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.

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.

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.

Perioperative Chemotherapy and Chemoradiotherapy for Patients With Resectable and Borderline Resectable Pancreatic Adenocarcinoma.

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDA) is the third most common cause of cancer death in the United States. Most patients who undergo resection develop recurrence. Standard treatment confers a median overall survival (OS) of 24 months. Exposure to alternate regimens may prevent chemoresistance. This study evaluated multiagent perioperative therapy for potentially resectable PDA patients to improve OS. METHODS: A single center, phase 2, trial of patients with resectable or borderline resectable PDA. Patients received neoadjuvant therapy with induction chemotherapy (gemcitabine, docetaxel, capecitabine) for 3 cycles, chemoradiation (intensity-modulated radiation therapy with capecitabine and oxaliplatin) followed by surgery, and 2 months of adjuvant gemcitabine and oxaliplatin and 2 months of gemcitabine. The primary endpoint was OS. The secondary endpoint was recurrence-free survival (RFS). RESULTS: Thirty-two eligible patients were enrolled. Twenty-two patients underwent surgical resection. After a median follow-up of 56.8 months, mOS was 31.6 months (95% confidence interval [CI], 14.2-58.1) for all patients, 58.1 months (95% CI, 31.6 to NR) for those who completed surgery. The mRFS was 31.3 months (95% CI, 12.5 to NR). CONCLUSIONS: Perioperative therapy with GTX, chemoradiotherapy, and adjuvant GemOx/Gem resulted in promising survival of 58 months for patients who underwent resection and may represent another treatment option for PDA.

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.

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.

Ca 125 is an independent prognostic marker in resected pancreatic cancer of the head of the pancreas.

The prognostic value of carbohydrate antigen 125 (Ca 125) is emerging also in pancreatic cancer (PDAC). In this study, we aim to define the prognostic value of Ca 125 in resected PDAC of the head of the pancreas. This is a single-center, retrospective study. Data from patients with a pre-operative assay of Ca 125 who underwent a pancreatic resection for PDAC between 2010 and 2018 were analyzed. As per National Comprehensive Cancer Guidelines, tumors were classified in resectable (R-PDAC), borderline resectable (BR-PDAC), and locally advanced (LA-PDAC). The Kaplan-Meier method was used to evaluate the overall survival. Cox proportional hazard regression was used to evaluate the role of pre-operative Ca 125 in predicting survival (while adjusting for confounders). The maximally selected log-rank statistic was used to identify a Ca 125 cut-off defining two groups with different survival probability. Inclusion criteria were met by 207 patients (R-PDAC: 80, BR-PDAC: 91, and LA-PDAC: 36). Ca 125 predicted overall survival before and after adjusting for confounding factors in all categories of anatomic resectability (R-PDAC: HR = 4.3; p = 0.0249) (BR-PDAC: HR = 7.82; p = 0.0024) (LA-PDAC: HR = 11.4; p = 0.0043). In BR-PDAC and LA-PDAC (n = 127), the division in two groups (high vs. low Ca 125) correlated with T stage (p = 0.0317), N stage (p = 0.0083), mean LN ratio (p = 0.0292), and tumor grading (p = 0.0143). This study confirmed the prognostic value of Ca125 in resected pancreatic cancer and, therefore, the importance of biologic over anatomic resectability. Ca 125 should be routinely assayed in surgical candidates with PDAC.

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.

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.

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.

Neoadjuvant and Adjuvant Treatments for Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma: The Current Status of Pancreatic Ductal Adenocarcinoma Treatment in Japan.

Resection is the only curative treatment for pancreatic ductal adenocarcinoma (PDAC). Although the outcome of technically resectable PDAC has improved with advances in surgery and adjuvant therapy, the 5-year survival rate remains low at 20% to 40%. More effective therapy is needed. Almost 15 years ago, the National Comprehensive Cancer Network guidelines proposed a resectability classification of PDAC based on preoperative imaging. Since then, treatment strategies for PDAC have been devised based on resectability. The standard of care for resectable PDAC is adjuvant chemotherapy after R0 resection, as shown by the results of pivotal clinical trials. With regard to neoadjuvant treatment, several recent clinical trials comparing neoadjuvant treatment with upfront resection have been conducted on resectable PDAC and borderline resectable PDAC, and the benefits and efficacy of neoadjuvant treatment for pancreatic cancer has become clearer. The significance of neoadjuvant treatment for resectable PDAC remains controversial, but in borderline resectable PDAC the efficacy of neoadjuvant treatment has been further recognised, although the standard of care has not yet been established. Several promising clinical trials for PDAC are ongoing. This review presents previous and ongoing trials of perioperative treatment for resectable and borderline resectable PDAC, focusing on the difference between Asian and Western countries.

