Predicting overall survival and resection in patients with locally advanced pancreatic cancer treated with FOLFIRINOX:Development and internal validation of two nomograms

Background and Objectives Patients with locally advanced pancreatic cancer (LAPC) are increasingly treated with FOLFIRINOX, resulting in improved survival and resection of tumors that were initially unresectable. It remains unclear, however, which specific patients benefit from FOLFIRINOX. Two nomograms were developed predicting overall survival (OS) and resection at the start of FOLFIRINOX for LAPC. Methods From our multicenter, prospective LAPC registry in 14 Dutch hospitals, LAPC patients starting first-line FOLFIRINOX (April 2015-December 2017) were included. Stepwise backward selection according to the Akaike Information Criterion was used to identify independent baseline predictors for OS and resection. Two prognostic nomograms were generated. Results A total of 252 patients were included, with a median OS of 14 months. Thirty-two patients (13%) underwent resection, with a median OS of 23 months. Older age, female sex, Charlson Comorbidity Index 1, involvement of the superior mesenteric artery, celiac trunk, and superior mesenteric vein >= 270 degrees were independent factors decreasing the probability of resection (c-index: 0.79). Conclusions Two nomograms were developed to predict OS and resection in patients with LAPC before starting treatment with FOLFIRINOX. These nomograms could be beneficial in the shared decision-making process and counseling of these patients

Treatment strategies and clinical outcomes in consecutive patients with locally advanced pancreatic cancer:A multicenter prospective cohort

Introduction: Since current studies on locally advanced pancreatic cancer (LAPC) mainly report from single, high-volume centers, it is unclear if outcomes can be translated to daily clinical practice. This study provides treatment strategies and clinical outcomes within a multicenter cohort of unselected patients with LAPC. Materials and methods: Consecutive patients with LAPC according to Dutch Pancreatic Cancer Group criteria, were prospectively included in 14 centers from April 2015 until December 2017. A centralized expert panel reviewed response according to RECIST v1.1 and potential surgical resectability. Primary outcome was median overall survival (mOS), stratified for primary treatment strategy. Results: Overall, 422 patients were included, of whom 77% (n = 326) received chemotherapy. The majority started with FOLFIRINOX (77%, 252/326) with a median of six cycles (IQR 4-10). Gemcitabine monotherapy was given to 13% (41/326) of patients and nab-paclitaxel/gemcitabine to 10% (33/326), with a median of two (IQR 3-5) and three (IQR 3-5) cycles respectively. The mOS of the entire cohort was 10 months (95%CI 9-11). In patients treated with FOLFIRINOX, gemcitabine monotherapy, or nab-paclitaxel/gemcitabine, mOS was 14 (95%CI 13-15), 9 (95%CI 8-10), and 9 months (95%CI 8-10), respectively. A resection was performed in 13% (32/252) of patients after FOLFIRINOX, resulting in a mOS of 23 months (95%CI 12-34). Conclusion: This multicenter unselected cohort of patients with LAPC resulted in a 14 month mOS and a 13% resection rate after FOLFIRINOX. These data put previous results in perspective, enable us to inform patients with more accurate survival numbers and will support decision-making in clinical practice. (C) 2020 The Authors. Published by Elsevier Ltd

Locally advanced pancreatic cancer: Work-up, staging, and local intervention strategies

Locally advanced pancreatic cancer (LAPC) has several definitions but essentially is a nonmetastasized pancreatic cancer, in which upfront resection is considered not beneficial due to extensive vascular involvement and consequent high chance of a nonradical resection. The introduction of FOLFIRINOX chemotherapy and gemcitabine-nab-paclitaxel (gem-nab) has had major implications for the management and outcome of patients with LAPC. After 4–6 months induction chemotherapy, the majority of patients have stable disease or even tumor-regression. Of these, 12 to 35% are successfully downstaged to resectable disease. Several studies have reported a 30–35 months overall survival after resection; although it currently remains unclear if this is a result of the resection or the good response to chemotherapy. Following chemotherapy, selection of patients for resection is difficult, as contrast-enhanced computed-tomography (CT) scan is unreliable in differentiating between viable tumor and fibrosis. In case a resection is not considered possible but stable disease is observed, local ablative techniques are being studied, such as irreversible electroporation, radiofrequency ablation, and stereotactic body radiation therapy. Pragmatic, multicenter, randomized studies will ultimately have to confirm the exact role of both surgical exploration and ablation in these patients. Since evidence-based guidelines for the management of LAPC are lacking, this review proposes a standardized approach for the treatment of LAPC based on the best available evidence

