Prognostic significance of occult vertebral fracture in patients undergoing pancreatic resection for pancreatic cancer.

OBJECTIVE: The prognostic impact of occult vertebral fracture (OVF) in patients with malignancies is a new cutting edge in cancer research. This study was performed to analyze the prognostic impact of OVF after surgery for pancreatic cancer. METHODS: This study involved 200 patients who underwent surgical treatment of pancreatic ductal adenocarcinoma. OVF was diagnosed by quantitative measurement using preoperative sagittal computed tomography image reconstruction from the 11th thoracic vertebra to the 5th lumbar vertebra. RESULTS: OVF was diagnosed in 65 (32.5 %) patients. The multivariate analyses showed that male sex (p = 0.01), osteopenia (p < 0.01), OVF (p < 0.01), a carbohydrate antigen 19-9 level of ≥400 U/mL (p < 0.01), advanced stage of cancer (p < 0.01), and non-adjuvant chemotherapy (p = 0.02) were independent risk factors for overall survival. An age of ≥74 years (p < 0.01) and obstructive jaundice (p = 0.03) were independent risk factors for OVF. Furthermore, the combination of OVF and osteopenia further worsened disease-free survival and overall survival compared with osteopenia or OVF alone (p < 0.01; respectively). CONCLUSION: Evaluation of preoperative OVF might be a useful prognostic indicator for patients with pancreatic ductal adenocarcinoma.

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.

Computed tomography and guidelines-based human-machine fusion model for predicting resectability of the pancreatic cancer.

BACKGROUND AND AIM: The study aims to develop a hybrid machine learning model for predicting resectability of the pancreatic cancer, which is based on computed tomography (CT) and National Comprehensive Cancer Network (NCCN) guidelines. METHOD: We retrospectively studied 349 patients. One hundred seventy-one cases from Center 1 and 92 cases from Center 2 were used as the primary training cohort, and 66 cases from Center 3 and 20 cases from Center 4 were used as the independent test dataset. Semi-automatic module of ITK-SNAP software was used to assist CT image segmentation to obtain three-dimensional (3D) imaging region of interest (ROI). There were 788 handcrafted features extracted for 3D ROI using PyRadiomics. The optimal feature subset consists of three features screened by three feature selection methods as the input of the SVM to construct the conventional radiomics-based predictive model (cRad). 3D ROI was used to unify the resolution by 3D spline interpolation method for constructing the 3D tumor imaging tensor. Using 3D tumor image tensor as input, 3D kernelled support tensor machine-based predictive model (KSTM), and 3D ResNet-based deep learning predictive model (ResNet) were constructed. Multi-classifier fusion ML model is constructed by fusing cRad, KSTM, and ResNet using multi-classifier fusion strategy. Two experts with more than 10 years of clinical experience were invited to reevaluate each patient based on their CECT following the NCCN guidelines to obtain resectable, unresectable, and borderline resectable diagnoses. The three results were converted into probability values of 0.25, 0.75, and 0.50, respectively, according to the traditional empirical method. Then it is used as an independent classifier and integrated with multi-classifier fusion machine learning (ML) model to obtain the human-machine fusion ML model (HMfML). RESULTS: Multi-classifier fusion ML model's area under receiver operating characteristic curve (AUC; 0.8610), predictive accuracy (ACC: 80.23%), sensitivity (SEN: 78.95%), and specificity (SPE: 80.60%) is better than cRad, KSTM, and ResNet-based single-classifier models and their two-classifier fusion models. This means that three different models have mined complementary CECT feature expression from different perspectives and can be integrated through CFS-ER, so that the fusion model has better performance. HMfML's AUC (0.8845), ACC (82.56%), SEN (84.21%), SPE (82.09%). This means that ML models might learn extra information from CECT that experts cannot distinguish, thus complementing expert experience and improving the performance of hybrid ML models. CONCLUSION: HMfML can predict PC resectability with high accuracy.

Surveillance With Serial Imaging and CA 19-9 Tumor Marker Testing After Resection of Pancreatic Cancer: A Single-Center Retrospective Study.

