Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial.

BACKGROUND: In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma. METHODS: NORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing. FINDINGS: Between Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49-71) in the neoadjuvant FOLFIRINOX group versus 73% (62-84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2-34·9) versus 38·5 months (27·6-not reached; hazard ratio [HR] 1·52 [95% CI 1·00-2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46-67) in the neoadjuvant FOLFIRINOX group versus 70% (55-83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2-34·9) versus 34·4 months (19·4-not reached; HR 1·46 [95% CI 0·99-2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event. INTERPRETATION: This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven. FUNDING: Norwegian Cancer Society, South Eastern Norwegian Health Authority, The Sjöberg Foundation, and Helsinki University Hospital Research Grants.

Translation and validation of the Norwegian version of the postoperative quality of recovery score QoR-15.

BACKGROUND: As patient-centered care gains more attention, assessing the patient's perspective on their recovery has become increasingly important. In response to the need for a reliable and valid patient reported outcome measurement tool for major surgical resections in Norway. The Norwegian Registry for Gastrointestinal Surgery (NORGAST) initiated a project to translate and evaluate QoR-15's psychometric properties for patients going through general, gastrointestinal (GI), and hepato-pancreato-biliary (HPB) resectional surgery. METHODS: After a translation and adaption of the original version of QoR-15 into Norwegian, the QoR-15NO was psychometrically evaluated including a confirmatory factor analysis to test for unidimensionality, as well as tests for content validity, internal consistency, measurement error, construct validity, feasibility, and responsiveness. This process included cognitive interviews using a structured interview guide. Further, patients who underwent various types of GI/HPB surgery at five hospitals in different parts of Norway completed the QoR-15NO before surgery and on the first or second day after surgery. The impact of surgery was classified according to Surgical Outcome Risk Tool v2 (SORT), in extra major/complex, major, intermediate, and minor. RESULTS: This study included 324 patients with 83% return rate with both pre- and postoperative forms. There were negative correlations between duration of surgery and postoperative QoR-15 score and the difference between post- and preoperative score (change score). Individuals who had gone through surgery with major impact had a lower postoperative mean QoR-15 score (97) than their counterparts who had experienced either medium (QoR-15: 110) or minor (QoR15: 119) impact surgery. Cronbach's alpha (0.88) and Omega Alpha Total (ωt = 0.90) indicate that the scale has good to very good internal consistency. Test-retest reliability was measured by Intra-class Correlation Coefficient to ICC = 0.70. Confirmatory factor analyses supported that a one-factor model with correlated residuals had a good fit to data. CONCLUSION: This study supports QoR-15NO as a valid, essentially unidimensional, feasible, and responsive instrument among patients undergoing general, GI, and HPB resectional surgery in Norway. The total QoR-15NO score provides important information that can be used in an everyday clinical setting and integrated into NORGAST.

Laparoscopic rectal cancer resection yields comparable clinical and oncological results with shorter hospital stay compared to open access: a 5-year national cohort.

PURPOSE: Although widely applied, the results following laparoscopic rectal resection (LRR) compared to open rectal resection (ORR) are still debated. The aim of this study was to assess clinical short- and long-term results as well as oncological resection quality following LRR or ORR for cancer in a 5-year national cohort. METHODS: Data from the Norwegian Registry for Gastrointestinal Surgery and the Norwegian Colorectal Cancer Registry were retrieved from January 2014 to December 2018 for patients who underwent elective resection for rectal cancer. Primary end point was 5-year overall survival. Secondary end points were local recurrence rates within 5 years, oncological resection quality, and short-term outcome measures. RESULTS: A total of 1796 patients were included, of whom 1284 had undergone LRR and 512 ORR. There was no difference in 5-year survival rates between the groups after adjusting for relevant covariates with Cox regression analyses. Crude 5-year survival was 77.1% following LRR compared to 74.8% following ORR (p = 0.015). The 5-year local recurrence rates were 3.1% following LRR and 4.1% following ORR (p = 0.249). Length of hospital stay was median 8.0 days (quartiles 7.0-13.0) after ORR compared to 6.0 (quartiles 4.0-8.0) days after LRR. After adjusting for relevant covariates, estimated additional length of stay after ORR was 3.1 days (p < 0.001, 95% CI 2.3-3.9). Rates of positive resection margins and number of harvested lymph nodes were similar. There were no other significant differences in short-term outcomes between the groups. CONCLUSION: LRR was performed with clinical and oncological outcomes similar to ORR, but with shorter hospital stay.