Locally Advanced Pancreatic Cancer: Exploring treatment strategies

With a worldwide incidence of approximately 496,000 new cases and 466,000 deaths in 2020, pancreatic cancer is among the most deadliest of cancers. The majority of patients present with an advanced stage of cancer at diagnosis. This includes 30-40% of patients with locally advanced pancreatic cancer (LAPC), due to extensive perivascular tumor infiltration without distant metastases. This thesis evaluates treatment strategies and clinical outcomes in patients with locally advanced pancreatic cancer (LAPC) in current clinical practice, investigates tools for selecting patients who will benefit chemotherapy, and prepares for the PELICAN trial: a randomized controlled trial investigating the efficacy of radiofrequency ablation in combination with chemotherapy in patients with LAPC. Part 1 Current treatment strategies This part provides a literature overview and evaluates the results of FOLFIRINOX-based treatment for patients with LAPC. From literature, the resection rate after FOLFIRINOX is 28% and median overall survival ranges between 8.9 and 25.0 months. Selection bias occurres in the included studies. Therefore a Dutch multicenter registry including unselected patients with LAPC was initiated. In total 77% of all patients start chemotherapy treatment after the diagnosis of LAPC. Most patients (77%) are able to receive FOLFIRINOX and have a median overall survival of 14 months. A proportion of 13% undergoes a resection after FOLFIRINOX with a median overall survival of 23 months. Part 2 Outcome prediction and patient selection In this part prediction models are developed to predict at baseline, those patients with favorable outcomes after FOLFIRINOX chemotherapy. Overall survival is difficult to predict at baseline, but positively influenced by older age, female sex, less comorbidity and a CA19.9<274. A surgical resection is predicted by performance score and vascular involvement at baseline (c-index 0.79), with the best patients having a chance for resection after chemotherapy of 35%. Part 3 Local ablative therapies In the last part of this thesis a basis is formed for an international multicenter randomized controlled trial, designed together with the Dutch Pancreatic Cancer Group. After applicability and safety of a new treatment strategy, radiofrequency ablation (RFA), was ensured, the PELICAN trial was initiated. RFA is performed with direct intra-operative ultrasound guidance and a predefined distance is kept to vital structures. Patients with LAPC, who have stable disease or an objective response without the possibility for a resection, after 2 months of chemotherapy are eligible for inclusion. Eligible patients are randomized to intra-operative RFA followed by continuation of chemotherapy versus chemotherapy without RFA. The PELICAN trial primary investigates survival. Since this is the only trial worldwide on this specific topic, executed by a large collaboration of 20 (inter)national centers, the results of the trial will be of great relevance. The trial is currently ongoing and results are estimated to become available in 2022. In summary the LAPC registry cohort, as described within this thesis, enables the Dutch clinical practitioners to inform patients with LAPC with real world data on survival and resection after FOLFIRINOX treatment. Moreover, this thesis provides the basis for the PELICAN trial

Predictors of fecal incontinence and related quality of life after a total mesorectal excision with primary anastomosis for patients with rectal cancer

PURPOSE: After total mesorectal excision (TME) with primary anastomosis for patients with rectal cancer, the quality of life (QoL) may be decreased due to fecal incontinence. This study aimed to identify predictors of fecal incontinence and related QoL. METHODS: Patients who underwent TME with primary anastomosis for rectal cancer between December 2008 and June 2012 completed the fecal incontinence quality of life scale (FIQoL) and Wexner incontinence score. Factors associated with these scores were identified using a linear regression analysis. RESULTS: A total of 80 patients were included. Multivariate analysis identified a diverting ileostomy (n = 58) as an independent predictor of an unfavorable outcome on the FIQoL subscale coping/behavior (P = 0.041). Ileostomy closure within and after 3 months resulted in median Wexner scores of 5.0 (interquartile range [IQR], 2.5-8.0) and 10.5 (IQR, 6.0-13.8), respectively (P < 0.001). The median FIQoL score was 15.0 (IQR, 13.1-16.0) for stoma closure within 3 months versus 12.0 (IQR, 10.5-13.9) for closure after 3 months (P = 0.001). CONCLUSION: A diverting ileostomy is a predictor for an impaired FIQoL after a TME for rectal cancer. Stoma reversal within 3 months showed better outcomes than reversal after 3 months. Patients with a diverting ileostomy should be informed about the impaired QoL, even after stoma closure