OBJECTIVES: Most patients receiving curative-intent surgery for pancreatic cancer will experience cancer recurrence. However, evidence that postoperative surveillance testing improves survival or quality of life is lacking. We evaluated the use and characteristics of surveillance with serial imaging and CA 19-9 tumor marker testing at an NCI-designated comprehensive cancer center. METHODS: We conducted a retrospective cohort study of patients who entered surveillance after curative-intent resection of pancreatic adenocarcinoma. We abstracted information from the electronic medical record about oncology office visits, surveillance testing (cross-sectional imaging and CA 19-9 tumor marker testing), and pancreatic cancer recurrence, with follow-up through 2 years after pancreatectomy. We conducted analyses to describe the use of surveillance testing and to characterize the sensitivity and specificity of CA 19-9 tumor marker testing for the identification of cancer recurrence. RESULTS: We identified 90 patients entering surveillance after pancreatectomy. CA 19-9 was the most frequently used surveillance test, followed by CT imaging. Forty-seven patients (52.2%) experienced recurrence within two years of pancreatectomy. Recurrence risk was 58.8% versus 31.8% in patients with elevated versus normal CA 19-9 at diagnosis ( P =0.03). Elevated CA 19-9 at any point during surveillance was significantly associated with 2-year recurrence risk ( P <0.001). Elevated CA 19-9 had a sensitivity of 83% (95% CI 0.72-0.95) and specificity of 87% (0.76-0.98) for identification of recurrence within 2 years of pancreatectomy. CONCLUSIONS: CA 19-9 demonstrates clinical validity for identifying recurrence of pancreatic cancer during surveillance. Surveillance approaches with reduced reliance on imaging should be prospectively evaluated.

In Neoadjuvant FOLFIRINOX Chemotherapy for Pancreatic Ductal Adenocarcinoma, Which Response is the More Reliable Indicator for Prognosis, Radiologic or Biochemical?

BACKGROUND: In this era of increasing neoadjuvant chemotherapy, methods for evaluating responses to neoadjuvant chemotherapy are still diverse among institutions. Additionally, the efficacy of adjuvant chemotherapy for patients undergoing neoadjuvant chemotherapy remains unclear. Therefore, this retrospective study was performed to evaluate the effectiveness of methods for assessing response to neoadjuvant chemotherapy and the need for adjuvant chemotherapy in treating patients with non-metastatic pancreatic ductal adenocarcinoma. METHODS: The study identified 150 patients who underwent neoadjuvant FOLFIRINOX chemotherapy followed by curative-intent pancreatectomy. The patients were stratified by biochemical response based on the normalization of carbohydrate antigen 19-9 and by radiologic response based on size change at imaging. RESULTS: The patients were classified into the following three groups based on their response to neoadjuvant chemotherapy and prognosis: biochemical responders (BR+), radiology-only responders (BR-/RR+), and non-responders (BR-/RR-). The 3-year overall survival rate was higher for BR+ (71.0%) than for BR-/RR+ (53.6%) or BR-/RR- (33.1%) (P < 0.001). Response to neoadjuvant chemotherapy also was identified as a significant risk factor for recurrence in a comparison between BR-/RR+ and BR+ (hazard ratio [HR], 2.15; 95% confidence interval [CI] 1.19-3.88; P = 0.011) and BR-/RR- (HR, 3.82; 95% CI 2.41-6.08; P < 0.001). Additionally, regardless of the response to neoadjuvant chemotherapy, patients who completed adjuvant chemotherapy had a significantly higher 3-year overall survival rate than those who did not. CONCLUSIONS: This response evaluation criterion for neoadjuvant chemotherapy is feasible and can significantly predict prognosis. Additionally, completion of adjuvant chemotherapy could be helpful to patients who undergo neoadjuvant chemotherapy regardless of their response to neoadjuvant chemotherapy.

Perioperative NALIRIFOX in patients with resectable pancreatic ductal adenocarcinoma: The open-label, multicenter, phase II nITRO trial.