Diverting stomas reduce reoperation rates for anastomotic leak but not overall reoperation rates within 30 days after anterior rectal resection: a national cohort study.

PURPOSE: A diverting stoma is commonly formed to reduce the rate of anastomotic leak following anterior resection with anastomosis, although some studies question this strategy. The aim of this study was to assess the leak rates and overall complication burden after anterior resection with and without a diverting stoma. METHODS: A 5-year national cohort with prospectively registered data of patients who underwent elective anterior resection for rectal cancer located < 15 cm from the anal verge. Data were retrieved from the Norwegian Registry for Gastrointestinal Surgery and the Norwegian Colorectal Cancer Registry. Primary end point was relaparotomy or relaparoscopy for anastomotic leak within 30 days from index surgery. Secondary endpoints were postoperative complications including reoperation for any cause. RESULTS: Some 1018 patients were included of whom 567 had a diverting stoma and 451 had not. Rate of reoperation for anastomotic leak was 13 out of 567 (2.3%) for patients with diverting stoma and 35 out of 451 (7.8%) (p > 0.001) for patients without. In multivariable analyses not having a diverting stoma (aOR 3.77, c.i 1.97-7.24, p < 0.001) was associated with increased risk for anastomotic leak. However, there were no differences in overall reoperation rates following anterior resection with or without diverting stoma (9.3% vs 10.9%, p = 0.423), and overall complication rates were similar. Reoperation was associated with increased mortality irrespective of the main intraoperative finding. CONCLUSION: Diverting stoma formation after anterior resection is protective against reoperation for anastomotic leak but does not affect overall rates of reoperation or complications within 30 days.

Treatment and survival of patients with pancreatic ductal adenocarcinoma: 15-year national cohort.

BACKGROUND: Improvement in survival from pancreatic ductal adenocarcinoma (PDAC) has been reported in trial settings but is less explored in unselected cohorts. The aim of this study was to assess trends in provision of treatments and survival in Norway over a 15-year period following the implementation of hepato-pancreato-biliary (HPB) multidisciplinary teams, centralization of surgery, and implementation of modern chemotherapy (CTx) regimens. METHODS: A population-based observational study was conducted by analysing all patients diagnosed with PDAC between 2004 and 2018 using coupled data from the Cancer Registry of Norway and the National Patient Registry. RESULTS: A total of 10 630 patients were identified, of whom 1492 (14.0 per cent) underwent surgical resection. The resection rate, median age of those resected, and provision of perioperative CTx all increased over time. Median overall survival after resection improved from 16.0 months in the period 2004 to 2008 to 25.1 months in the period 2014 to 2018 (P < 0.001). For non-resected patients there was a rise in the provision of palliative chemotherapy, but little survival gain over time (median overall survival for 2004 to 2008 was 3.2 months versus 4.2 months for 2014 to 2018; P < 0.001). The rate of patients who did not receive any tumour-directed treatment (neither CTx nor surgery) was 44.3 per cent (2481 of 5603 patients) and decreased from 52.9 per cent in 2010 to 37.9 per cent in 2018 (P < 0.001). The median overall survival for all patients with PDAC increased from 3.7 months for 2004 to 2008 to 5.8 months for 2014 to 2018 (P < 0.001). CONCLUSION: Survival after resection increased substantially, as did national resection rates. Little development in the provision of CTx or survival was observed for non-resected patients.

Lower conversion rate with robotic assisted rectal resections compared with conventional laparoscopy; a national cohort study.