Computed tomography findings after radiofrequency ablation in locally advanced pancreatic cancer

Purpose: The purpose of the study was to provide a systematic evaluation of the computed tomography(CT) findings after radiofrequency ablation (RFA) in locally advanced pancreatic cancer(LAPC). Methods: Eighteen patients with intra-operative RFA-treated LAPC were included in a prospective case series. All CT-scans performed prior to RFA and 1 week and 3 months of post-RFA, according to standard regimen, were assessed by two radiologists in consensus, using standardized radiological scoring lists. Results: 51 CT-scans were assessed. One week after RFA, the ablation zone was visible in all patients as a (partially) sharply defined (83%), heterogeneous area (94%). At 3 months of follow-up, the ablation zone was completely invaded by tumor in 67% of patients and still present, but decreased in 33%. In two patients (11%), local thrombosis and/or occlusion of the superior mesenteric vein occurred. The occlusions persisted without clinical consequences and the thrombosis disappeared. A peripancreatic fluid collection was visible 1 week after RFA in 3 patients, wherein the ablation zone extended ventrally outside of the pancreas. Conclusions: Directly after RFA for LAPC, a well-defined ablation zone is visible on CT-imaging. This ablation zone is usually replaced by tumor ingrowth after 3 months. Moreover, the ablation zone regularly included vascular structures, with rare asymptomatic venous occlusion or thrombosis and without adverse effects on arteries

Computed tomography findings after radiofrequency ablation in locally advanced pancreatic cancer

Purpose: The purpose of the study was to provide a systematic evaluation of the computed tomography(CT) findings after radiofrequency ablation (RFA) in locally advanced pancreatic cancer(LAPC). Methods: Eighteen patients with intra-operative RFA-treated LAPC were included in a prospective case series. All CT-scans performed prior to RFA and 1 week and 3 months of post-RFA, according to standard regimen, were assessed by two radiologists in consensus, using standardized radiological scoring lists. Results: 51 CT-scans were assessed. One week after RFA, the ablation zone was visible in all patients as a (partially) sharply defined (83%), heterogeneous area (94%). At 3 months of follow-up, the ablation zone was completely invaded by tumor in 67% of patients and still present, but decreased in 33%. In two patients (11%), local thrombosis and/or occlusion of the superior mesenteric vein occurred. The occlusions persisted without clinical consequences and the thrombosis disappeared. A peripancreatic fluid collection was visible 1 week after RFA in 3 patients, wherein the ablation zone extended ventrally outside of the pancreas. Conclusions: Directly after RFA for LAPC, a well-defined ablation zone is visible on CT-imaging. This ablation zone is usually replaced by tumor ingrowth after 3 months. Moreover, the ablation zone regularly included vascular structures, with rare asymptomatic venous occlusion or thrombosis and without adverse effects on arteries

Systematic Review of Resection Rates and Clinical Outcomes After FOLFIRINOX-Based Treatment in Patients with Locally Advanced Pancreatic Cancer

FOLFIRINOX prolongs survival in patients with metastatic pancreatic cancer and may also benefit patients with locally advanced pancreatic cancer (LAPC). Furthermore, it may downstage a proportion of LAPC into (borderline) resectable disease, however data are lacking. This review assessed outcomes after FOLFIRINOX-based therapy in LAPC. The PubMed, EMBASE and Cochrane library databases were systematically searched for studies published to 31 August 2015. Primary outcome was the (R0) resection rate. Fourteen studies involving 365 patients with LAPC were included; three studies administered a modified FOLFIRINOX regimen. Of all patients, 57 % (n = 208) received radiotherapy. The pooled resection rate was 28 % (n = 103, 77 % R0), with a perioperative mortality of 3 % (n = 2), and median overall survival ranged from 8.9 to 25.0 months. Survival data after resection were scarce, with only one study reporting a median overall survival of 24.9 months in 28 patients. A complete pathologic response was found in 6 of 85 (7 %) resected specimens. Dose reductions were described in up to 65 % of patients, grade 3-4 toxicity occurred in 23 % (n = 51) of patients, and 2 % (n = 5) had to discontinue treatment. Data of patients treated solely with FOLFIRINOX, without additional radiotherapy, were available from 292 patients: resection rate was 12 % (n = 29, 70 % R0), with 15.7 months median overall survival and 19 % (n = 34) grade 3-4 toxicity. Outcomes after FOLFIRINOX-based therapy in patients with LAPC seem very promising but further prospective studies are needed, especially with regard to survival after resectio