BACKGROUND: Upfront surgery followed by postoperative treatment is a commonly adopted treatment for resectable pancreatic ductal adenocarcinoma (rPDAC). However, the risk of positive surgical margins, the poor recovery that often impairs postoperative treatments, and the risk of recurrence might limit the outcome of this strategy. This study evaluated the safety and the activity of liposomal irinotecan 50 mg/m2 + 5-fluorouracil 2400 mg/m2 + leucovorin 400 mg/m2 + oxaliplatin 60 mg/m2 (NALIRIFOX) in the perioperative treatment of patients with rPDAC. METHODS: Eligible patients had a rPDAC with < 180° interface with major veins' wall. Patients received 3 cycles before and 3 cycles after resection with NALIRIFOX, days 1 and 15 of a 28-day cycle. The primary endpoint was the proportion of patients undergoing an R0 resection. RESULTS: 107 patients began preoperative treatment. Nine patients discontinued the treatment because of related or unrelated adverse events. Disease-control rate was 92.9%. 87 patients underwent surgical exploration, 11 had intraoperative evidence of metastatic disease, and 1 died for surgical complications. R0 resection rate was 65.3%. 49 patients completed the three postoperative cycles. The most common grade ≥ 3 adverse events were diarrhea and neutropenia. Median overall survival (OS) of ITT patients was 32.3 months (95% CI 27.8-44.3). Median disease-free and OS from surgery of resected patients were 19.3 (95% CI 12.6-34.1) and 40.3 months (95% CI 29-NA), respectively. CONCLUSION: Perioperative NALIRIFOX was manageable and active, and deserves further investigation in randomized trials comparing it with standard upfront surgery followed by adjuvant therapy.

Machine Learning of Histopathological Images Predicts Recurrences of Resected Pancreatic Ductal Adenocarcinoma With Adjuvant Treatment.

OBJECTIVES: Pancreatic ductal adenocarcinoma is an intractable disease with frequent recurrence after resection and adjuvant therapy. The present study aimed to clarify whether artificial intelligence-assisted analysis of histopathological images can predict recurrence in patients with pancreatic ductal adenocarcinoma who underwent resection and adjuvant chemotherapy with tegafur/5-chloro-2,4-dihydroxypyridine/potassium oxonate. MATERIALS AND METHODS: Eighty-nine patients were enrolled in the study. Machine-learning algorithms were applied to 10-billion-scale pixel data of whole-slide histopathological images to generate key features using multiple deep autoencoders. Areas under the curve were calculated from receiver operating characteristic curves using a support vector machine with key features alone and by combining with clinical data (age and carbohydrate antigen 19-9 and carcinoembryonic antigen levels) for predicting recurrence. Supervised learning with pathological annotations was conducted to determine the significant features for predicting recurrence. RESULTS: Areas under the curves obtained were 0.73 (95% confidence interval, 0.59-0.87) by the histopathological data analysis and 0.84 (95% confidence interval, 0.73-0.94) by the combinatorial analysis of histopathological data and clinical data. Supervised learning model demonstrated that poor tumor differentiation was significantly associated with recurrence. CONCLUSIONS: Results indicate that machine learning with the integration of artificial intelligence-driven evaluation of histopathological images and conventional clinical data provides relevant prognostic information for patients with pancreatic ductal adenocarcinoma.

Nationwide Use and Outcome of Surgery for Locally Advanced Pancreatic Cancer Following Induction Chemotherapy.

BACKGROUND: Several international high-volume centers have reported good outcomes after resection of locally advanced pancreatic cancer (LAPC) following chemo(radio)therapy, but it is unclear how this translates to nationwide clinical practice and outcome. This study aims to assess the nationwide use and outcome of resection of LAPC following induction chemo(radio)therapy. PATIENTS AND METHODS: A multicenter retrospective study including all patients who underwent resection for LAPC following chemo(radio)therapy in all 16 Dutch pancreatic surgery centers (2014-2020), registered in the mandatory Dutch Pancreatic Cancer Audit. LAPC is defined as arterial involvement > 90° and/or portomesenteric venous > 270° involvement or occlusion. RESULTS: Overall, 142 patients underwent resection for LAPC, of whom 34.5% met the 2022 National Comprehensive Cancer Network criteria. FOLFIRINOX was the most commonly (93.7%) used chemotherapy [median 5 cycles (IQR 4-8)]. Venous and arterial resections were performed in 51.4% and 14.8% of patients. Most resections (73.9%) were performed in high-volume centers (i.e., ≥ 60 pancreatoduodenectomies/year). Overall median volume of LAPC resections/center was 4 (IQR 1-7). In-hospital/30-day major morbidity was 37.3% and 90-day mortality was 4.2%. Median OS from diagnosis was 26 months (95% CI 23-28) and 5-year OS 18%. Surgery in high-volume centers [HR = 0.542 (95% CI 0.318-0.923)], ypN1-2 [HR = 3.141 (95% CI 1.886-5.234)], and major morbidity [HR = 2.031 (95% CI 1.272-3.244)] were associated with OS. CONCLUSIONS: Resection of LAPC following chemo(radio)therapy is infrequently performed in the Netherlands, albeit with acceptable morbidity, mortality, and OS. Given these findings, a structured nationwide approach involving international centers of excellence would be needed to improve selection of patients with LAPC for surgical resection following induction therapy.

