Dataset Information

Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial.

ABSTRACT: Importance:Patients with locally advanced pancreatic cancer have historically poor outcomes. Evaluation of a total neoadjuvant approach is warranted. Objective:To evaluate the margin-negative (R0) resection rate of neoadjuvant FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and losartan followed by chemoradiotherapy for locally advanced pancreatic cancer. Design, Setting, and Participants:A single-arm phase 2 clinical trial was conducted at a large academic hospital from August 22, 2013, to May 22, 2018, among 49 patients with previously untreated locally advanced unresectable pancreatic cancer as determined by multidisciplinary review. Patients had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 17.1 months (range, 5.0-53.7) among 27 patients still alive at study completion. Interventions:Patients received FOLFIRINOX and losartan for 8 cycles. Patients with radiographically resectable tumor after chemotherapy received short-course chemoradiotherapy (5 GyE?×?5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy (50.4 Gy with a vascular boost to 58.8 Gy) with fluorouracil or capecitabine. Main Outcomes and Measures:R0 resection rate. Results:Of the 49 patients (26 women and 23 men; median age 63 years [range, 42-78 years]), 39 completed 8 cycles of FOLFIRINOX and losartan; 10 patients had fewer than 8 cycles due to progression (5 patients), losartan intolerance (3 patients), and toxicity (2 patients). Seven patients (16%) had short-course chemoradiotherapy while 38 (84%) had long-course chemoradiotherapy. Forty-two (86%) patients underwent attempted surgery, with R0 resection achieved in 34 of 49 patients (69%; 95% CI, 55%-82%). Overall median progression-free survival was 17.5 months (95% CI: 13.9-22.7) and median overall survival was 31.4 months (95% CI, 18.1-38.5). Among patients who underwent resection, median progression-free survival was 21.3 months (95% CI, 16.6-28.2), and median overall survival was 33.0 months (95% CI, 31.4 to not reached). Conclusions and Relevance:Total neoadjuvant therapy with FOLFIRINOX, losartan, and chemoradiotherapy provides downstaging of locally advanced pancreatic ductal adenocarcinoma and is associated with an R0 resection rate of 61%. Trial Registration:ClinicalTrials.gov identifier: NCT01821729.

SUBMITTER: Murphy JE

PROVIDER: S-EPMC6547247 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial.

Murphy Janet E JE Wo Jennifer Y JY Ryan David P DP Clark Jeffrey W JW Jiang Wenqing W Yeap Beow Y BY Drapek Lorraine C LC Ly Leilana L Baglini Christian V CV Blaszkowsky Lawrence S LS Ferrone Cristina R CR Parikh Aparna R AR Weekes Colin D CD Nipp Ryan D RD Kwak Eunice L EL Allen Jill N JN Corcoran Ryan B RB Ting David T DT Faris Jason E JE Zhu Andrew X AX Goyal Lipika L Berger David L DL Qadan Motaz M Lillemoe Keith D KD Talele Nilesh N Jain Rakesh K RK DeLaney Thomas F TF Duda Dan G DG Boucher Yves Y Fernández-Del Castillo Carlos C Hong Theodore S TS

JAMA oncology 20190701 7

<h4>Importance</h4>Patients with locally advanced pancreatic cancer have historically poor outcomes. Evaluation of a total neoadjuvant approach is warranted.<h4>Objective</h4>To evaluate the margin-negative (R0) resection rate of neoadjuvant FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and losartan followed by chemoradiotherapy for locally advanced pancreatic cancer.<h4>Design, setting, and participants</h4>A single-arm phase 2 clinical trial was conducted at a large academ ...[more]

