After neoadjuvant CT, a significant response was observed in 13 (9%) patients with 5 (4%) patients showing a complete response. Complete resection margins (R0) were achieved in 77% in the neoadjuvant group versus 86% in the adjuvant treated group (p = 0.037). Significantly less tumor positive lymph nodes were found in the neoadjuvant group (median 0 vs. 2, p < 0.001). Major complication rates and 5-year overall survival did not differ between both groups (67-65%, p = 0.87). CONCLUSION: Neoadjuvant CT seems safe and feasible with similar long-term survival compared to patients who are treated with adjuvant CT.

MRI-based guidelines for selective neoadjuvant treatment in rectal cancer: Does MRI adequately predict the indication for radiotherapy in daily practice in a large teaching hospital.

OBJECTIVES: According to new Dutch guidelines for rectal cancer, MRI-defined tumour stage determines whether preoperative radiotherapy is indicated. Therefore, we sought to evaluate if preoperative MRI accurately predicts the indication for neoadjuvant treatment in rectal cancer cases in daily practice according to the new Dutch guidelines. METHODS: Data for all rectal cancer patients who underwent mesorectal excision in our hospital, between January 2011 and January 2018 were collected retrospectively. We compared histopathologic outcome with tumour staging on preoperative MRI for patients who received no radiotherapy prior to resection or short-course radiotherapy directly followed by resection. RESULTS: Of 223 patients treated according to the old guidelines, 94% received neoadjuvant therapy. Of 301 patients treated according to the new guidelines, only 49% did. Under the old guidelines, MRI predicted lymph node metastases with a sensitivity of 74.2% and a specificity of 52.6%. With the new guidelines, sensitivity was 47.5% and specificity was 77.3%. The new guidelines resulted in 45% more patients not being exposed to disadvantages of radiotherapy, but 13% of all patients were undertreated. CONCLUSIONS: Concordance between clinical lymph node staging on preoperative MRI and histopathologic staging is limited, resulting in many rectal cancer patients not receiving adequate neoadjuvant therapy.