Functional sequelae after pancreatic resection for cancer.

The morbidity and mortality of pancreatic cancer surgery has seen substantial improvement due to the standardization of surgical techniques, the optimization of perioperative multidisciplinary management and the organization of specialized care systems. The identification and treatment of postoperative functional and nutritional sequelae have thereby become major issues in patients who undergo pancreatic surgery. This review addresses the functional sequelae of pancreatic resection for cancerous and pre-cancerous lesions (excluding chronic pancreatitis). Its aim is to specify the prevalence and severity of sequelae according to the type of pancreatic resection and to document, where appropriate, the therapeutic management. Exocrine pancreatic insufficiency (ExPI) is observed in nearly one out of three patients at one year after surgery, and endocrine pancreatic insufficiency (EnPI) is present in one out of five patients after pancreatoduodenectomy (PD) and one out of three patients after distal pancreatectomy (DP). In addition, digestive functional disorders may appear, such as delayed gastric emptying (DGE), which affects 10 to 45% of patients after PD and nearly 8% after DP. Beyond these functional sequelae, pancreatic surgery can also induce nutritional and vitamin deficiencies secondary to a lack of uptake for certain vitamins or to the loss of absorption site in the duodenum. In addition to the treatment of ExPI with oral pancreatic enzymes, nutritional management is based on a high-calorie, high-protein diet with normal lipid intake in frequent small feedings, combined with vitamin supplementation adapted to monitored deficiencies. Better knowledge of the functional consequences of pancreatic cancer surgery can improve the overall management of patients.

Predictive factors for survival in borderline resectable and locally advanced pancreatic cancer: are these really two different entities?

BACKGROUND: The treatment of borderline resectable (BR) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) has evolved with a wider application of neoadjuvant chemotherapy (NACHT). The aim of this study was to identify predictive factors for survival in BR and LA PDAC. METHODS: Clinicopathologic data of patients with BR and LA PDAC who underwent surgical exploration between January 2011 and June 2021 were retrospectively collected. Survival from the date of surgery was estimated using the Kaplan-Meier method. Simple and multiple Cox proportional hazards models were fitted to identify factors associated with survival. Surgical resection was analyzed in combination with the involvement of lymph nodes as this last was only known after a formal resection. RESULTS: Ninety patients were surgically explored (BR: 45, LA: 45), of which 51 (57%) were resected (BR: 31, LA: 20). NACHT was administered to 43 patients with FOLFIRINOX being the most frequent regimen applied (33/43, 77%). Major complications (Clavien-Dindo grade III and IV) occurred in 7.8% of patients and 90-day mortality rate was 3.3%. The median overall survival since surgery was 16 months (95% CI 12-20) in the group which underwent surgical resection and 10 months (95% CI 7-13) in the group with an unresectable tumor (p=0.001). Cox proportional hazards models showed significantly lower mortality hazard for surgical resection compared to no surgical resection, even after adjusting for National Comprehensive Cancer Network  (NCCN) classification and administration of NACHT [surgical resection with involved lymph nodes vs no surgical resection (cHR 0.49; 95% CI 0.29-0.82; p=0.007)]. There was no significant difference in survival between patients with BR and LA disease (cHR= 1.01; 95% CI 0.63-1.62; p=0.98). CONCLUSIONS: Surgical resection is the only predictor of survival in patients with BR and LA PDAC, regardless of their initial classification as BR or LA. Our results suggest that surgery should not be denied to patients with LA PDAC a priori. Prospective studies including patients from the moment of diagnosis are required to identify biologic and molecular markers which may allow a better selection of patients who will benefit from surgery.

Predicting resection margin status of pancreatic neuroendocrine tumors on CT: performance of NCCN resectability criteria.

