Preoperative chemoradiotherapy but not chemotherapy is associated with reduced risk of postoperative pancreatic fistula after pancreatoduodenectomy for pancreatic ductal adenocarcinoma: a nationwide analysis.

BACKGROUND: Postoperative pancreatic fistula remains the leading cause of significant morbidity after pancreatoduodenectomy for pancreatic ductal adenocarcinoma. Preoperative chemoradiotherapy has been described to reduce the risk of postoperative pancreatic fistula, but randomized trials on neoadjuvant treatment in pancreatic ductal adenocarcinoma focus increasingly on preoperative chemotherapy rather than preoperative chemoradiotherapy. This study aimed to investigate the impact of preoperative chemotherapy and preoperative chemoradiotherapy on postoperative pancreatic fistula and other pancreatic-specific surgery related complications on a nationwide level. METHODS: All patients after pancreatoduodenectomy for pancreatic ductal adenocarcinoma were included in the mandatory nationwide prospective Dutch Pancreatic Cancer Audit (2014-2020). Baseline and treatment characteristics were compared between immediate surgery, preoperative chemotherapy, and preoperative chemoradiotherapy. The relationship between preoperative chemotherapy, chemoradiotherapy, and clinically relevant postoperative pancreatic fistula (International Study Group of Pancreatic Surgery grade B/C) was investigated using multivariable logistic regression analyses. RESULTS: Overall, 2,019 patients after pancreatoduodenectomy for pancreatic ductal adenocarcinoma were included, of whom 1,678 underwent immediate surgery (83.1%), 192 (9.5%) received preoperative chemotherapy, and 149 (7.4%) received preoperative chemoradiotherapy. Postoperative pancreatic fistula occurred in 8.3% of patients after immediate surgery, 4.2% after preoperative chemotherapy, and 2.0% after preoperative chemoradiotherapy (P = .004). In multivariable analysis, the use of preoperative chemoradiotherapy was associated with reduced risk of postoperative pancreatic fistula (odds ratio, 0.21; 95% confidence interval, 0.03-0.69; P = .033) compared with immediate surgery, whereas preoperative chemotherapy was not (odds ratio, 0.59; 95% confidence interval, 0.25-1.25; P = .199). Intraoperatively hard, or fibrotic pancreatic texture was most frequently observed after preoperative chemoradiotherapy (53% immediate surgery, 62% preoperative chemotherapy, 77% preoperative chemoradiotherapy, P < .001). CONCLUSION: This nationwide analysis demonstrated that in patients undergoing pancreatoduodenectomy for pancreatic ductal adenocarcinoma, only preoperative chemoradiotherapy, but not preoperative chemotherapy, was associated with a reduced risk of postoperative pancreatic fistula.

Impact of complications after resection of pancreatic cancer on disease recurrence and survival, and mediation effect of adjuvant chemotherapy: nationwide, observational cohort study.

BACKGROUND: The causal pathway between complications after pancreatic cancer resection and impaired long-term survival remains unknown. The aim of this study was to investigate the impact of complications after pancreatic cancer resection on disease-free interval and overall survival, with adjuvant chemotherapy as a mediator. METHODS: This observational study included all patients undergoing pancreatic cancer resection in the Netherlands (2014-2017). Clinical data were extracted from the prospective Dutch Pancreatic Cancer Audit. Recurrence and survival data were collected additionally. In causal mediation analysis, direct and indirect effect estimates via adjuvant chemotherapy were calculated. RESULTS: In total, 1071 patients were included. Major complications (hazards ratio 1.22 (95 per cent c.i. 1.04 to 1.43); P = 0.015 and hazards ratio 1.25 (95 per cent c.i. 1.08 to 1.46); P = 0.003) and organ failure (hazards ratio 1.86 (95 per cent c.i. 1.32 to 2.62); P < 0.001 and hazards ratio 1.89 (95 per cent c.i. 1.36 to 2.63); P < 0.001) were associated with shorter disease-free interval and overall survival respectively. The effects of major complications and organ failure on disease-free interval (-1.71 (95 per cent c.i. -2.27 to -1.05) and -3.05 (95 per cent c.i. -4.03 to -1.80) respectively) and overall survival (-1.92 (95 per cent c.i. -2.60 to -1.16) and -3.49 (95 per cent c.i. -4.84 to -2.03) respectively) were mediated by adjuvant chemotherapy. Additionally, organ failure directly affected disease-free interval (-5.38 (95 per cent c.i. -9.27 to -1.94)) and overall survival (-6.32 (95 per cent c.i. -10.43 to -1.99)). In subgroup analyses, the association was found in patients undergoing pancreaticoduodenectomy, but not in patients undergoing distal pancreatectomy. CONCLUSION: Major complications, including organ failure, negatively impact survival in patients after pancreatic cancer resection, largely mediated by adjuvant chemotherapy. Prevention or adequate treatment of complications and use of neoadjuvant treatment may improve oncological outcomes.

