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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.
JAMA Oncol 2019; 5(7):1020-1027JO

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.

Authors+Show Affiliations

Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31145418

Citation

Murphy, Janet E., et al. "Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed By Chemoradiotherapy for Locally Advanced Pancreatic Cancer: a Phase 2 Clinical Trial." JAMA Oncology, vol. 5, no. 7, 2019, pp. 1020-1027.
Murphy JE, Wo JY, Ryan DP, et al. Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial. JAMA Oncol. 2019;5(7):1020-1027.
Murphy, J. E., Wo, J. Y., Ryan, D. P., Clark, J. W., Jiang, W., Yeap, B. Y., ... Hong, T. S. (2019). Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial. JAMA Oncology, 5(7), pp. 1020-1027. doi:10.1001/jamaoncol.2019.0892.
Murphy JE, et al. Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed By Chemoradiotherapy for Locally Advanced Pancreatic Cancer: a Phase 2 Clinical Trial. JAMA Oncol. 2019 Jul 1;5(7):1020-1027. PubMed PMID: 31145418.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial. AU - Murphy,Janet E, AU - Wo,Jennifer Y, AU - Ryan,David P, AU - Clark,Jeffrey W, AU - Jiang,Wenqing, AU - Yeap,Beow Y, AU - Drapek,Lorraine C, AU - Ly,Leilana, AU - Baglini,Christian V, AU - Blaszkowsky,Lawrence S, AU - Ferrone,Cristina R, AU - Parikh,Aparna R, AU - Weekes,Colin D, AU - Nipp,Ryan D, AU - Kwak,Eunice L, AU - Allen,Jill N, AU - Corcoran,Ryan B, AU - Ting,David T, AU - Faris,Jason E, AU - Zhu,Andrew X, AU - Goyal,Lipika, AU - Berger,David L, AU - Qadan,Motaz, AU - Lillemoe,Keith D, AU - Talele,Nilesh, AU - Jain,Rakesh K, AU - DeLaney,Thomas F, AU - Duda,Dan G, AU - Boucher,Yves, AU - Fernández-Del Castillo,Carlos, AU - Hong,Theodore S, PY - 2019/5/31/pubmed PY - 2019/5/31/medline PY - 2019/5/31/entrez SP - 1020 EP - 1027 JF - JAMA oncology JO - JAMA Oncol VL - 5 IS - 7 N2 - 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. SN - 2374-2445 UR - https://www.unboundmedicine.com/medline/citation/31145418/Total_Neoadjuvant_Therapy_With_FOLFIRINOX_in_Combination_With_Losartan_Followed_by_Chemoradiotherapy_for_Locally_Advanced_Pancreatic_Cancer:_A_Phase_2_Clinical_Trial_ L2 - https://jamanetwork.com/journals/jamaoncology/fullarticle/10.1001/jamaoncol.2019.0892 DB - PRIME DP - Unbound Medicine ER -