Timothy H. Mungroop

FOLFIRINOX in Locally Advanced and Metastatic Pancreatic Cancer: A Single Centre Cohort Study

Introduction: FOLFIRINOX is emerging as new standard of care for fit patients with locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC). However, some of the physicians are reluctant to use FOLFIRINOX due to high toxicity rates reported in earlier studies. We reviewed our experience with FOLFIRINOX in LAPC and MPC, focussing on dose adjustments, toxicity and efficacy. Methods: We reviewed all patients with LAPC or MPC treated with FOLFIRINOX in our institution between April 2011 and December 2015. Unresectability (stage III and IV) was determined by the institutions multidisciplinary team for pancreatic cancer. Results: Fifty patients (18 LAPC and 32 MPC) were enrolled, with a median age of 55 years (IQR 49-66) and WHO performance status of 0/1. FOLFIRINOX was given as first-line treatment in 82% of patients. Dose modifications were applied in 90% of patients. The median number of completed cycles was 8 (IQR 5-9). Grade 3-4 toxicity occurred in 52% and grade 5 toxicity in 2%. The response rate was 25% (12% in LAPC, 32% in MPC). Median overall survival and progression-free survival were 14.8 and 10.3 months in LAPC, and 9.0 and 5.9 months in MPC, respectively. Overall 1- and 2-year survival was 65% and 10% in LAPC and 40% and 5% in MPC. Within the LAPC group, 6 patients (33%) underwent local ablative therapy and 1 patient (6%) a resection, leading to a median survival of 21.8 months. Conclusion: FOLFIRINOX treatment with nearly routine dose modification was associated with acceptable toxicity rates, relatively high response rates and an encouraging overall survival.

Continuous wound infiltration or epidural analgesia for pain prevention after hepato-pancreato-biliary surgery within an enhanced recovery program (POP-UP trial): study protocol for a randomized controlled trial

BackgroundPostoperative pain prevention is essential for the recovery of surgical patients. Continuous (thoracic) epidural analgesia (CEA) is routinely practiced for major abdominal surgery, but evidence is conflicting on its benefits in this setting. Potential disadvantages of epidural analgesia are a) perioperative hypotension, frequently requiring additional intravenous fluid boluses or prolonged use of vasopressors; b) relatively high failure rates, with periods of inadequate analgesia; and c) the risk of rare but serious, at times persistent, neurologic complications (hematoma and abscess). In recent years, continuous (subfascial) wound infiltration (CWI) plus patient-controlled analgesia (PCA) has been suggested as a safe and reliable alternative, which does not have the previously mentioned disadvantages, but evidence from multicenter trials targeting a specific surgical population is lacking. We hypothesize that CWI+PCA is equally as effective as CEA, without the mentioned disadvantages.Methods/designPOP-UP is a randomized controlled noninferiority multicenter trial, recruiting adult patients scheduled for elective hepato-pancreato-biliary surgery via laparotomy in an enhanced recovery setting. A total of 102 patients are being randomly allocated to CWI+PCA or (P)CEA. Our primary endpoint is the Overall Benefit of Analgesic Score (OBAS), a composite endpoint of pain intensity, opioid-related adverse effects and patient satisfaction, during postoperative days 1 to 5. Secondary endpoints include length of the hospital stay, number of patients with severe pain, and the use of rescue medication.DiscussionPOP-UP is a pragmatic trial that will provide evidence of whether CWI+PCA is noninferior as compared to (P)CEA after elective hepato-pancreato-biliary surgery via laparotomy in an enhanced recovery setting. If this hypothesis is confirmed, this finding could contribute to more widespread implementation of this technique, especially when the described disadvantages of epidural analgesia are less often observed with CWI+PCA.Trial registrationNetherlands Trial Register NTR4948 (registry date 2 January 2015).

Continuous wound infiltration versus epidural analgesia after hepato-pancreato-biliary surgery (POP-UP): a randomised controlled, open-label, non-inferiority trial

