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      Response to the Letter to the Editor ‘Reply to “Clinical Safety and Efficacy of Secondary Prophylactic Pegylated G-CSF in Advanced Pancreatic Cancer Patients Treated with mFOLFIRINOX: A Single-center Retrospective Study” by Dr. Peng Chen’

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          Abstract

          The Authors Reply We thank Dr. Chen et al. for their interest in our article, in which we assessed the clinical efficacy and safety of modified FOLFIRINOX (mFOLFIRINOX) combined with secondary prophylaxis using Pegylated granulocyte colony-stimulating factor (Peg G) in advanced pancreatic cancer patients (1). They raised several concerns regarding our study. First, Dr. Chen et al. pointed out that the incidence of grade 3 or 4 anorexia and nausea was lower in our study than in a previous study in which pancreatic cancer patients were treated with FOLFIRINOX combined with primary prophylaxis using Peg G (2). Thus, the incidence of these non-hematological toxicities accompanied by mFOLFIRINOX and Peg G was comparable to that of mFOLFIRINOX combined with primary prophylaxis using Peg G studies (3-5) and mFOLFIRINOX-only studies (6, 7). These previous findings along with our own suggest that FOLFIRINOX combined with using Peg G might increase the incidence of anorexia and nausea compared with mFOLFIRINOX with or without Peg G. However, we must be cautious regarding the interpretation of the data obtained by our group and Terazawa et al. (2), since the numbers of patients enrolled in both studies are limited. Thus, the incidence of nausea and anorexia accompanied by mFOLFIRINOX combined with Peg G needs to be re-evaluated in future studies including a larger number of patients. Dr. Chen et al. raised another issue regarding the incidence of bone pain accompanied by multiple Peg G injections. As they pointed out, multiple G-CSF injections often induce bone pain. Unexpectedly, we did not experience the discontinuation of mFOLFIRINOX regimen due to musculoskeletal pain in this study despite multiple injections of Peg G. The lack of patients complaining of musculoskeletal pain might be attributed to the fact that the primary disease in our study was advanced pancreatic cancer, and many patients were being administered non-steroidal anti-inflammatory drugs (NSAIDs) for cancer-related pain relief. Given that NSAIDs are effective in relieving both bone pain and cancer-related pain, it is likely that the administration of NSAIDs might have ameliorated bone pain. Finally, Dr. Chen et al. argue that it is too early to determine the cost-effectiveness of mFOLFIRINOX combined with Peg G. We agree with this opinion and feel that large-scale, multi-center prospective trials will be required in order to determine the cost-effectiveness. Such future studies will be useful for assessing not only the cost-effectiveness but also the non-hematological toxicities of mFOLFIRINOX combined with Peg G. The authors state that they have no Conflict of Interest (COI).

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          Neoadjuvant modified (m) FOLFIRINOX for locally advanced unresectable (LAPC) and borderline resectable (BRPC) adenocarcinoma of the pancreas.

          For patients with metastatic pancreatic cancer, FOLFIRINOX (fluorouracil [5-FU], leucovorin [LV], irinotecan [IRI], and oxaliplatin) has shown improved survival rates compared with gemcitabine but with significant toxicity, particularly in patients with a high tumor burden. Because of reported response rates exceeding 30 %, the authors began to use a modified (m) FOLFIRINOX regimen for patients with advanced nonmetastatic disease aimed at downstaging for resection. This report describes their experience with mFOLFIRINOX and aggressive surgical resection.
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            Final analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer

            Background: Modifications of FOLFIRINOX are widely used despite the absence of prospective data validating efficacy in metastatic disease (metastatic pancreatic cancer (MPC)) or locally advanced pancreatic cancer (LAPC). We conducted a multicentre phase II study of modified FOLFIRINOX in advanced pancreatic cancer to assess the impact of dose attenuation in MPC and efficacy in LAPC. Methods: Patients with untreated MPC or LAPC received modified FOLFIRINOX (irinotecan and bolus 5-fluorouracil reduced by 25%). Adverse events (AEs) were compared with full-dose FOLFIRINOX. Response rate (RR), median progression-free survival (PFS) and median overall survival (OS) were determined. Results: In total, 31 and 44 patients with LAPC and MPC were enrolled, respectively. In MPC, efficacy of modified FOLFIRINOX was comparable with FOLFIRINOX with RR 35.1%, OS 10.2 months (95% CI 7.65–14.32) and PFS 6.1 months (95% CI 5.19–8.31). In LAPC, efficacy was notable with RR 17.2%, resection rate 41.9%, PFS 17.8 months (95% CI 11.0–23.9) and OS 26.6 months (95% CI 16.7, NA). Neutropenia (P<0.0001), vomiting (P<0.001) and fatigue (P=0.01) were significantly decreased. [18F]-Fluorodeoxyglucose positron emission tomography imaging response did not correlate with PFS or OS. Conclusions: In this first prospective study of modified FOLFIRINOX in MPC and LAPC, we observed decreased AEs compared with historical control patients. In MPC, the efficacy appears comparable with FOLFIRINOX. In LAPC, PFS and OS were prolonged and support the continued use of FOLFIRINOX in this setting.
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              Modified FOLFIRINOX regimen with improved safety and maintained efficacy in pancreatic adenocarcinoma.

              FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, and irinotecan) as compared with gemcitabine in pancreatic cancer (PC) has superior activity and increased toxicity. The bolus 5-FU contributes to the toxicity. We hypothesized that the elimination of bolus 5-FU and use of hematopoietic growth factor will improve the safety profile without compromising the activity of FOLFIRINOX.
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                Author and article information

                Journal
                Intern Med
                Intern. Med
                Internal Medicine
                The Japanese Society of Internal Medicine
                0918-2918
                1349-7235
                18 November 2019
                15 March 2020
                : 59
                : 6
                : 879
                Affiliations
                [1 ]Department of Gastroenterology and Hepatology, Kindai University Hospital, Faculty of Medicine, Japan
                Author notes

                Correspondence to Dr. Kentaro Yamao, k-yamao@ 123456med.kindai.ac.jp

                Article
                10.2169/internalmedicine.3958-19
                7118373
                31735800
                a38c511f-16a4-464b-a8a9-43ec0d076f8c
                Copyright © 2020 by The Japanese Society of Internal Medicine

                The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit ( https://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 24 September 2019
                : 29 September 2019
                Categories
                Letters to the Editor

                pegylated g-csf,mfolfirinox,pancreatic cancer
                pegylated g-csf, mfolfirinox, pancreatic cancer

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