Summary Background 35% of patients with pancreatic cancer have unresectable locally advanced disease at diagnosis. Several studies have examined systemic chemotherapy with FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) in patients with locally advanced pancreatic cancer. We aimed to assess the effectiveness of FOLFIRINOX as first-line treatment in this patient population. Methods We systematically searched Embase, MEDLINE (OvidSP), Web of Science, Scopus, PubMed Publisher, Cochrane, and Google Scholar from July 1, 1994, to July 2, 2015, for studies of treatment-naive patients of any age who received FOLFIRINOX as first-line treatment of locally advanced pancreatic cancer. Our primary outcome was overall survival. Secondary outcomes were progression-free survival; rates of grade 3 or 4 adverse events; and the proportion of patients who underwent radiotherapy or chemoradiotherapy, surgical resection after FOLFIRINOX, and R0 resection. We evaluated survival outcomes with the Kaplan–Meier method with patient-level data. Grade 3 or 4 adverse events, and the proportion of patients who underwent subsequent radiotherapy or chemoradiotherapy or resection, were pooled in a random-effects model. Findings We included 13 studies comprising 689 patients, of whom 355 (52%) patients had locally advanced pancreatic cancer. 11 studies, comprising 315 patients with locally advanced disease, reported survival outcomes and were eligible for patient-level meta-analysis. Median overall survival from the start of FOLFIRINOX ranged from 10·0 months (95% CI 4·0–16·0) to 32·7 months (23·1–42·3) across studies with a pooled patient-level median overall survival of 24·2 months (95% CI 21·7–26·8). Median progression-free survival ranged from 3·0 months (95% CI not calculable) to 20·4 months (6·5–34·3) across studies with a patient-level median progression-free survival of 15·0 months (95% 13·8–16·2). In ten studies comprising 490 patients, 296 grade 3 or 4 adverse events were reported (60·4 events per 100 patients). No deaths were attributed to FOLFIRINOX toxicity. The proportion of patients who underwent radiotherapy or chemoradiotherapy ranged from 31% to 100% across studies. In eight studies, 154 (57%) of 271 patients received radiotherapy or chemoradiotherapy after FOLFIRINOX. The pooled proportion of patients who received any radiotherapy treatment was 63·5% (95% CI 43·3–81·6, I 2 90%). The proportion of patients who underwent surgical resection for locally advanced pancreatic cancer ranged from 0% to 43%. The proportion of patients who had R0 resection of those who underwent resection ranged from 50% to 100% across studies. In 12 studies, 91 (28%) of 325 patients underwent resection after FOLFIRINOX. The pooled proportion of patients who had resection was 25·9% (95% CI 20·2–31·9, I 2 24%). R0 resection was reported in 60 (74%) of 81 patients. The pooled proportion of patients who had R0 resection was 78·4% (95% CI 60·2–92·2, I 2 64%). Interpretation Patients with locally advanced pancreatic cancer treated with FOLFIRINOX had a median overall survival of 24·2 months—longer than that reported with gemcitabine (6–13 months). Future research should assess these promising results in a randomised controlled trial, and should establish which patients might benefit from radiotherapy or chemoradiotherapy or resection after FOLFIRINOX. Funding None.

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FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis

The overall 5-year survival for pancreatic cancer has changed little over the past few decades, and pancreatic cancer is predicted to be the second leading cause of cancer-related mortality in the next decade in Western countries. The past few years, however, have seen improvements in first-line and second-line palliative therapies and considerable progress in increasing survival with adjuvant treatment. The use of biomarkers to help define treatment and the potential of neoadjuvant therapies also offer opportunities to improve outcomes. This Review brings together information on achievements to date, what is working currently and where successes are likely to be achieved in the future. Furthermore, we address the questions of how we should approach the development of pancreatic cancer treatments, including those for patients with metastatic, locally advanced and borderline resectable pancreatic cancer, as well as for patients with resected tumours. In addition to embracing newer strategies comprising genomics, stromal therapies and immunotherapies, conventional approaches using chemotherapy and radiotherapy still offer considerable prospects for greater traction and synergy with evolving concepts.

Therapeutic developments in pancreatic cancer: current and future perspectives.

Objective:For patients with locally advanced and unresectable pancreatic cancer (PDAC), neodadjuvant treatment and consecutive surgical exploration have been studied during the last decade with various neoadjuvant therapies including chemotherapy and combinations with radiation. Aim of the study was

Locally Advanced Pancreatic Cancer: Neoadjuvant Therapy With Folfirinox Results in Resectability in 60% of the Patients.