OBJECTIVE: To test the performance of the National Comprehensive Cancer Network (NCCN) CT resectability criteria for predicting the surgical margin status of pancreatic neuroendocrine tumor (PNET) and to identify factors associated with margin-positive resection. METHODS: Eighty patients with pre-operative CT and upfront surgery were retrospectively enrolled. Two radiologists assessed the CT resectability (resectable [R], borderline resectable [BR], unresectable [UR]) of the PNET according to NCCN criteria. Logistic regression was used to identify factors associated with resection margin status. κ statistics were used to evaluate interreader agreements. Kaplan-Meier method with log-rank test was used to estimate and compare recurrence-free survival (RFS). RESULTS: Forty-five patients (56.2%) received R0 resection and 35 (43.8%) received R1 or R2 resection. R0 resection rates were 63.6-64.2%, 20.0-33.3%, and 0% for R, BR, and UR diseases, respectively (all p ≤ 0.002), with a good interreader agreement (κ, 0.74). Tumor size (<2 cm, 2-4 cm, and >4 cm; odds ratio (OR), 9.042-18.110; all p ≤ 0.007) and NCCN BR/UR diseases (OR, 5.918; p = 0.032) were predictors for R1 or R2 resection. The R0 resection rate was 91.7% for R disease <2 cm and decreased for larger R disease. R0 resection and smaller tumor size in R disease improved RFS. CONCLUSION: NCCN resectability criteria can stratify patients with PNET into distinct groups of R0 resectability. Adding tumor size to R disease substantially improves the prediction of R0 resection, especially for PNETs <2 cm. ADVANCES IN KNOWLEDGE: Tumor size and radiologic resectability independently predicted margin status of PNETs.

Smoking impairs the effect of neoadjuvant FOLFIRINOX on postresection survival in pancreatic cancer.

INTRODUCTION: Smoking plays an important role in carcinogenesis, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about the association between smoking status and prognosis in resected PDAC. METHODS: All patients who underwent resection for PDAC were identified from two prospective institutional databases. Clinicopathologic data as well as demographics including smoking status were extracted. Survival analysis and multivariable Cox regression modelling was performed. Restricted cubic splines were used for linear data to define cut-off points. RESULTS: Out of 848 patients, 357 (42.1%) received neoadjuvant treatment (NAT), 491 upfront resection (57.9%), and 475 (56%) adjuvant therapy. The median overall survival (OS) was 27.8 months, 36.1 months, and 23.0 months for the entire cohort, after NAT and upfront resection. 464 patients were never smokers (54.7%), 250 former smokers (29.5%), and 134 active smokers (15.8%). In the multivariable model, the interaction of neoadjuvant FOLFIRINOX and active smoking was associated with the highest risk for decreased OS (harzard ratio (HR) 2.35; 95% confidence interval 1.13-4.90) and strongly mitigated the benefit of FOLFIRNOX (HR 0.40; 95% CI 0.25-0.63). Adjusted median OS in NAT patients with FOLFIRINOX was not reached for never and former smokers, compared to 26.2 months in active smokers. Based on the model, a nomogram was generated to illustrate the probability of 5-year survival after PDAC resection. CONCLUSION: The present study confirms that neoadjuvant FOLFIRINOX is associated with excellent survival and demonstrates that active smoking reduces its benefit. The nomogram can assist in daily clinical practice and emphasises the importance of smoking cessation in patients with PDAC, especially prior to NAT with FOLFIRINOX.

Perioperative or adjuvant mFOLFIRINOX for resectable pancreatic cancer (PREOPANC-3): study protocol for a multicenter randomized controlled trial.

BACKGROUND: Surgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach. METHODS: This multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and ≤ 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2 at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m2). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized. DISCUSSION: The multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer. TRIAL REGISTRATION: Clinical Trials: NCT04927780. Registered June 16, 2021.

Optimization of laser dosimetry based on patient-specific anatomical models for the ablation of pancreatic ductal adenocarcinoma tumor.