PMID: 31145418

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Project description:Importance:Patients with borderline-resectable pancreatic ductal adenocarcinoma have historically poor outcomes with surgery followed by adjuvant chemotherapy. Evaluation of a total neoadjuvant approach with highly active therapy is warranted. Objective:To evaluate the margin-negative (R0) resection rate in borderline-resectable pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX (fluorouracil, irinotecan, and oxaliplatin) therapy and individualized chemoradiotherapy. Design, Setting, and Participants:A single-arm, phase 2 clinical trial was conducted at a large academic hospital with expertise in pancreatic surgery from August 3, 2012, through August 31, 2016, among 48 patients with newly diagnosed, previously untreated, localized pancreatic cancer determined to be borderline resectable by multidisciplinary review, who had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 18.0 months among the 30 patients still alive at study completion. Interventions:Patients received FOLFIRINOX for 8 cycles. Upon restaging, patients with resolution of vascular involvement received short-course chemoradiotherapy (5 Gy × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy with fluorouracil or capecitabine. Main Outcomes and Measures:The primary outcome was R0 resection rate; secondary outcomes were median progression-free survival (PFS) and median overall survival (OS). Results:Of the 48 eligible patients, 27 were men and 21 were women, with a median age of 62 years (range, 46-74 years). Of the 43 patients who planned to receive 8 preoperative cycles of chemotherapy, 34 (79%) were able to complete all cycles. Twenty-seven patients (56%) had short-course chemoradiotherapy, while 17 patients (35%) had long-course chemoradiotherapy. R0 resection was achieved in 31 of the 48 eligible patients (65%; 95% CI, 49%-78%). Among the 32 patients who underwent resection, the R0 resection rate was 97% (n = 31). Median PFS among all eligible patients was 14.7 months (95% CI, 10.5 to not reached), with 2-year PFS of 43%; median OS was 37.7 months (95% CI, 19.4 to not reached), with 2-year OS of 56%. Among patients who underwent resection, median PFS was 48.6 months (95% CI, 14.4 to not reached) and median OS has not been reached, with a 2-year PFS of 55% and a 2-year OS of 72%. Conclusions and Relevance:Preoperative FOLFIRINOX followed by individualized chemoradiotherapy in borderline resectable pancreatic cancer results in high rates of R0 resection and prolonged median PFS and median OS, supporting ongoing phase 3 trials. Trial Registration:ClinicalTrials.gov Identifier: NCT01591733.

Project description:BackgroundConcurrent chemoradiotherapy followed by adjuvant chemotherapy (CCRT-AC) is currently recommended as the standard treatment for locally advanced nasopharyngeal carcinoma (LA-NPC). Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy (NAC-CCRT) is an alternative strategy for decreasing tumor size and controlling micrometastases before main treatment. The aim of this study was to investigate and compare survival outcomes between LA-NPC patients treated with CCRT-AC and those treated with NAC-CCRT.MethodsThis retrospective cohort study included consecutive histologically confirmed LA-NPC patients that were treated with NAC-CCRT or CCRT-AC at Siriraj Hospital during the March 2010 to October 2014 study period. CCRT in both protocols consisted of 3-week cycles of cisplatin 100 mg/m2 with concurrent radiotherapy. Either NAC or AC consisted of 3-week cycles of cisplatin on day 1 and fluorouracil/leucovorin on days 1-4 for a maximum three cycles. The primary endpoint was 5-year overall survival (OS). Flexible parametric survival analysis was used, because the proportional hazards assumption of Cox regression was violated.ResultsOf the 266 LA-NPC patients that received treatment during the study period, 79 received NAC-CCRT and 187 received CCRT-AC. Median follow-up was 37 months. Significantly more patients with advanced clinical stage (stage IVA-IVB) received NAC-CCRT (86% in NAC-CCRT vs. 29% in CCRT-AC; p < 0.001). Compared to CCRT-AC in crude analysis, 3-year and 5-year OS of NAC-CCRT were 72% vs. 86% and 62% vs. 75% respectively (p = 0.059). Interestingly, the 3-year and 5-year post-estimation adjusted OS was 84% and 74% for NAC-CCRT and 81% and 70% for CCRT-AC, respectively (HR: 0.83, 95% confidence interval (CI): 0.45-1.56; p = 0.571). Also, adjusted analysis of distant-metastasis survival, NAC-CCRT showed HR was 0.79 (95% CI:0.37-1.72, p = 0.557). Conversely, adjusted analysis of locoregional relapse (LLR)-free survival revealed NAC-CCRT to have a significantly higher risk of LRR (HR: 2.18, 95% CI: 0.98-4.87; p = 0.057).ConclusionsThe results suggested that prognosis in the NAC-CCRT treated patients was not superior to that of the CCRT-AC treated individuals. In patients that receive neoadjuvant chemotherapy, locoregional relapse should be of concern. High-risk distant metastasis patients (N3 stage) that could achieve survival advantage from NAC-CCRT is an interesting and important topic for further study.