Importance Although consensus statements support the preoperative treatment of borderline resectable pancreatic cancer, no prospective, quality-controlled, multicenter studies of this strategy have been conducted. Existing studies are retrospective and confounded by heterogeneity in patients studied, therapeutic algorithms used, and outcomes reported. Objective To determine the feasibility of conducting studies of multimodality therapy for borderline resectable pancreatic cancer in the cooperative group setting. Design, Setting, and Participants A prospective, multicenter, single-arm trial of a multimodality treatment regimen administered within a study framework using centralized quality control with the cooperation of 14 member institutions of the National Clinical Trials Network. Twenty-nine patients with biopsy-confirmed pancreatic cancer preregistered, and 23 patients with tumors who met centrally reviewed radiographic criteria registered. Twenty-two patients initiated therapy (median age, 64 years [range, 50-76 years]; 55% female). Patients registered between May 29, 2013, and February 7, 2014. Interventions Patients received modified FOLFIRINOX treatment (85 mg/m2 of oxaliplatin, 180 mg/m2of irinotecan hydrochloride, 400 mg/m2of leucovorin calcium, and then 2400 mg/m2of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m2orally twice daily) prior to pancreatectomy. Main Outcomes and Measures Feasibility, defined by the accrual rate, the safety of the preoperative regimen, and the pancreatectomy rate. Results The accrual rate of 2.6 patients per month was superior to the anticipated rate. Although 14 of the 22 patients (64% [95% CI, 41%-83%]) had grade 3 or higher adverse events, 15 of the 22 patients (68% [95% CI, 49%-88%]) underwent pancreatectomy. Of these 15 patients, 12 (80%) required vascular resection, 14 (93%) had microscopically negative margins, 5 (33%) had specimens that had less than 5% residual cancer cells, and 2 (13%) had specimens that had pathologic complete responses. The median overall survival of all patients was 21.7 months (95% CI, 15.7 to not reached) from registration. Conclusions and Relevance The successful completion of this collaborative study demonstrates the feasibility of conducting quality-controlled trials for this disease stage in the multi-institutional setting. The data generated by this study and the logistical elements that facilitated the trial’s completion are currently being used to develop cooperative group trials with the goal of improving outcomes for this subset of patients. Trial Registration clinicaltrials.gov Identifier:NCT01821612

https://jamanetwork.com/journals/jamasurgery/articlepdf/2527155/soi160019.pdf

Preoperative Modified FOLFIRINOX Treatment Followed by Capecitabine-Based Chemoradiation for Borderline Resectable Pancreatic Cancer: Alliance for Clinical Trials in Oncology Trial A021101.

Objectives:Ablative therapies have been increasingly utilized in the treatment of locally advanced pancreatic cancer (LAPC). Irreversible electroporation (IRE) is an energy delivery system, effective in ablating tumors by inducing irreversible membrane destruction of cells. We aimed to demonstrate e

Treatment of 200 locally advanced (stage III) pancreatic adenocarcinoma patients with irreversible electroporation: safety and efficacy.

The prevalence of pancreatic adenocarcinoma (PDAC) continues to increase. The American Cancer Society predicts 46,420 new cases and 39,590 deaths in the United States in 2014. The majority of patients present with metastatic disease, whereas 30% present with locally advanced (LA) cancers.1 Unfortunately, overall survival (OS) of pancreatic cancer patients remains low, with surgical resection offering the only chance for potential cure. However, even then the OS is reported to be less than 20%.2–4 In the hopes of rendering LA PDAC patients resectable, combination chemotherapy often followed by 50.4 Gy of radiation with low-dose chemotherapy is administered.5,6

However, historically only 19% to 30% of patients are rendered resectable.7–10 If an R0 resection can be achieved, OS is similar to patients who are considered resectable at presentation.9 Unfortunately, these heavily treated patients with LA PDAC have an increased surgical morbidity and mortality.9,11

A significant breakthrough for patients with metastatic PDAC was achieved in 2011 with the ACCORD trial.12 This trial demonstrated that the OS with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) was improved when compared with gemcitabine for patients with metastatic pancreatic cancer (6.8 vs 11.1 months, P < 0.001).12 On the basis of these encouraging results, FOLFIRINOX became a rational choice to render patients with LA PDAC resectable.13

Resectability of PDAC is determined by radiologic imaging. The most commonly used imaging modality to stage PDAC is a triple-phase contrast-enhanced thin-slice (multidetector row) helical computed tomography with 3-dimensional reconstructions. Unfortunately, the definitions for LA and borderline lesions vary significantly. This ambiguity prompted 4 guideline statements from the National Comprehensive Cancer Network, the University of Texas MD Anderson Cancer Center, the Americas Hepato-Pancreato-Biliary Association (AHPBA)/Society of Surgical Oncology (SSO)/Society for Surgery of the Alimentary Tract (SSAT).14–17 These guidelines address vascular involvement, which is a major determinant of unresectability.

This study provides the largest series of neoadjuvantly treated FOLFIRINOX patients who underwent surgical resection. Radiologic and clinicopathologic features of patients with either LA or borderline resectable pancreatic cancer who received neoadjuvant FOLFIRINOX were compared with resectable patients who underwent exploration without neoadjuvant treatment. The first aim of this study is to critically evaluate the accuracy of imaging in determining resectability after FOLFIRINOX with or without chemoradiation. The second aim is to compare the surgical outcomes and clinicopathologic results of pancreatic resections in this cohort of FOLFIRINOX-treated patients with patients who received no neoadjuvant therapy.

Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer.

230 Background: Cholangiocarcinoma continues to have a dismal prognosis. The lack of effective therapy prompted us to determine whether patients develop an immune response against their own tumors....

Daniela Dias Santos

Papers

Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer.

Variability in immune infiltrates and HLA expression in cholangiocarcinoma.