BACKGROUND: Conversion from laparoscopic to open access colorectal surgery is associated with a poorer postoperative outcome. The aim of this study was to assess conversion rates and outcomes after standard laparoscopic rectal resection (LR) and robotic laparoscopic rectal resection (RR). METHODS: A national 5-year cohort study utilizing prospectively recorded data on patients who underwent elective major laparoscopic resection for rectal cancer. Data were retrieved from the Norwegian Registry for Gastrointestinal Surgery and from the Norwegian Colorectal Cancer Registry. Primary end point was conversion rate. Secondary end points were postoperative complications within 30 days and histopathological results. Chi-square test, two-sided T test, and Mann-Whitney U test were used for univariable analyses. Both univariable and multivariable logistic regression analyses were used to analyze the relations between different predictors and outcomes, and propensity score matching was performed to address potential treatment assignment bias. RESULTS: A total of 1284 patients were included, of whom 375 underwent RR and 909 LR. Conversion rate was 8 out of 375 (2.1%) for RR compared with 87 out of 909 (9.6%) for LR (p < 0.001). RR was associated with reduced risk for conversion compared with LR (aOR 0.22, 95% CI 0.10-0.46). There were no other outcome differences between RR and LR. Factors associated with increased risk for conversion were male gender, severe cardiac disease and BMI > 30. Conversion was associated with higher rates of major complications (20 out of 95 (21.2%) vs 135 out of 1189 (11.4%) p = 0.005), reoperations (13 out of 95 (13.7%) vs 93 out of 1189 (7.1%) p = 0.020), and longer hospital stay (median 8 days vs 6 days, p = 0.001). CONCLUSION: Conversion rate was lower with robotic assisted rectal resections compared with conventional laparoscopy. Conversions were associated with higher rates of postoperative complications.

Weight loss and BMI criteria in GLIM's definition of malnutrition is associated with postoperative complications following abdominal resections - Results from a National Quality Registry.

BACKGROUND & AIMS: Although malnutrition is thought to be common among patients with intraabdominal diseases and is recognized as a risk factor for postoperative complications, diagnostic criteria for malnutrition have not been consistent. Thus, the Global Leadership Initiative in Malnutrition (GLIM) has recently published new criteria for malnutrition. The aims of this study were to investigate the prevalence of malnutrition according to weight loss and BMI criteria in GLIM's second step for the diagnosis and their association with severe postoperative complications in patients undergoing gastrointestinal resections. METHOD: The current study includes adult patients who were prospectively included in the Norwegian Registry for Gastrointestinal Surgery in the period between 2015 and 2018. Exclusion criteria were acute surgery and lack of information regarding preoperative weight and/or postoperative complications. Severe surgical complications were classified according to the Revised Accordion Classification system and malnutrition with the GLIM criteria. Associations were assessed by logistic regression analyses, and the adjusted odds ratio included age (continuous), gender (male/female) and scores from the American Society of Anesthesiologists Physical Status Classification System and the Eastern Cooperative Oncology Group. RESULTS: Out of 6110 patients, 2161 (35.4%) were classified as with malnutrition, 1206 (19.7%) with moderate and 955 (15.6%) with severe malnutrition. Malnourished patients were 1.29 (95% CI: 1.13-1.47) times more likely to develop severe surgical complications, and 2.15 (95% CI: 1.27-3.65) times more likely to die within 30 days, as compared to those who were not. CONCLUSION: Preoperative malnutrition is common among patients having gastrointestinal resections and is associated with an increased risk of severe surgical complications.

Contemporary practice and short-term outcomes after liver resections in a complete national cohort.

BACKGROUND: Improved outcome after liver resections have been reported in several series, but outcomes from national cohorts are scarce. Our aim was to evaluate nationwide practice and short-term outcomes after liver surgery in a universal healthcare system. METHODS: A complete 5-year cohort of all liver resections from the Norwegian Patient Registry (NPR). Short-term outcomes were aggregated length of stay (a-LoS), reoperation and 90-day mortality. RESULTS: Of 2118 liver resections, 605 (28.6%) were major, median age was 65 years and 1184 (55%) were male. Most common indication was metastatic disease (n = 1554; 73.4%) and primary malignancy (n = 328; 15.3%). Laparoscopy was performed in 513 (33.9%) of minor and 37 (6.1%) of major liver resections and increased over time to 39.1% of minor resections in 2016. Median a-LoS was 12 days for major resections, 8 days for open minor and 3 days for laparoscopic minor resections. Reoperation was reported for 159 (7.4%) and 90-day mortality for 44 (2.1%). Primary malignancy, male gender, elderly patients and major resections were associated with poorer outcome. CONCLUSIONS: In a national cohort, laparoscopy is used for a substantial proportion of minor resections and was associated with reduced a-LoS. Risk factors for reoperation and mortality were male gender, increased age and major resection for primary malignancy.

