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Clinical Trial
. 2019 Jul 1;5(7):1020-1027.
doi: 10.1001/jamaoncol.2019.0892.

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

Janet E Murphy  1 , Jennifer Y Wo  2 , David P Ryan  1 , Jeffrey W Clark  1 , Wenqing Jiang  1 , Beow Y Yeap  1 , Lorraine C Drapek  2 , Leilana Ly  2 , Christian V Baglini  2 , Lawrence S Blaszkowsky  1 , Cristina R Ferrone  3 , Aparna R Parikh  1 , Colin D Weekes  1 , Ryan D Nipp  1 , Eunice L Kwak  1 , Jill N Allen  1 , Ryan B Corcoran  1 , David T Ting  1 , Jason E Faris  1 , Andrew X Zhu  1 , Lipika Goyal  1 , David L Berger  3 , Motaz Qadan  3 , Keith D Lillemoe  3 , Nilesh Talele  2 , Rakesh K Jain  2 , Thomas F DeLaney  2 , Dan G Duda  2 , Yves Boucher  2 , Carlos Fernández-Del Castillo  3 , Theodore S Hong  2
Affiliations
Clinical Trial

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

Janet E Murphy et al. JAMA Oncol. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ryan reported personal fees from MPM Capital, Gritstone Oncology, Oncorus, UpToDate, McGraw Hill, and Johns Hopkins University Press as well as other support from Pfizer outside the submitted work. Dr Drapek reported a one-time webinar on opioid-induced constipation for Integritas. Dr Parikh reported personal fees from Puretech and Eisai outside the submitted work. Dr Kwak reported current employment at Novartis, with employment at MGH at the time of participation in the clinical trial. Dr Corcoran reported personal fees from Amgen, Array Biopharma, Astex Pharmaceuticals, Avidity Biosciences, Bristol-Myers Squibb, Chugai, FOG Pharma, Genentech, LOXO, Merrimack, N-of-One, nRichDx, Roche, Roivant, Shire, Spectrum Pharmaceuticals, Symphogen, Taiho, and WarpDrive Bio as well as grants from Asana, AstraZeneca, and Sanofi outside the submitted work. Dr Ting reported other support from ACD-Biotechne and PanTher Therapeutics as well as personal fees from EMD Millipore-Sigma, Merrimack Pharmaceuticals, and Ventana Roche outside the submitted work. Dr Faris reported grants and personal fees from Novartis; nonfinancial support from Exelixis; and grants from Roche/Genentech, Millenium, and Sanofi outside the submitted work. Dr Zhu reported other support from Bayer, Bristol-Myers Squibb, Merck, Lilly, Eisai, AstraZeneca, and Exelixis outside the submitted work. Dr Qadan reported personal fees from Olympus outside the submitted work. Dr Jain reported grants from the National Cancer Institute (NCI) during the conduct of the study; had a patent to Novel Composition and Uses of Anti-Hypertension Agents for Cancer Therapy pending and issued; received an honorarium from Amgen; received consultant fees from Merck, Ophthotech, Pfizer, SPARC, SynDevRx, and XTuit; owns equity in Enlight, Ophthotech, and SynDevRx; and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund. Neither any reagent nor any funding from these organizations was used in this study. Drs Jain and Duda had a patent to Novel Compositions and Uses of Anti-Hypertension Agents for Cancer Therapy (patent CA2872652 A1) issued, licensed, and with royalties paid. Dr Duda reported grants and personal fees from Bayer and Bristol-Myers Squibb; grants from Exelixis and Leap; and personal fees from twoXAR and Tilos outside the submitted work. Dr Boucher reported personal fees from Xtuit Inc outside the submitted work. Dr Hong reported personal fees from EMD Serono outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
Flowchart of enrolled patients; those who completed chemotherapy with FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan); those who proceeded to photon or proton radiation; and those who proceeded to attempted surgical resection.
Figure 2.
Figure 2.. Waterfall Plot of Percentage Change in Tumor Dimension
The dashed line above the x-axis represents 20% increase in sum of target lesions from baseline (disease progression), and dashed line below the x-axis represents 30% decrease in sum of target lesions from baseline (partial response). Twenty-three patients (47%) had a partial response, while 21 (43%) had stable disease for an overall disease control rate of 96%. Two patients (4%) had progressive disease.
Figure 3.
Figure 3.. Survival Curves
A, Overall survival among evaluable patients (n = 49). B, Progression-free survival among evaluable patients (n = 49). C, Overall survival among patients who underwent resection (n = 34). D, Progression-free survival among patients who underwent resection (n = 34).
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