Laser-induced thermotherapy has shown promising potential for the treatment of unresectable primary pancreatic ductal adenocarcinoma tumors. Nevertheless, heterogeneous tumor environment and complex thermal interaction phenomena that are established under hyperthermic conditions can lead to under/over estimation of laser thermotherapy efficacy. Using numerical modeling, this paper presents an optimized laser setting for Nd:YAG laser delivered by a bare optical fiber (300 µm in diameter) at 1064 nm working in continuous mode within a power range of 2-10 W. For the thermal analysis, patient-specific 3D models were used, consisting of tumors in different portions of the pancreas. The optimized laser power and time for ablating the tumor completely and producing thermal toxic effects on the possible residual tumor cells beyond the tumor margins were found to be 5 W for 550 s, 7 W for 550 s, and 8 W for 550 s for the pancreatic tail, body, and head tumors, respectively. Based on the results, during the laser irradiation at the optimized doses, thermal injury was not evident either in the 15 mm lateral distances from the optical fiber or in the nearby healthy organs. The present computational-based predictions are also in line with the previous ex vivo and in vivo studies, hence, they can assist in the estimation of the therapeutic outcome of laser ablation for pancreatic neoplasms prior to clinical trials.

Impact of Adherence to Operative Standards and Stage-Specific Guideline-Recommended Therapy in Nonmetastatic Pancreatic Adenocarcinoma.

BACKGROUND: Achieving optimal surgical outcomes in pancreatic adenocarcinoma requires a combination of both curative-intent resection to oncologic standards and stage-specific neoadjuvant or adjuvant therapy. This investigation sought to examine factors associated with receipt of standard-adherent surgery (SAS) and guideline-recommended therapy (GRT) and determine the impact of compliance on patient survival. PATIENTS AND METHODS: From the 2006-2016 National Cancer Database, 21,304 patients underwent resection for nonmetastatic pancreatic adenocarcinoma. SAS was defined as pancreatic resection with negative margins and ≥ 15 lymph nodes examined. Stage-specific GRT was defined by current National Comprehensive Cancer Network guidelines. Multivariable models were used to determine predictors of adherence to SAS and GRT and prognostic impact on overall survival. RESULTS: Overall, SAS was achieved in 39% and GRT in 65% of patients, but only 30% received both SAS and GRT. Increasing age, minority race, uninsured status, and greater comorbidities were associated with a decreased odds of receiving both SAS and GRT (all p < 0.05). SAS (HR 0.79; CI 0.76-0.81; p < 0.001) and GRT (HR 0.67; CI 0.65-0.69; p < 0.001) were each independently associated with a survival advantage. Receipt of both SAS and GRT was associated with significant improvement in median OS compared with receiving neither (2.2 years vs 1.1 years; p < 0.001) which was independently associated with a 78% increased risk of death (HR 1.78; CI 1.70-1.86; p < 0.001). CONCLUSIONS: Despite survival benefits associated with adherence to operative standards and receipt of guideline-recommended therapy, compliance remains poor. Future efforts must be directed toward improved education and implementation efforts around both operative standards and therapy guidelines.

Therapeutic drug monitoring of neoadjuvant mFOLFIRINOX in resected pancreatic ductal adenocarcinoma.

BACKGROUND: Despite a potentially curative treatment, the prognosis after upfront surgery and adjuvant chemotherapy for patients with resectable pancreatic ductal adenocarcinoma (PDAC) is poor. Modified FOLFIRINOX (mFOLFIRINOX) is a cornerstone in the systemic treatment of PDAC, including the neoadjuvant setting. Pharmacokinetic-guided (PKG) dosing has demonstrated beneficial effects in other tumors, but scarce data is available in pancreatic cancer. METHODS: Forty-six patients with resected PDAC after mFOLFIRINOX neoadjuvant approach and included in an institutional protocol for anticancer drug monitoring were retrospectively analyzed. 5-Fluorouracil (5-FU) dosage was adjusted throughout neoadjuvant treatment according to pharmacokinetic parameters and Irinotecan (CPT-11) pharmacokinetic variables were retrospectively estimated. RESULTS: By exploratory univariate analyses, a significantly longer progression-free survival was observed for patients with either 5-FU area under the curve (AUC) above 28 mcg·h/mL or CPT-11 AUC values below 10 mcg·h/mL. In the multivariate analyses adjusted by age, gender, performance status and resectability after stratification according to both pharmacokinetic parameters, the risk of progression was significantly reduced in patients with 5-FU AUC ≥28 mcg·h/mL [HR = 0.251, 95% CI 0.096-0.656; p = 0.005] and CPT-11 AUC <10 mcg·h/mL [HR = 0.189, 95% CI 0.073-0.486, p = 0.001]. CONCLUSIONS: Pharmacokinetically-guided dose adjustment of standard chemotherapy treatments might improve survival outcomes in patients with pancreatic ductal adenocarcinoma.