Immediate surgery compared with short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy in patients with borderline resectable pancreatic cancer (ESPAC5): a four-arm, multicentre, randomised, phase 2 trial.

BACKGROUND: Patients with borderline resectable pancreatic ductal adenocarcinoma have relatively low resection rates and poor survival despite the use of adjuvant chemotherapy. The aim of our study was to establish the feasibility and efficacy of three different types of short-course neoadjuvant therapy compared with immediate surgery. METHODS: ESPAC5 (formerly known as ESPAC-5f) was a multicentre, open label, randomised controlled trial done in 16 pancreatic centres in two countries (UK and Germany). Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, biopsy proven pancreatic ductal adenocarcinoma in the pancreatic head, and were staged as having a borderline resectable tumour by contrast-enhanced CT criteria following central review. Participants were randomly assigned by means of minimisation to one of four groups: immediate surgery; neoadjuvant gemcitabine and capecitabine (gemcitabine 1000 mg/m2 on days 1, 8, and 15, and oral capecitabine 830 mg/m2 twice a day on days 1-21 of a 28-day cycle for two cycles); neoadjuvant FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, folinic acid given according to local practice, and fluorouracil 400 mg/m2 bolus injection on days 1 and 15 followed by 2400 mg/m2 46 h intravenous infusion given on days 1 and 15, repeated every 2 weeks for four cycles); or neoadjuvant capecitabine-based chemoradiation (total dose 50·4 Gy in 28 daily fractions over 5·5 weeks [1·8 Gy per fraction, Monday to Friday] with capecitabine 830 mg/m2 twice daily [Monday to Friday] throughout radiotherapy). Patients underwent restaging contrast-enhanced CT at 4-6 weeks after neoadjuvant therapy and underwent surgical exploration if the tumour was still at least borderline resectable. All patients who had their tumour resected received adjuvant therapy at the oncologist's discretion. Primary endpoints were recruitment rate and resection rate. Analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN, 89500674, and is complete. FINDINGS: Between Sept 3, 2014, and Dec 20, 2018, from 478 patients screened, 90 were randomly assigned to a group (33 to immediate surgery, 20 to gemcitabine plus capecitabine, 20 to FOLFIRINOX, and 17 to capecitabine-based chemoradiation); four patients were excluded from the intention-to-treat analysis (one in the capecitabine-based chemoradiotherapy withdrew consent before starting therapy and three [two in the immediate surgery group and one in the gemcitabine plus capecitabine group] were found to be ineligible after randomisation). 44 (80%) of 55 patients completed neoadjuvant therapy. The recruitment rate was 25·92 patients per year from 16 sites; 21 (68%) of 31 patients in the immediate surgery and 30 (55%) of 55 patients in the combined neoadjuvant therapy groups underwent resection (p=0·33). R0 resection was achieved in three (14%) of 21 patients in the immediate surgery group and seven (23%) of 30 in the neoadjuvant therapy groups combined (p=0·49). Surgical complications were observed in 29 (43%) of 68 patients who underwent surgery; no patients died within 30 days. 46 (84%) of 55 patients receiving neoadjuvant therapy were available for restaging. Six (13%) of 46 had a partial response. Median follow-up time was 12·2 months (95% CI 12·0-12·4). 1-year overall survival was 39% (95% CI 24-61) for immediate surgery, 78% (60-100) for gemcitabine plus capecitabine, 84% (70-100) for FOLFIRINOX, and 60% (37-97) for capecitabine-based chemoradiotherapy (p=0·0028). 1-year disease-free survival from surgery was 33% (95% CI 19-58) for immediate surgery and 59% (46-74) for the combined neoadjuvant therapies (hazard ratio 0·53 [95% CI 0·28-0·98], p=0·016). Three patients reported local disease recurrence (two in the immediate surgery group and one in the FOLFIRINOX group). 78 (91%) patients were included in the safety set and assessed for toxicity events. 19 (24%) of 78 patients reported a grade 3 or worse adverse event (two [7%] of 28 patients in the immediate surgery group and 17 [34%] of 50 patients in the neoadjuvant therapy groups combined), the most common of which were neutropenia, infection, and hyperglycaemia. INTERPRETATION: Recruitment was challenging. There was no significant difference in resection rates between patients who underwent immediate surgery and those who underwent neoadjuvant therapy. Short-course (8 week) neoadjuvant therapy had a significant survival benefit compared with immediate surgery. Neoadjuvant chemotherapy with either gemcitabine plus capecitabine or FOLFIRINOX had the best survival compared with immediate surgery. These findings support the use of short-course neoadjuvant chemotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

Outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) undergoing robotic (RPD) or open pancreaticoduodenectomies (OPD): a propensity score-weighted survival analysis.

The purpose of this study was to compare the survival, recurrence, and complication rates in patients with pancreatic ductal adenocarcinoma (PDAC) who underwent robotic pancreaticoduodenectomy (RPD) or open pancreaticoduodenectomy (OPD) and who received adjuvant therapy. The study was a single-center retrospective analysis of consecutive PDAC patients who underwent RPD/OPD. Patient characteristics, tumor findings, neoadjuvant therapy, adjuvant therapies, overall survival (OS) and recurrence-free survival (RFS) were compared between the OPD and RPD cohorts. Cox proportional hazard regression with and without propensity score matching was used to establish the association between predictors and outcomes. One hundred PDAC patients underwent OPD (n = 36) or RPD (n = 64) from 2013 to 2019. Cox proportional hazard models showed that baseline bilirubin (HR 1.6, p = 0.0006) and operative characteristics such as the number of positive lymph nodes (HR 1.1, p = 0.002), lymph node ratio (HR 1.6, p = 0.001), tumor grade (HR 1.7, p = 0.02), and TNM classification (HR 2.3, p = 0.01) were associated with OS. The independent predictors post-intervention associated with mortality were adjuvant therapy (HR 0.4, p = 0.0003), ISGPS complications (HR 2.8, p = 0.02), and 90-day readmission (HR 2, p = 0.004). After adjustment for these predictors, adjuvant therapy, baseline bilirubin, lymph node ratio, and tumor grade remained the main predictors of mortality. Baseline bilirubin, adjuvant therapy, lymph node ratio, and tumor grade were the main determinants of mortality after OPD or RPD. There was no significant difference in OS and RFS after RPD or OPD in PC patients who received adjuvant therapy.

Identification of an Immune-Related BAT Signature for Predicting Adjuvant Chemotherapy Response and Overall Survival in Patients with Resected Ductal Adenocarcinoma of the Pancreas.

BACKGROUND: Adjuvant chemotherapy (ACT) is widely accepted in patients with pancreatic ductal adenocarcinoma (PDAC) after surgery; however, effective models for predicting ACT response are scarce. Thus, the objective of this study was to develop a novel signature for predicting its response and overall survival (OS) in resected PDAC patients. METHODS: A total of 50 PDAC patients with the transcriptome expression profiles, information about chemotherapy, and relevant clinical data were retrieved from the Cancer Genome Atlas (TCGA), and twenty-nine patients with tissue specimens and clinical data from our hospital were included as a validation. A novel gene signature was developed using bioinformatic differentially expressed genes (DEGs) analysis, Lasso-penalized Cox regression, and multivariate Cox regression studies. RESULTS: Between chemotherapy-resistant and chemotherapy-sensitive cohorts, 569 DEGs were identified, with 490 upregulated and 79 downregulated genes mainly specialized in the regulation of peptide/protein/hormone secretion, calcium ion homeostasis, and T cell activation regulation in biological processes. After Lasso-penalized Cox and multivariate Cox regression analysis, BAT (BCHE, ADH1A, and TNS4) signature was established to predict ACT response and OS. Moreover, BAT signature was verified as an independent risk factor for ACT response (p = 0.042) and OS (median OS: 17.5 months vs. 34.8 months, p = 0.040) and significantly associated with immune infiltrations (p < 0.05). Then, this signature was further validated as the independent risk factor for recurrence-free survival (RFS) in PDAC patients receiving postoperative ACT (median RFS: 9.0 months vs. not reached, p = 0.014), and tumor-infiltrating CD4+ and CD8+ T cells were further validated to be significantly decreased in tissues with higher BAT signature scores (p = 0.015 and 0.021, respectively). CONCLUSION: The BAT signature is a novel formulated and independent risk factor for predicting ACT response and long-term survival in patients with resected PDAC. This signature could comprehensively reflect local immune-related response, tumor purity, potential biological behavior, and chemo drug susceptibility.