The yield of staging laparoscopy for resectable and borderline resectable pancreatic cancer in the PREOPANC randomized controlled trial.

BACKGROUND: The necessity of the staging laparoscopy in patients with pancreatic cancer is still debated. The objective of this study was to assess the yield of staging laparoscopy for detecting occult metastases in patients with resectable or borderline resectable pancreatic cancer. METHOD: This was a post-hoc analysis of the randomized controlled PREOPANC trial in which patients with resectable or borderline resectable pancreatic cancer were randomized between preoperative chemoradiotherapy or immediate surgery. Patients assigned to preoperative treatment underwent a staging laparoscopy prior to preoperative treatment according to protocol, to avoid unnecessary chemoradiotherapy in patients with occult metastatic disease. RESULTS: Of the 246 included patients, 7 did not undergo surgery. A staging laparoscopy was performed in 133 patients (55.6%) and explorative laparotomy in 106 patients (44.4%). At staging laparoscopy, occult metastases were detected in 13 patients (9.8%); 12 liver metastases and 1 peritoneal metastasis. At direct explorative laparotomy, occult metastases were found in 9 patients (8.5%); 6 with liver metastases, 1 with peritoneal metastases, and 2 with metastases at multiple sites. One patient had peritoneal metastases at exploration after a negative staging laparoscopy. Patients with occult metastases were more likely to receive palliative chemotherapy if found with staging laparoscopy compared to laparotomy (76.9% vs. 30.0%, p = 0.040). CONCLUSIONS: Staging laparoscopy detected occult metastases in about 10% of patients with resectable or borderline resectable pancreatic cancer. These patients were more likely to receive palliative systemic chemotherapy compared to patients in whom occult metastases were detected with laparotomy. A staging laparoscopy is recommended before planned resection.

Fistula Risk Score for Auditing Pancreatoduodenectomy: The Auditing-FRS.

OBJECTIVE: To develop a fistula risk score for auditing, to be able to compare postoperative pancreatic fistula (POPF) after pancreatoduodenectomy among hospitals. BACKGROUND: For proper comparisons of outcomes in surgical audits, case-mix variation should be accounted for. METHODS: This study included consecutive patients after pancreatoduodenectomy from the mandatory nationwide Dutch Pancreatic Cancer Audit. Derivation of the score was performed with the data from 2014 to 2018 and validation with 2019 to 2020 data. The primary endpoint of the study was POPF (grade B or C). Multivariable logistic regression analysis was performed for case-mix adjustment of known risk factors. RESULTS: In the derivation cohort, 3271 patients were included, of whom 479 (14.6%) developed POPF. Male sex [odds ratio (OR)=1.34; 95% confidence interval (CI): 1.09-1.66], higher body mass index (OR=1.07; 95% CI: 1.05-1.10), a final diagnosis other than pancreatic ductal adenocarcinoma/pancreatitis (OR=2.41; 95% CI: 1.90-3.06), and a smaller duct diameter (OR=1.43/mm decrease; 95% CI: 1.32-1.55) were independently associated with POPF. Diabetes mellitus (OR=0.73; 95% CI: 0.55-0.98) was independently associated with a decreased risk of POPF. Model discrimination was good with a C -statistic of 0.73 in the derivation cohort and 0.75 in the validation cohort (n=913). Hospitals differed in particular in the proportion of pancreatic ductal adenocarcinoma/pancreatitis patients, ranging from 36.0% to 58.1%. The observed POPF risk per center ranged from 2.9% to 25.4%. The expected POPF rate based on the 5 risk factors ranged from 11.6% to 18.0% among hospitals. CONCLUSIONS: The auditing fistula risk score was successful in case-mix adjustment and enables fair comparisons of POPF rates among hospitals.

High Systemic Immune Inflammation Index Is Associated With Low Skeletal Muscle Quantity in Resectable Pancreatic Ductal Adenocarcinoma.