Predictive value of computed tomography on surgical resectability in locally advanced pancreatic cancer treated with multiagent induction chemotherapy: Results from a prospective, multicentre phase 2 trial (NEOLAP-AIO-PAK-0113).

PURPOSE: To assess the role of current imaging-based resectability criteria and the degree of radiological downsizing in locally advanced pancreatic adenocarcinoma (LAPC) after multiagent induction chemotherapy (ICT) in multicentre, open-label, randomized phase 2 trial. METHOD: LAPC patients were prospectively treated with multiagent ICT followed by surgical exploration within the NEOLAP trial. All patients underwent CT scan at baseline and after ICT to assess resectability status according to national comprehensive cancer network guidelines (NCCN) criteria and response evaluation criteria in solid tumors (RECIST) at the local study center and retrospectively in a central review. Imaging results were compared in terms of local and central staging, downsizing and pathological resection status. RESULTS: 83 patients were evaluable for central review of baseline and restaging imaging results. Downstaging by central review was rarely seen after multiagent ICT (7.7%), whereas tumor downsizing was documented frequently (any downsizing 90.4%, downsizing to partial response (PR) according to RECIST: 26.5%). Patients with any downsizing showed no significant different R0 resection rate (37.3%) as patients that fulfilled the criteria of PR (40.9%). The sensitivity of any downsizing for predicting R0 resection was 97% with a negative predictive value (NPV) of 0.88. ROC-analysis revealed that tumor downsizing was a predictor of R0 resection (AUC 0.647, p = 0.028) with a best cut-off value of 22.5% downsizing yielding a sensitivity of 65% and a specificity of 61%. CONCLUSIONS: Imaging-based tumor downsizing and not downstaging can guide the selection of patients with a realistic chance of R0-resection in LAPC after multi-agent ICT.

High-resolution pancreatic computed tomography for assessing pancreatic ductal adenocarcinoma resectability: a multicenter prospective study.

OBJECTIVE: This prospective multicenter study aimed to evaluate the diagnostic performance of 80-kVp thin-section pancreatic CT in determining pancreatic ductal adenocarcinoma (PDAC) resectability according to the recent National Comprehensive Cancer Network (NCCN) guidelines. METHODS: We prospectively enrolled surgical resection candidates for PDAC from six tertiary referral hospitals (study identifier: NCT03895177). All participants underwent pancreatic CT using 80 kVp tube voltage with 1-mm reconstruction interval. The local resectability was prospectively evaluated using NCCN guidelines at each center and classified into three categories: resectable, borderline resectable, and unresectable. RESULTS: A total of 138 patients were enrolled; among them, 60 patients underwent neoadjuvant therapy. R0 resection was achieved in 103 patients (74.6%). The R0 resection rates were 88.7% (47/53), 52.4% (11/21), and 0.0% (0/4) for resectable, borderline resectable, and unresectable disease, respectively, in 78 patients who underwent upfront surgery. Meanwhile, the rates were 90.9% (20/22), 76.7% (23/30), and 25.0% (2/8) for resectable, borderline resectable, and unresectable PDAC, respectively, in patients who received neoadjuvant therapy. The area under curve of high-resolution CT in predicting R0 resection was 0.784, with sensitivity, specificity, and accuracy of 87.4% (90/103), 48.6% (17/35), and 77.5% (107/138), respectively. Tumor response was significantly associated with the R0 resection after neoadjuvant therapy (odds ratio [OR] = 38.99, p = 0.016). CONCLUSION: An 80-kVp thin-section pancreatic CT has excellent diagnostic performance in assessing PDAC resectability, enabling R0 resection rates of 88.7% and 90.9% for patients with resectable PDAC who underwent upfront surgery and patients with resectable PDAC after neoadjuvant therapy, respectively. KEY POINTS: • The margin-negative (R0) resection rates were 88.7% (47/53), 52.4% (11/21), and 0.0% (0/4) for resectable, borderline resectable, and unresectable pancreatic ductal adenocarcinoma (PDAC), respectively, on 80-kVp thin-section pancreatic CT in the 78 patients who underwent upfront surgery. • Among the 60 patients who underwent neoadjuvant therapy, the R0 rates were 90.9% (20/22), 76.7% (23/30), and 25.0% (2/8) for resectable, borderline resectable, and unresectable PDAC, respectively. • Tumor response, along with the resectability status on pancreatic CT, was significantly associated with the R0 resection rate after neoadjuvant therapy.

