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https:/doi.org/10.1177/1758835919853196 https:/doi.org/10.1177/1758835919853196Therapeutic Advances in Medical O 1Ther Adv Med Oncol2019,Vol.11:1 13DOI:10.1177/1758835919853196 The Author(s),2019.Article reuse guidelines: Commons Non Commercial CC BY-NC:This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http:/www.creativecommons.org/licenses/by-nc/4.0/)which permits non-commercial use,reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages(https:/ ductal adenocarcinoma(PAC)is a lethal disease with a devastating 5-year overall sur-vival(OS)of approximately 7%.Although,just 4%of all malignant diseases are attributed to PAC,it is projected to become the second leading cause of cancer-related deaths in the United States before 2030.1 Since the introduction of the new chemotherapy regimens including albumin-bound paclitaxel(nab-paclitaxel)plus gemcitabine and FOLFIRINOX,after the gemcitabine monother-apy era,survival of patients with PAC has improved.2,3 This led to a change in the before rather theoretical debate about second-line treat-ment in the management of PAC and opened the clinical field for the exploration of continuum of care strategies.In 2015,there was the first approval of a second-line treatment option for patients with advanced PAC who have been previously treated with gemcitabine-based chemotherapy based A real-world analysis of second-line treatment options in pancreatic cancer:liposomal-irinotecan plus 5-fluorouracil and folinic acidMarkus Kieler,Matthias Unseld,Daniela Bianconi,Werner Scheithauer and Gerald W.PragerAbstractBackground:Nanoliposomal irinotecan(nal-IRI)plus 5-fluorouracil/leucovorin(5-FU/LV)is a novel treatment option for gemcitabine-pretreated metastatic pancreatic adenocarcinoma(PAC)patients,but real-world evidence is rare.Our aim was to determine the effectiveness and tolerability of this regimen in advanced PAC patients and to compare it with oxaliplatin plus fluoropyrimidines in the second-line setting after failure of gemcitabine.Methods:This is a retrospective single-center analysis of all patients who have been treated with nal-IRI plus 5-FU/LV.To compare its effectiveness with other second-line treatment options,all patients who had received oxaliplatin plus fluoropyrimidines after gemcitabine-based chemotherapy were also eligible for analysis.Results:Fifty-two patients were treated with nal-IRI plus 5-FU/LV between April 2016 and August 2018.The median progression-free survival(PFS)was 3.84 months and the median overall survival(OS)was 6.79 months.Median OS from the beginning of the treatment for advanced disease was 19.9 months.Median PFS in patients that received nal-IRI plus 5-FU/LV as second-line treatment after gemcitabine-based chemotherapy was 4.49 months whereas median PFS in a matched cohort of patients treated with oxaliplatin plus fluoropyrimidines was 3.44 months(p=0.007).Between these two groups the median OS of patients with CA 19-9 levels above the statistical median(772.8 kU/l)differed significantly(9.33 versus 6.18 months,p=0.038).Conclusion:Our data confirms the effectiveness of nal-IRI plus 5-FU/LV treatment as a well-tolerated regimen in the treatment of advanced PAC and extends available data on its use as a second-line treatment option when compared with oxaliplatin plus fluoropyrimidines.Keywords:5-fluorouracil,liposomal irinotecan,oxaliplatin,pancreatic cancer,second-line treatmentReceived:23 October 2018;revised manuscript accepted:12 April 2019.Correspondence to:Gerald W.Prager Department of Medicine I,Division of Oncology,Comprehensive Cancer Center,Medical University Vienna,Waehringer Guertel 1820,1090 Vienna,Austria gerald.pragermeduniwien.ac.atMarkus Kieler Matthias Unseld Daniela Bianconi Werner Scheithauer Department of Medicine I,Division of Oncology,Comprehensive Cancer Center,Medical University Vienna,Austria853196TAM0010.1177/1758835919853196Therapeutic Advances in Medical OncologyM Kieler,M Unseldresearch-article20192019Original ResearchTherapeutic Advances in Medical Oncology 112 the results of the phase III NAPOLI-1 trial.4 In this trial,417 patients with metastatic PAC were randomized to three treatment arms and the combination treatment with nanoliposomal irinotecan(nal-IRI)and 5-fluorouracil/leucovorin(5-FU/LV)demonstrated superior survival com-pared with 5-FU/LV monotherapy(median OS of 6.1 versus 4.2 months;p=0.012).Real-world clinical data about safety,effective-ness,dosing schedules as well as integration in a continuum of care treatment algorithm is still rare and therefore important to expand our knowledge on the performance of this therapy.Thus,we aimed to summarize our clinical experience with the use of nal-IRI plus 5-FU/LV by this retro-spective,single-institution analysis.Furthermore,we compared the clinical effectiveness of matched second-line treatments cohorts who received either the combination treatment of nal-IRI plus 