BACKGROUND Epidural analgesia is the international standard for pain treatment in abdominal surgery. Although some studies have advocated continuous wound infiltration with local anaesthetics, robust evidence is lacking, especially on patient-reported outcome measures. We aimed to determine the effectiveness of continuous wound infiltration in hepato-pancreato-biliary surgery. METHODS In this randomised controlled, open label, non-inferiority trial (POP-UP), we enrolled adult patients undergoing hepato-pancreato-biliary surgery by subcostal or midline laparotomy in two Dutch hospitals. Patients were centrally randomised (1:1) to receive either pain treatment with continuous wound infiltration using bupivacaine plus patient-controlled analgesia with morphine or to receive (patient-controlled) epidural analgesia with bupivacaine and sufentanil. All patients were treated within an enhanced recovery setting. Randomisation was stratified by centre and type of incision. The primary outcome was the mean Overall Benefit of Analgesic Score (OBAS) from day 1-5, a validated composite endpoint of pain scores, opioid side-effects, and patient satisfaction (range 0 [best] to 28 [worst]). Analysis was per-protocol. The non-inferiority limit of the mean difference was + 3·0. This trial is registered with the Netherlands Trial Registry, number NTR4948. FINDINGS Between Jan 20, 2015, and Sept 16, 2015, we randomly assigned 105 eligible patients: 53 to receive continuous wound infiltration and 52 to receive epidural analgesia. One patient in the continuous wound infiltration group discontinued treatment, as did five in the epidural analgesia group; of these five patients, preoperative placement failed in three (these patients were treated with continuous wound infiltration instead), one patient refused an epidural, and data for the primary endpoint was lost for one. Thus, 55 patients were included in the continuous wound infiltration group and 47 in the epidural analgesia group for the per-protocol analyses. Mean OBAS was 3·8 (SD 2·4) in the continuous wound infiltration group versus 4·4 (2·2) in the epidural group (mean difference -0·62, 95% CI -1·54 to 0·30). Because the upper bound of the one-sided 95% CI did not exceed +3·0, non-inferiority was shown. Four (7%) patients in the continuous wound infiltration group and five (11%) of those in the epidural group had an adverse event. One patient in the continuous wound infiltration group had a serious adverse event (temporary hypotension and arrhythmia after bolus injection); no serious adverse events were noted in the epidural group. INTERPRETATION These data suggest that continuous wound infiltration is non-inferior to epidural analgesia in hepato-pancreato-biliary surgery within an enhanced recovery setting. Further large-scale trials are required to make a definitive assessment of non-inferiority. FUNDING Academic Medical Centre, Amsterdam, Netherlands.

Alternative Fistula Risk Score for Pancreatoduodenectomy (a-FRS): Design and International External Validation

Objective: The aim of this study was to develop an alternative fistula risk score (a-FRS) for postoperative pancreatic fistula (POPF) after pancreatoduodenectomy, without blood loss as a predictor. Background: Blood loss, one of the predictors of the original-FRS, was not a significant factor during 2 recent external validations. Methods: The a-FRS was developed in 2 databases: the Dutch Pancreatic Cancer Audit (18 centers) and the University Hospital Southampton NHS. Primary outcome was grade B/C POPF according to the 2005 International Study Group on Pancreatic Surgery (ISGPS) definition. The score was externally validated in 2 independent databases (University Hospital of Verona and University Hospital of Pennsylvania), using both 2005 and 2016 ISGPS definitions. The a-FRS was also compared with the original-FRS. Results: For model design, 1924 patients were included of whom 12% developed POPF. Three predictors were strongly associated with POPF: soft pancreatic texture [odds ratio (OR) 2.58, 95% confidence interval (95% CI) 1.80–3.69], small pancreatic duct diameter (per mm increase, OR: 0.68, 95% CI: 0.61–0.76), and high body mass index (BMI) (per kg/m2 increase, OR: 1.07, 95% CI: 1.04–1.11). Discrimination was adequate with an area under curve (AUC) of 0.75 (95% CI: 0.71–0.78) after internal validation, and 0.78 (0.74–0.82) after external validation. The predictive capacity of a-FRS was comparable with the original-FRS, both for the 2005 definition (AUC 0.78 vs 0.75, P = 0.03), and 2016 definition (AUC 0.72 vs 0.70, P = 0.05). Conclusion: The a-FRS predicts POPF after pancreatoduodenectomy based on 3 easily available variables (pancreatic texture, duct diameter, BMI) without blood loss and pathology, and was successfully validated for both the 2005 and 2016 POPF definition. The online calculator is available at www.pancreascalculator.com.

What Is a Good Perioperative Intravenous Fluid Therapy in Liver Surgery

With great interest, we read the article, “Goal-directed fluid therapy using stroke volume variation for resuscitation after low central venous pressure-assisted liver resection: a randomized clinical trial” by Correa-Gallego and colleagues. Goal-directed fluid therapy (GDT) has proved to be a successful method to reduce morbidity in patients undergoing high-risk surgery. Correa-Gallego and coworkers should be commended for performing the first randomized trial on GDT in liver surgery. The study was stopped because of futility after including half of the intended number of patients (n 1⁄4 135). The challenge during liver surgery is the need for a low liver blood flow and blood content. This is most often attempted by means of a low central venous pressure (CVP). Low CVP has limited evidence, but it is the best we currently have. Simultaneously, we want to optimize cardiac output to get sufficient organ oxygenation, which is the hallmark of GDT. This remains a difficult balance. There are a few items we would like to address and that need to be clarified to be able to better interpret the results. First, there are a few methodologic issues. The authors report that 158 patients were excluded because treating physicians declined study participation; this high number might jeopardize the external validity of the study. In addition, sample size calculation was performed for the whole population. A positive trend was seen for the surgical patients with the highest risk for morbidity. After study cessation, this subgroup was likely to be too small to draw any conclusions. Second, we would like to address the GDT protocol that was used. Stroke volume variation (SVV) was used as a target parameter. Stroke volume variation can be unreliable when tidal volumes below 8 mL/kg ideal body weight are used. No information on this is available in the Methods section. Interestingly, cardiac output and