Systematic review and meta-analysis of diagnostic performance of CT imaging for assessing resectability of pancreatic ductal adenocarcinoma after neoadjuvant therapy: importance of CT criteria.

PURPOSE: To assess the CT diagnostic performance for evaluating resectability of pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy and identify the factor(s) that affect(s) diagnostic performance. METHODS: Databases were searched to identify studies published from January 1, 2000, to November 5, 2019 that evaluated the CT diagnostic performance for assessing resectability of post-neoadjuvant PDAC. Two reviewers independently extracted data and assessed the study quality. A meta-analysis was performed to obtain summary sensitivity and specificity values using a bivariate random-effects model, and heterogeneity across studies was assessed. Univariable meta-regression analysis was performed with eight variables, including the different CT criteria for resectability, conventional National Comprehensive Cancer Network (NCCN) criteria for upfront surgery, and modified criteria for post-neoadjuvant surgery. RESULTS: Ten studies were included and analyzed. The summary sensitivity and specificity for resectability were 78% (95% CI 68-86%) and 60% (95% CI 44-74%), respectively. No significant heterogeneity was identified (bivariate correlation coefficient ρ = - 1, p-value for hierarchical summary receiver operating characteristics model ß = 0.667). The two different CT criteria showed different diagnostic performance (p < 0.01), with higher sensitivity (81% [95% CI 73-90%] vs. 28% [95% CI 15-42%], p < 0.01) and lower specificity (57% [95% CI 41-73%] vs. 90% [95% CI 80-100%], p < 0.01) for the modified criteria. No other variables affected the diagnostic performance. CONCLUSION: CT criteria were the factors that affected the diagnostic performance. Modification of the conventional criteria improved sensitivity but lowered specificity. Further modifications are required to improve specificity and uniformity.

A review of response in neoadjuvant therapy for exocrine pancreatic cancer.

Despite overall advances in cancer therapy, patients with pancreatic ductal adenocarcinoma continue to have a poor prognosis. While adjuvant therapy is still considered standard, there is mounting evidence that neoadjuvant therapy confers similar benefits in patients with locally advanced disease. The primary measures of response are radiographic, biochemical, margin status, and pathologic. Given overall low response rates and the need for new treatment strategies, standard metrics remain important to the investigation of new systemic agents.

Treatment landscape of metastatic pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with a dismal prognosis. The lack of symptoms in the early phase of the disease makes early diagnosis challenging, and about 80-85% of the patients are diagnosed only after the disease is locally advanced or metastatic. The current front-line treatment landscape in local stages comprises surgical resection and adjuvant chemotherapy. In Switzerland, although both FOLFIRINOX and gemcitabine plus nab-paclitaxel regimens are feasible and comparable in the first-line setting, FOLFIRINOX is preferred in the treatment of fit (Eastern Cooperative Oncology Group [ECOG] performance status [PS]: 0-1), young (<65 years old) patients with few comorbidities and normal liver function, while gemcitabine plus nab-paclitaxel is used to treat less fit (ECOG PS: 1-2) and more vulnerable patients. In the second-line setting of advanced PDAC, there is currently only one approved regimen, based on the phase III NAPOLI-1 trial. Furthermore, the use of liposomal-irinotecan in the second line is supported by real-world data. Beyond the standard of care, various alternative treatment modalities are being explored in clinical studies. Immunotherapy has demonstrated only limited benefits until now, and only in cases of high microsatellite instability (MSI-H). However, data on the benefit of poly (ADP-ribose) polymerase (PARP) inhibition as maintenance therapy in patients with germline BRCA-mutated tumors might signal of an advance in targeted therapy. Currently, there is a lack of molecular and genetic biomarkers for optimal stratification of patients and in guiding treatment decisions. Thus, identification of predictive and prognostic biomarkers and evaluating novel treatment strategies are equally relevant for improving the prognosis of metastatic pancreatic cancer patients.