Priority and prejudice: does low socioeconomic status bias waiting time for endoscopy? A blinded, randomized survey.

INTRODUCTION: An unwanted socioeconomic health gap is observed in Western countries with easily accessible, government-financed health care systems. Survival rates from several malignancies differ between socioeconomic clusters and the disparities remain after adjusting for major co-morbidities and health related behavior. The possibility of biased conduct among health care workers has been proposed as a contributing factor, but evidence is sparse. METHODS: A blinded, randomized online questionnaire survey was conducted among specialists in gastroenterology in Norway. Each respondent was asked to give priority for colonoscopy to three different referrals. By randomized sequence, half the referrals contained a discreet piece of information indicating low socioeconomic status (SES). The SES information given was focused on known low-status clusters in Norway, namely the morbidly obese and receivers of disability pensions. RESULTS: There were 107 respondents giving a response rate of 67%. A lower priority was consistently given to the referrals containing information on low SES, but the difference only reached statistical significance (p = .018) for one of the referrals. CONCLUSION: Information on low SES may influence how referrals for endoscopy are prioritized.

Systemic antibiotic prophylaxis prior to gastrointestinal surgery - is oral administration of doxycycline and metronidazole adequate?

BACKGROUND: Antibiotic prophylaxis is recommended prior to a wide range of gastrointestinal operations to reduce the rate of surgical site infections (SSIs). Traditional intravenous (IV) drugs are costly and their preparation strains nursing resources at the wards. While oral administration may attenuate these limitations, its use remains limited. We aimed to assess whether a dual oral antibiotic prophylaxis regimen provides adequate serum concentrations throughout the surgical procedure. METHODS: We measured serum concentrations of doxycycline and metronidazole following single oral doses of 400 mg doxycycline and 1200 mg metronidazole at first incision and repeated at wound closure in a cohort of patients undergoing elective gastrointestinal surgery. Both drugs were dispensed at least two hours before skin incision. Serum concentrations were compared to minimum inhibitory concentrations (MIC) and epidemiological cut-off values (ECOFFs) for relevant pathogens. RESULTS: Mean serum concentrations of doxycycline at first incision and at wound closure were 5.75 mg/L and 4.66 mg/L and of metronidazole 18.88 mg/L and 15.56 mg/L, respectively. Metronidazole concentrations were above ECOFF (2 mg/L) for relevant anaerobic species in 103/104 of patients in both samples. Doxycycline serum concentrations were above the ECOFF for common Enterobacteriaceae species (4 mg/L) in both samples in 58/104 patients (55.8%). CONCLUSIONS: A single dose of orally administered metronidazole provides adequate concentrations throughout surgery in a heterogeneous cohort of patients. Uncertainty persists regarding the adequacy of doxycycline concentrations, as the optimal serum level of doxycycline in a prophylactic setting has not been established.

Treatment results with debridement and retention of infected hip prostheses.

A retrospective systematic review of the management of a periprosthetic joint infection (PJI) cohort of 78 cases was conducted at a single-centre, middle-sized Norwegian hospital from 1997 to 2007. We analysed 40 cases that were managed by surgical debridement with hip prosthesis retention followed by long-lasting pathogen-directed antibiotic therapy. A follow-up time of 58 to 510 weeks free from PJI relapse occurred in 27 of 40 PJI cases (67.5%). The need for a more advanced secondary orthopaedic procedure was recognized in 13 cases. The pathogen responsible for PJI was recovered in only 80% of cases, hence 20% were managed as culture-negative PJI. In cases without prior hip infection or hip surgery, success rate reached 96.3%. Multiple risk factors were found in most cases undergoing PJI relapse. Debridement with hip prosthesis retention should be restricted to only current management guidelines.