Hospital Designations and Their Impact on Guideline-Concordant Care and Survival in Pancreatic Cancer. Do They Matter?

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) requires complex multidisciplinary care. European evidence suggests potential benefit from regionalization, however, data characterizing the ideal setting in the United States are sparse. Our study compares the significance of four hospital designations on guideline-concordant care (GCC) and overall survival (OS). PATIENTS AND METHODS: The Texas Cancer Registry was queried for 17,071 patients with PDAC treated between 2004 and 2015. Clinical data were correlated with hospital designations: NCI designated (NCI), high volume (HV), safety net (SNH), and American College of Surgeons Commission on Cancer accredited (ACS). Univariable (UVA) and multivariable (MVA) logistic regression were used to assess associations with GCC [on the basis of National Comprehensive Cancer Network (NCCN) recommendations]. Cox regression analysis assessed survival. RESULTS: Only 43% of patients received GCC. NCI had the largest associated risk reduction (HR 0.61, CI 0.58-0.65), followed by HV (HR 0.87, CI 0.83-0.90) and ACS (HR 0.91, CI 0.87-0.95). GCC was associated with a survival benefit in the full (HR 0.75, CI 0.69-0.81) and resected cohort (HR 0.74, CI 0.68-0.80). NCI (OR 1.52, CI 1.37-1.70), HV (OR 1.14, CI 1.05-1.23), and SNH (OR 0.78, CI 0.68-0.91) all correlated with receipt of GCC. For resected patients, ACS (OR 0.63, CI 0.50-0.79) and SNH (OR 0.50, CI 0.33-0.75) correlate with GCC. CONCLUSIONS: A total of 43% of patients received GCC. Treatment at NCI and HV correlated with improved GCC and survival. Including GCC as a metric in accreditation standards could impact survival for patients with PDAC.

Disparities in NCCN Guideline-Compliant Care for Patients with Early-Stage Pancreatic Adenocarcinoma at Minority-Serving versus Non-Minority-Serving Hospitals.

BACKGROUND: Racial/ethnic disparities in pancreatic adenocarcinoma (PDAC) outcomes may relate to receipt of National Comprehensive Cancer Network (NCCN) guideline-compliant care. We assessed the association between treatment at minority-serving hospitals (MSH) and receipt of NCCN-compliant care. PATIENTS AND METHODS: Patients who underwent resection of early-stage PDAC between 2006 and 2019 were identified from the National Cancer Database (NCDB). MSH was defined as the top decile of facilities treating minority ethnicities (Black and/or Hispanic). Factors associated with receipt of NCCN-compliant care and its impact on overall survival (OS) were assessed. RESULTS: Among 44,873 patients who underwent resection of PDAC, most were treated at non-MSH (n = 42,571, 94.9%), while a smaller subset were treated at MSH (n = 2302, 5.1%). Patients treated at MSH were more likely to be at a younger median age (MSH 66 years versus non-MSH 67 years), Black or Hispanic (MSH 58.4% versus non-MSH 12.0%), and not insured (MSH 7.8% versus non-MSH 1.6%). While 71.7% (n = 31,182) of patients were compliant with NCCN care, guideline-compliant care was lower at MSH (MSH 62.5% versus non-MSH 72.2%). On multivariable analysis, receiving care at MSH was associated with not receiving guideline-compliant care [odds ratio (OR) 0.63, 95% confidence interval (CI) 0.53-0.74]. At non-MSH, non-white patients had lower odds of receiving guideline-compliant PDCA care (OR 0.85, 95% CI 0.78-0.91). Failure to comply was associated with worse overall survival (OS) [hazard ratio (HR) 1.50, 95% CI 1.46-1.54, all p < 0.001]. CONCLUSIONS: Patients with PDAC treated at MSH and minorities treated at non-MSH were less likely to receive NCCN-compliant care. Failure to comply with guideline-based PDAC treatment was associated with worse OS.