Background and Aims: Failing immune surveillance in pancreatic ductal adenocarcinoma (PDAC) is related to poor prognosis. PDAC is also characterized by its substantial alterations to patients' body composition. Therefore, we investigated associations between the host systemic immune inflammation response and body composition in patients with resected PDAC. Methods: Patients who underwent a pancreatectomy for PDAC between 2004 and 2016 in two tertiary referral centers were included. Skeletal muscle mass quantity and muscle attenuation, as well as subcutaneous and visceral adipose tissue at the time of diagnosis, were determined by CT imaging measured transversely at the third lumbar vertebra level. Baseline clinicopathological characteristics, laboratory values including the systemic immune inflammation index (SIII), postoperative, and survival outcomes were collected. Results: A total of 415 patients were included, and low skeletal muscle mass quantity was found in 273 (65.7%) patients. Of the body composition indices, only low skeletal muscle mass quantity was independently associated with a high (≥900) SIII (OR 7.37, 95% CI 2.31-23.5, p=0.001). The SIII was independently associated with disease-free survival (HR 1.86, 95% CI 1.12-3.04), and cancer-specific survival (HR 2.21, 95% CI 1.33-3.67). None of the body composition indices were associated with survival outcomes. Conclusion: This study showed a strong association between preoperative low skeletal muscle mass quantity and elevated host systemic immune inflammation in patients with resected PDAC. Understanding how systemic inflammation may contribute to changes in body composition or whether reversing these changes may affect the host systemic immune inflammation response could expose new therapeutic possibilities for improving patients' survival outcomes.

Surgical Complications in a Multicenter Randomized Trial Comparing Preoperative Chemoradiotherapy and Immediate Surgery in Patients With Resectable and Borderline Resectable Pancreatic Cancer (PREOPANC Trial).

OBJECTIVES: To investigate the effect of preoperative chemoradiotherapy on surgical complications in patients after pancreatic resection for (borderline-)resectable pancreatic cancer. SUMMARY OF BACKGROUND DATA: Preoperative chemoradiotherapy is increasingly used in patients with (borderline-)resectable pancreatic cancer. concerns have been raised about the potential harmful effect of any preoperative therapy on the surgical complication rate after pancreatic resection. METHODS: An observational analysis was performed within the multicenter randomized controlled PREOPANC trial (April 2013-July 2017). The trial randomly assigned (1:1) patients to preoperative chemoradiotherapy followed by surgery and the remaining adjuvant chemotherapy or to immediate surgery, followed by adjuvant chemotherapy. The main analysis consisted of a per-protocol approach. The endpoints of the present analyses were the rate of postoperative complications. RESULTS: This study included 246 patients from 16 centers, of whom 66 patients underwent resection after preoperative therapy and 98 patients after immediate surgery. No differences were found regarding major complications (37.9% vs 30.6%, P=0.400), postpancreatectomy hemorrhage (9.1% vs 5.1%, P=0.352), delayed gastric emptying (21.2% vs 22.4%, P=0.930), bile leakage (4.5% vs 3.1%, P=0.686), intra-abdominal infections (12.1% vs 10.2%, P=0.800), and mortality (3.0% vs 4.1%, P=1.000). There was a significant lower incidence of postoperative pancreatic fistula in patients who received preoperative chemoradiotherapy (0% vs 9.2%, P=0.011). CONCLUSIONS: Preoperative chemoradiotherapy did not increase the incidence of surgical complications or mortality and reduced the rate of postoperative pancreatic fistula after resection in patients with (borderline-)resectable pancreatic cancer.

Age and prognosis in patients with pancreatic cancer: a population-based study.

BACKGROUND: The diagnosis of pancreatic ductal adenocarcinoma (PDAC) has an enormous impact on patients, and even more so if they are of younger age. It is unclear how their treatment and outcome compare to older patients. This study compares clinicopathological characteristics and overall survival (OS) of PDAC patients aged <60 years to older PDAC patients. METHOD: This is a retrospective, population-based cohort study using Netherlands Cancer Registry data of patients diagnosed with PDAC (1 January 2015-31 December 2018). Kaplan-Meier curves and Cox proportional hazards models were used to assess OS. RESULTS: Overall, 10,298 patients were included, of whom 1551 (15%) were <60 years. Patients <60 years were more often male, had better performance status, less comorbidities and less stage I disease, and more often received anticancer treatment (67 vs. 33%, p < 0.001) than older patients. Patients <60 years underwent resection of the tumour more often (22 vs. 14%p < 0.001), more often received chemotherapy, and had a better median OS (6.9 vs. 3.3 months, p < 0.001) compared to older patients. No differences in median OS were demonstrated between both age groups of patients who underwent resection (19.7 vs. 19.4 months, p = 0.123), received chemotherapy alone (7.8 vs. 8.5 months, p = 0.191), or received no anticancer treatment (1.8 vs. 1.9 months, p = 0.600). Patients <60 years with stage-IV disease receiving chemotherapy had a somewhat better OS (7.5 vs. 6.3 months, p = 0.026). CONCLUSION: Patients with PDAC <60 years more often underwent resection despite less stage I disease and had superior OS. Stratified for treatment, however, survival was largely similar.

The effect of preoperative chemotherapy and chemoradiotherapy on pancreatic fistula and other surgical complications after pancreatic resection: a systematic review and meta-analysis of comparative studies.