Project description:AbstractCurrently, the combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) is the standard therapy for metastatic pancreatic cancer. In recent years, FOLFIRINOX-based neoadjuvant therapy for locally advanced pancreatic cancer (LAPC) has been gaining an increasing amount of attention, owing to its ability to reduce disease stage and transform LAPC to borderline resectable or even resectable pancreatic cancer. Accordingly, we aimed to evaluate the efficacy of first-line FOLFIRINOX chemotherapy in patients with LAPC.We searched PubMed, Embase, and Cochrane Library from the time of establishment till January 1, 2020 and included studies focusing on LAPC patients who received FOLFIRINOX as first-line neoadjuvant treatment. The primary outcomes were: resection rate and radical (R0) resection rate while the secondary outcomes were: objective response rate, overall survival, progression-free survival, and rate of grade 3 to 4 adverse events. The meta package for R 3.6.2 was used for heterogeneity and publication bias testing.Twenty-one studies, including 653 patients with LAPC, were selected. After treatment with FOLFIRINOX, the resection rate was 26% (95% confidence interval [CI] = 20%-32%, I2 = 61%) and R0 resection rate was 88% (95% CI = 78%-95%, I2 = 62%). The response rate was 34% (95% CI = 25%-43%, I2 = 56%). The median overall survival and progression-free survival durations ranged from 10.0 to 32.7 months and 3.0 to 25.3 months, respectively. The observed grade 3 to 4 adverse events were neutropenia (20.0 per 100 patients, 95% CI = 14%-27%, I2 = 75%), febrile neutropenia (7.0 per 100 patients, 95% CI = 5%-9%, I2 = 42%), thrombocytopenia (6.0 per 100 patients, 95% CI = 5%-8%, I2 = 27%), nausea/vomiting (7.0 per 100 patients, 95% CI = 7%-12%, I2 = 76%), diarrhea (10.0 per 100 patients, 95% CI = 8%-12%, I2 = 38%), and fatigue (9.0 per 100 patients, 95% CI = 7%-11%, I2 = 43%).FOLFIRINOX-based neoadjuvant chemotherapy has the potential to improve the rates of resection, R0 resection, and median OS in LAPC. Our results require further validation in large, high-quality randomized controlled trials.

Project description:IntroductionFOLFIRINOX (the combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) is the preferred systemic regimen for locally advanced pancreatic cancer (LAPC). Furthermore, stereotactic body radiation therapy (SBRT) is a promising treatment option for achieving local control in these patients. However, clinical outcomes in patients with LAPC treated using FOLFIRINOX followed by SBRT have not been clarified. Therefore, we aimed to evaluate clinical outcomes of induction FOLFIRINOX treatment followed by SBRT in patients with LAPC.MethodsTo this end, we retrospectively reviewed the medical records of patients with LAPC treated with induction FOLFIRINOX followed by SBRT in a single tertiary hospital. We evaluated overall survival (OS), progression-free survival (PFS), resection rate, SBRT-related adverse events, and prognostic factors affecting survival.ResultsFifty patients were treated with induction FOLFIRINOX for a median of 8 cycles (range: 3-28), which was followed by SBRT. The median OS and PFS were 26.4 (95% confidence interval [CI]: 22.4-30.3) and 16.7 months (95% CI: 13.0-20.3), respectively. Nine patients underwent conversion surgery (eight achieved R0) and showed better OS than those who did not (not reached vs. 24.1 months, p = 0.022). During a follow-up period of 23.6 months, three cases of grade 3 gastrointestinal bleeding at the pseudoaneurysm site were noted, which were managed successfully. Analysis of the factors affecting clinical outcomes revealed that a high radiation dose (≥ 35 Gy) resulted in a higher rate of conversion surgery (25% [8/32] vs. 5.6% [1/18], respectively) and was an independent favorable prognostic factor for OS in the adjusted analysis (hazard ratio: 2.024, 95% CI: 1.042-3.930, p = 0.037).ConclusionOur findings suggest that induction FOLFIRINOX followed by SBRT in patients with LAPC results in better survival with manageable toxicities. A high total SBRT dose was associated with a high rate of conversion surgery and could afford better survival.

Dataset Information

Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial.

Publications

Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial.

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