5-FU/LV or oxaliplatin plus fluoropyrimidines,which is another available second-line treatment option in the management of patients with advanced PAC after failure of gemcitabine.57Materials and methodsSubjects and study designThis is a single-center,retrospective,observational study including patients with histologically proven nonresectable PAC that was either locally advanced or metastasized who were treated at the Medical University of Vienna between January 2012 and August 2018.For the primary study cohort the data for all patients that received treatment with one or more doses of nal-IRI plus 5-FU/LV was retrieved.For the comparison of second-line sys-temic treatments the data for all patients who had received combination treatment with nal-IRI and 5-FU/LV or oxaliplatin and fluoropyrimidines as second-line treatment after gemcitabine-based first-line treatment was received.The electronic medical history was queried for patient demo-graphics,performance status Eastern Cooperative Oncology Group(ECOG),date of diagnosis,date of advanced disease,diagnosis and carbohydrate antigen 19-9(CA 19-9)level at baseline,bilirubin at baseline,prior treatment details and duration,treatment starting dose,treatment dose reduc-tions,treatment duration,adverse events,and pro-gression-free survival(PFS)and OS.All treatment-related adverse events were graded per National Cancer Institute Common Terminology Criteria for Adverse Events(NCI-CTCAE V4.0).To assess effectiveness,the individual patients response was determined every 812 weeks by computed tomography(CT).Disease response was assessed using RECIST version 1.1 criteria.Response was evaluated by independent radiologi-cal review.Date of disease progression on treat-ment and date of death were recorded.Informed consent was obtained for data analysis.The here presented data analysis received prior approval by the ethical committee of the Medical University of Vienna(EK.No.1806/2017)and was performed according to the Helsinki criteria for good scien-tific practice.Descriptive statistics were calculated as mean,median,or percentages as appropriate.PFS was calculated from the time of first treatment admin-istration to disease progression or death.OS was calculated from time of first treatment adminis-tration to death.OS and PFS were depicted by KaplanMeier plots.For subgroup comparisons of these variables,the log rank test and the Breslow test(in the case of nonconstant hazard ratios)were used,respectively.The assessment of constant and nonconstant hazard ratios was based on a graphical approach.Multiple Cox regression analysis was used to investigate the influence of covariates on OS.No formal sample size calcula-tion has been performed because of the retrospec-tive character of the study.Statistical analysis was performed using the open-source R statistical software package,version 3.4.3(The R Foundation for Statistical Computing,Vienna,Austria)and GraphPad Prism Software Prism 7 for Windows,Version 7.03,20 February 2017(GraphPad Software,La Jolla,CA,USA).ResultsPatient characteristicsA total of 52 patients with advanced PAC were identified who received treatment with nal-IRI plus 5-FU/LV at our institution between April 2016 and August 2018.Table 1 lists patient and tumor characteristics of the entire nal-IRI plus 5-FU/LV study cohort.The median age was 64.6 years interquartile range(IQR)58.973.1 years.The majority of patients presented with metastatic disease at the start of treatment with nal-IRI plus 5-FU/LV and only four patients(8%)had locally advanced disease that was technically not resectable.CA 19-9 levels at the time of initiation of treatment were elevated M Kieler,M Unseld et 3Table 1.Characteristics of patients and tumors of the whole study cohort that received nal-IRI plus 5-FU/LV.n=52(%)Median age at diagnosis of advanced disease(years,range)64.6(58.973.1)Gender Male20(38)Female32(62)Stage at beginning of treatment with nal-IRI+5-FU/LV Locally advanced unresectable diseases4(8)Metastatic48(92)CA 19-9 levels in kU/l at onset of treatment with nal-IRI+5-FU/LV within normal range11(21)above normal range38(73)n/a3(6)Median CA 19-9 levels in kU/l at onset of treatment with nal-IRI+5-FU/LV(range)399(304730)Site of metastatic disease Liver36(69)Lung9(17)Peritoneal13(25)Other7(13)Number of metastatic sites 04(8)133(63)213(25)32(4)ECOG performance status 021(40)126(50)21(2)n/a4(8)Prior lines of advanced disease therapy 01(2)130(58)214(27)3 or more7(13)ECOG,Eastern Cooperative Oncology Group;CA 19-9,carbohydrate antigen 19-9;n/a,not available;nal-IRI,nanoliposomal irinotecan;5-FU/LV,5-fluorouracil/leucovorin.Therapeutic Advances in Medical Oncology 114 38 patients(73%)and median CA 19-9 levels were 399 kU/l(IQR 304730 kU/l).Liver was the predominant site of metastatic spread(69%),fol-lowed by peritoneum(25%)and lungs(17%).Nearly two thirds of all patients(63%)had one organ affected from metastasis,whereas 15 patients(29%)had two or