BACKGROUND: Preoperative chemo- or chemoradiotherapy is recommended for borderline-resectable pancreatic cancer. The aim of this study was to determine the impact of preoperative therapy on surgical complications in patients with resected pancreatic cancer. METHODS: This systematic review and meta-analysis included studies reporting on the rate of surgical complications after preoperative chemo- or chemoradiotherapy versus immediate surgery in pancreatic cancer patients. The primary endpoint was the rate of grade B/C POPF. Pooled odds ratios were calculated using random-effects models. RESULTS: Forty-one comparative studies including 25,389 patients were included. Vascular resections were more often performed after preoperative therapy (29.4% vs. 15.7%, p < 0.001). Preoperative therapy was associated with a lower rate of grade B/C POPF as compared to immediate surgery (pooled OR 0.47, 95%CI 0.38-0.58). This reduction was mostly obtained by preoperative chemoradiotherapy (OR 0.46, 95%CI 0.29-0.73), but not by preoperative chemotherapy alone (OR 0.83, 95%CI 0.59-1.16). No difference was demonstrated for major morbidity, mortality, postpancreatectomy haemorrhage, delayed gastric emptying and overall morbidity. CONCLUSION: Preoperative chemo- and chemoradiotherapy in patients with pancreatic cancer appears to be safe with respect to POPF and other surgical complications as compared to immediate surgery. The reduced rate of POPF appears to be attributable to preoperative chemoradiation.

The value of serum amylase and drain fluid amylase to predict postoperative pancreatic fistula after pancreatoduodenectomy: a retrospective cohort study.

PURPOSE: Serum and drain amylase have been identified as important predictors of postoperative pancreatic fistula (POPF) and might be useful to guide postoperative drain management after pancreatoduodenectomy. We aimed to determine and compare the value of serum amylase and drain fluid amylase to predict postoperative pancreatic fistula after pancreatoduodenectomy. METHODS: This retrospective cohort study included patients after pancreatoduodenectomy from 2012 to 2019. The primary endpoint of our study was grade B/C POPF. Serum amylase on postoperative day 1 (SA-1) and drain fluid amylase on postoperative day 2 (DFA-2) were analyzed. RESULTS: A total of 92 of 437 patients (21.1%) developed a grade B/C POPF. SA-1 was higher in patients who developed a grade B/C POPF (336 U/L vs. 97 U/L, p<0.001). Similarly, DFA-2 was higher in patients who developed a grade B/C POPF (1764 U/L vs. 78 U/L, p<0.001). SA-1 and DFA-2 had similar predictive accuracy (AUC: 0.82 vs. 0.85, respectively, p=0.329). Patients with SA-1<100 U/L (n=178) had a risk of 2.2% of developing grade B/C POPF, compared to 38.2% in patients with SA-1 >100 U/L (n=207). Patients with DFA-2<100 U/L (n=141) had a risk of 0% of developing grade B/C POPF, compared to 36.2% in patients with DFA-2>100 U/L (n=196). SA-1 and DFA-2 were strongly associated at a cut-off of 100 U/L (p<0.001, 89% concordance rate). CONCLUSION: Postoperative serum and drain amylase values below 100 U/L both effectively rule out POPF after pancreatoduodenectomy. The advantage of serum amylase measurement is that it can be used in patients who are managed without surgical drains.

C-reactive protein is superior to white blood cell count for early detection of complications after pancreatoduodenectomy: a retrospective multicenter cohort study.

BACKGROUND: Early detection of major complications after pancreatoduodenectomy could improve patient management and decrease the "failure-to-rescue" rate. In this retrospective cohort study, we aimed to compare the value of C-reactive protein (CRP) and white blood cell count (WBC) in the early detection of complications after pancreatoduodenectomy. METHODS: We assessed pancreatoduodenectomies between January 2012 and December 2017. Major complications were defined as grade III or higher according to the Clavien-Dindo classification. Postoperative pancreatic fistula (POPF) was a secondary endpoint. ROC-curve and logistic regression analysis were performed for CRP and WBC. Results were validated in an external cohort. RESULTS: In the development cohort (n = 285), 103 (36.1%) patients experienced a major complication. CRP was superior to WBC in detecting major complications on postoperative day (POD) 3 (AUC:0.74 vs. 0.54, P < 0.001) and POD 5 (AUC:0.77 vs. 0.68, P = 0.031), however not on POD 7 (AUC:0.77 vs. 0.76, P = 0.773). These results were confirmed in multivariable analysis and in the validation cohort (n = 202). CRP was also superior to WBC in detecting POPF on POD 3 (AUC: 0.78 vs. 0.54, P < 0.001) and POD 5 (AUC: 0.83 vs. 0.71, P < 0.001). CONCLUSION: CRP appears to be superior to WBC in the early detection of major complications and POPF after pancreatoduodenectomy.