Tailored adjuvant gemcitabine versus 5-fluorouracil/folinic acid based on hENT1 immunohistochemical staining in resected pancreatic ductal adenocarcinoma: A biomarker stratified prospective trial.

BACKGROUND: The study aimed to evaluate the clinical outcomes of tailored adjuvant chemotherapy according to human equilibrative nucleoside transporter 1 (hENT1) expression in resected pancreatic ductal adenocarcinoma (PDA). METHODS: Patients who underwent pancreatectomy for PDA were enrolled prospectively. According to intra-tumoral hENT1 expression, the high hENT1 (≥50%) group received gemcitabine and the low hENT1 (<50%) group received 5-fluorouracil plus folinic acid (5-FU/FA). The propensity score-matched control consisted of patients who received hENT1-independent adjuvant chemotherapy. The primary outcome was recurrence free survival (RFS) and the secondary outcomes were overall survival (OS) and toxicities. RESULTS: Between May 2015 and June 2017, we enrolled 44 patients with resected PDA. During a median follow-up period of 28.5 months, the intention-to-treat population showed much longer median RFS [22.9 (95% CI, 11.3-34.5) vs. 10.9 (95% CI, 6.9-14.9) months, P = 0.043] and median OS [36.2 (95% CI, 26.5-45.9) vs. 22.1 (95% CI, 17.7-26.6) months, P = 0.001] compared to the controls. Among 5 patients in the low hENT1 group who discontinued treatment, 2 patients receiving 5-FU/FA discontinued treatment due to drug toxicities (febrile neutropenia and toxic epidermal necrolysis). CONCLUSION: Tailored adjuvant chemotherapy based on hENT1 staining provides excellent clinical outcomes among patients with resected PDA. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT02486497.

Optimal Management of Resectable Pancreatic Head Cancer in the Elderly Patient: Does Neoadjuvant Therapy Offer a Survival Benefit?

INTRODUCTION: Neoadjuvant therapy (NAT) is a growing strategy for patients with resectable pancreatic ductal adenocarcinoma (PDAC). Elderly patients are at increased risk of treatment withdrawal due to functional decline, and the benefit of NAT in this cohort remains to be studied. OBJECTIVE: The objective of this study was to compare outcomes of elderly patients with resectable head PDAC who underwent NAT or a surgery-first (SF) approach. METHODS: All patients 75 years of age and older with radiographically resectable (National Comprehensive Cancer Network criteria) PDAC who underwent pancreaticoduodenectomy at a single institution from 2008 to 2017 were analyzed. Baseline characteristics and perioperative outcomes were compared between the SF and NAT cohorts. Recurrence-free survival and overall survival (OS) were analyzed by treatment strategy. RESULTS: Overall, 158 patients were identified: SF cohort = 90 (57%) and NAT cohort = 68 (43%). Patients in the SF cohort were older (80 vs. 78 years; p = 0.01) but there were no differences in preoperative comorbidities or frailty indices. SF patients had a trend toward higher rates of major complications (38% vs. 24%; p = 0.06) with higher Comprehensive Complication Index totals (20.9 vs. 20; p = 0.03). There were similar rates of adjuvant therapy. NAT was associated with significantly longer OS (24.6 vs. 17.6 months; p = 0.01) in both the intent-to-treat and resected cohorts. On multivariable analysis (MVA), NAT remained an independent predictor of OS (hazard ratio 0.60; p = 0.02). CONCLUSION: NAT is safe and effective for elderly patients with PDAC. This study suggests NAT is associated with fewer complications after surgery, equal rates of adjuvant therapy receipt, and increased OS over a surgery-first approach.