New-onset diabetes after pancreatoduodenectomy: A systematic review and meta-analysis

Background: Pancreatoduodenectomy may lead to new‐onset diabetes mellitus, also known as type 3c diabetes, but the exact risk of this complication is unknown. The aim of this review was to assess the risk of new‐onset diabetes mellitus after pancreatoduodenectomy. Methods: A literature search was performed in PubMed, Embase (Ovid), and the Cochrane Library for English articles published from March 1993 until March 2017 (PROSPERO registry number: CRD42016039784). Studies reporting on the risk of new‐onset diabetes mellitus after pancreatoduodenectomy were included. For meta‐analysis, studies were pooled using the random‐effects model. All studies were appraised according to the Newcastle‐Ottawa Scale. Results: After screening 1,523 studies, 22 studies involving 1,121 patients were eligible. The mean weighted overall proportion of new‐onset diabetes mellitus after pancreatoduodenectomy was 16% (95% confidence interval, 12%–20%). We found no significant difference in risk of new‐onset diabetes mellitus when pancreatoduodenectomy was performed for nonmalignant disease after excluding patients with chronic pancreatitis (19% risk; 95% confidence interval, 7%–43%; 6 studies) or for malignant disease (22% risk; 95% confidence interval, 14%–32%; 11 studies), P = .71. Among all patients, 6% (95% confidence interval, 4%–10%) developed insulin‐dependent new‐onset diabetes mellitus. Conclusion: This systematic review identified a clinically relevant risk of new‐onset diabetes mellitus after pancreatoduodenectomy of which patients should be informed preoperatively.

Fluid and pain management in liver surgery (MILESTONE): A worldwide study among surgeons and anesthesiologists

Background: Fluid and pain management during liver surgery (eg, low central venous pressure) is a classic topic of controversy between anesthesiologists and surgeons. Little is known about practices worldwide. The aim of this study was to assess perioperative practices in liver surgery among and between surgeons and anesthesiologists worldwide that could guide the design of future international studies. Methods: An online questionnaire was sent to 22 societies, including 4 international hepatopancreatobiliary societies, the American Society of Anesthesiologists, and 17 other (inter‐)national societies. Results: A total of 913 participants (495 surgeons and 418 anesthesiologists) from 66 countries were surveyed. A large heterogeneity in fluid management practices was identified, with 66% using low central venous pressure, 22% goal‐directed fluid therapy, and 6% normovolemia. In addition, large heterogeneity was found regarding pain management practices, with 49% using epidural analgesia, 25% patient‐controlled analgesia with opioids, and 12% regional techniques. Most participants assume that there is a relation between perioperative pain management and morbidity and mortality (78% of surgeons vs 89% of anesthesiologists; P < .001). Both surgeons and anesthesiologists have the highest expectations for minimally invasive surgery and enhanced recovery pathways for improving outcomes in liver surgery. No clear differences between continents were found. Conclusion: Worldwide there is a large heterogeneity in fluid and pain management practices in liver surgery. This survey identified several areas of interest for future international studies aiming to improve outcomes in liver surgery.

Serum levels of bupivacaine after pre-peritoneal bolus vs. epidural bolus injection for analgesia in abdominal surgery: A safety study within a randomized controlled trial

Background Continuous wound infiltration (CWI) has become increasingly popular in recent years as an alternative to epidural analgesia. As catheters are not placed until the end of surgery, more intraoperative opioid analgesics might be needed. We, therefore, added a single pre-peritoneal bolus of bupivacaine at the start of laparotomy, similar to the bolus given with epidural analgesia. Methods This was a comparative study within a randomized controlled trial (NTR4948). Patients undergoing hepato-pancreato-biliary surgery received either a pre-peritoneal bolus of 30ml bupivacaine 0.25%, or an epidural bolus of 10ml bupivacaine 0.25% at the start of laparotomy. In a subgroup of patients, we sampled blood and determined bupivacaine serum levels 20, 40, 60 and 80 minutes after bolus injection. We assumed toxicity of bupivacaine to be >1000 ng/ml. Results A total of 20 patients participated in this sub-study. All plasma levels measured as well as the upper limit of the predicted 99% confidence intervals per time point were well below the toxicity limit. In a mixed linear-effect model both groups did not differ statistically significant (p = 0.131). The intra-operative use of opioids was higher with CWI as compared to epidural (86 (SD 73) μg sufentanil vs. 50 (SD 32). Conclusions In this exploratory study, the pre-peritoneal bolus using bupivacaine resulted in serum bupivacaine concentrations well below the commonly accepted toxic threshold. With CWI more additional analgesics are needed intraoperatively as compared to epidural analgesia, although this is compensated by a reduction in use of vasopressors with CWI. Trial registration Netherlands Trial Register NTR4948