more metastatic sites.Most of the patients(90%)had an ECOG performance status of 0 or 1,whereas only one patient(2%)had an ECOG performance status of 2.In four patients(8%)data was not available.A total of 60%of patients received nal-IRI plus 5-FU/LV before third-line treatment and the other 40%of patients received this treatment after sec-ond-line treatment.Concerning the pre nal-IRI systemic treatment,there was one patient(2%)who received nal-IRI due to onset of new meta-static lesions after previous adjuvant treatment with gemcitabine.All other patients experienced disease progression under a gemcitabine-based chemother-apy in a previous treatment line for advanced dis-ease.For a detailed list of administered chemotherapies,we refer the reader to Table 2.Dosing schedules and dose reductionsNearly all patients(98%)started with the full rec-ommended dose of 80 mg/m nal-IRI.The major-ity of patients with a nal-IRI dose reduction(86%)required only one dose reduction;two patients(14%)had two dose reductions.The average dose of patients with at least one dose reduction was 65 mg/m,which is an average rela-tive dose of 81%.A total of 14 patients(27%)received a reduced dose of 5664 mg/m and two patients(6%)subsequently received a reduced dose of 3440 mg/m.The main reason for dose reduction was diarrhea(50%),followed by nau-sea(15%)as well as fatigue,emesis,thrombocy-topenia,neutropenia,and mucositis(each 7%).Details are listed in Table 3.EffectivenessMedian PFS for the entire cohort was 3.84 months and the median OS was 6.79 months.Two patients had a complete response(4%)and eight patients a partial response(15%)according to RECIST 1.1 criteria.The overall response rate(ORR)was 19.2%.Fourteen patients(27%)had stable dis-ease(SD).Together,with the responding patients this resulted in a disease control rate(DCR)of 46.2%.A total of 27 patients(52%)experienced immediate disease progression during nal-IRI plus 5-FU/LV and in one patient(2%)data concerning response to therapy was not available.The median OS from beginning of first-line systemic treatment for the entire patient cohort was 19.9 months.For the KaplanMeier curves we refer the reader to Figure 1 and for details to Table 4.When comparing patients who received nal-IRI plus 5-FU/LV in an earlier treatment line(at most second line)opposed to in a later line(third or later line),a significant correlation with PFS but not OS was observed(Figure 2A and B).Median PFS was 4.49 and 3 months p=0.0275;hazard ratio(HR)0.53,95%confidence interval(CI)0.281.01.Dose reductions did not result in Table 2.Administered chemotherapies before nal-IRI treatment.Line of nal-IRI treatment2nd linen=30(%)3rd linen=14(%)4th linen=6(%)5th linen=1(%)Previous therapy Gemcitabine30(100)14(100)6(100)1(100)Nab-paclitaxel25(83)10(71)4(67)1(100)Oxaliplatin0(0)10(71)5(83)1(100)Irinotecan0(0)3(21)4(67)1(100)Fluoropyrimidines0(0)11(79)5(83)1(100)Chemoradiation0(0)1(7)2(33)0(0)Erlotinib0(0)1(7)1(17)0(0)nal-IRI,nanoliposomal irinotecan.M Kieler,M Unseld et 5significant differences in PFS or OS(Figure 2C and D).Patients who had at least one dose reduc-tion compared with none had a median PFS of 4.26 and 3.44 months(p=0.6230;HR 0.86,95%CI 0.461.6)and a median OS of 6.95 and 6.79 months(p=0.7421;HR 0.89,95%CI 0.461.7).A disease control(response or stable disease)in the last treatment line prior to nal-IRI plus 5-FU/LV therapy was significantly associated with PFS and OS(Figure 2E and F).Patients who experienced disease control in the prior treatment line compared with nonresponding patients had a median PFS of 4.36 versus 3.13 months (p=0.0412;HR 0.65,95%CI 0.351.20).The median OS was 10.0 versus 5.9 months (p=0.0105;HR 0.60,95%CI 0.311.17).SafetyThe most common treatment-related adverse events in patients receiving nal-IRI plus 5-FU/LV were anemia,diarrhea,nausea,fatigue,anorexia,and neutropenia.There was only one case with a nonfebrile grade 4 neutropenia.All other higher-grade adverse events were grade 3.Consistent with the toxicity profile of nal-IRI,the majority of these grade 3 adverse events were gastrointestinal symptoms(Table 5).Table 3.Dosing and dose reductions.n=52(%)Starting nal-IRI dose(mg/m)8051(98)561(2)Dose reductionsn=14(%)038(73)112(23)22(4)Reason for dose reduction Diarrhea7(50)Nausea2(15)Vomiting1(7)Fatigue1(7)Emesis1(7)Thrombocytopenia1(7)Neutropenia1(7)Mucositis1(7)Reduced doses 5664 mg/m14(27)3440 mg/m2(4)Average overall dose(mg/m)(%of maximal administrable dose)581(96)Average dose of patients with at least one dose reduction(mg/m)(%of recommended dose)65(81)nal-IRI,nanoliposomal irinotecan.Therapeutic Advances in Medical Oncology 116 of second-line treatment with nal-IRI plus 5-FU/LV after gemcitabine-based chemotherapyTo compare the effectiveness of second-line treat-ments,all patients who received second-line treatment after a gemcitabine-based first line chemotherapy in our cancer center between January 2012 and August 2018 were analyzed.From