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1、5406|Cancer Medicine.2020;9: January 2020|Revised:13 May 2020|Accepted:26 May 2020DOI:10.1002/cam4.3229 O RIG I NA L R E SEA RCHModified gemcitabine plus nab-paclitaxel regimen in advanced pancreatic ductal adenocarcinomaJane E.Rogers1|Jonathan D.Mizrahi2|LianchunXiao3|ChirayuMohindroo4|Rachna T.Shr

2、off5|RobertWolff5|Gauri R.Varadhachary5|Milind M.Javle5|MichaelOverman5|David R.Fogelman5|Kanwal P.S.Raghav5|ShubhamPant5,6|FlorenciaMcAllister4,5,71Pharmacy Clinical Programs,University of Texas MD Anderson Cancer Center,Houston,TX,USA2Department of Cancer Medicine,University of Texas MD Anderson C

3、ancer Center,Houston,TX,USA3Department of Biostatistics,University of Texas MD Anderson Cancer Center,Houston,TX,USA4Department of Clinical Cancer Prevention,University of Texas MD Anderson Cancer Center,Houston,TX,USA5Department of Gastrointestinal Medical Oncology,University of Texas MD Anderson C

4、ancer Center,Houston,TX,USA6Department of Investigation Cancer Therapeutics,University of Texas MD Anderson Cancer Center,Houston,TX,USA7Clinical Cancer Genetics Program,University of Texas MD Anderson Cancer Center,Houston,TX,USAThis is an open access article under the terms of the Creative Commons

5、 Attribution License,which permits use,distribution and reproduction in any medium,provided the original work is properly cited.2020 The Authors.Cancer Medicine published by John Wiley&Sons Ltd.CorrespondenceJane E.Rogers,Clinical Pharmacy Specialist,U.T.M.D.Anderson Cancer Center,1515 Holcombe Blvd

6、,Unit 377,Houston,TX 77030,USA.Email:jerogersmdanderson.orgPresent addressRachna T.Shroff,University of Arizona Cancer Center,Phoenix,AZ,USAFunding informationFM was supported by V Foundation,Paul Calabresi K12(NCI grant awarded to MDACC K12CA088084-16A1),Sabin Family Foundation,and AGA Foundation.A

7、bstractBackground:Gemcitabine(GEM)plus nab-paclitaxel(NabP)(GEM 1000mg/m2 IV over 30minutes+NabP 125mg/m2 IV given days 1,8,and 15 every 28days)is one of the two standard of care combination therapies for metastatic pancreatic ductal adenocarcinoma(PDAC).Our cancer center has utilized GEM-NabP given

8、 every two-weeks due to tolerability and patient convenience.Here,we review the safety and efficacy of this modified regimen.Methods:Metastatic PDAC patients(pts)who initiated front-line or second-line GEM-NabP during 2013-2017 were retrospectively reviewed.Primary objective was overall survival.Sec

9、ondary objectives were disease control rate,progression-free survival,and the incidence of dose delays and/or adjustments.Results:From a total of 235 patients,140 pts received GEM-NabP front-line while 95 pts received GEM-NabP second-line.Median dosing was 600mg/m2 at fixed-dose rate for GEM and 125

10、mg/m2 for NabP given predominantly(90%)every two-weeks.Eastern Cooperative Group performance status of 0 and 1 pts had front-line OS of 12.7 and 9.6months and when given second-line had OS of 8months and 7.3months,respectively.ECOG 0 and 1 pts had front-line progression-free survival(PFS)of 5.3month

11、s and 2.8months and second-line PFS was 3.5months and 2.4 months,respectively.Treatment was well tolerated with limited dose modifications.|5407ROGERS Et al.1|INTRODUCTIONPancreatic ductal adenocarcinoma(PDAC)accounts for 90%of pancreatic cancers.1-3 PDAC continues to carry a dismal prognosis and re

12、presents the fourth most common cause of cancer-related deaths in both the United States and Europe.1,4 Overall 5-year survival rate is 9%and declines further to less than 3%in patients with distant disease.5 In the Unites States,pancreatic cancer is projected to be the second most common cause of c

13、ancer related death by 2030.3Historically,gemcitabine(GEM)monotherapy was the standard front-line therapy approved based on clinical benefit and limited survival improvement for metastatic patients.6 GEM-based chemotherapy combinations tri-als were conducted following GEM approval;however,a standard

14、 combination failed for years to emerge,and treat-ment advancement stalled until 2011.At that time,Conroy et al established a pivotal metastatic PDAC management advancement.7 The investigators conducted a phase II-III multicenter,randomized controlled trial in patients with an Eastern Cooperative On

15、cology Group performance status of 0 or 1 comparing standard of care GEM alone to a fluo-ropyrimidine combination regimen of 5-fluorouracil+leu-covorin+oxaliplatin+irinotecan(FOLFIRINOX).Median OS and progression-free survival(PFS)were improved in the FOLFIRINOX arm(P.001).Median OS advantage was ap

16、proximately 4months(FOLFIRINOX median OS 11.1months vs GEM median OS 6.8months,P.001)and median PFS advantage of 3months(FOLFIRINOX median PFS 6.4months vs GEM median PFS 3.3months,P.001).Front-line FOLFIRINOX became the standard of care for metastatic PDAC patients able to tolerate intensive therap

17、y.In 2013,Von Hoff et al(MPACT trial)reported the results of a multicenter phase III-randomized trial in patients with Karnofsky performance status score of 70 or more compar-ing GEM+nab-paclitaxel(NabP)to GEM alone in meta-static PDAC.8 The combination consisted GEM 1000mg/m2 intravenous(IV)over 30

18、minutes+NabP at 125mg/m2 IV given over 30minutes on days 1,8,and 15 every 4weeks.Similar to FOLFIRINOX,the combination regi-men improved outcomes compared to GEM alone.Median OS advantage was 2 months(Gem-NabP median OS 8.5months vs GEM median OS 6.7months,P.001)and median PFS advantage was 2 months

19、(Gem-NabP median PFS 5.5months vs GEM median PFS 3.7months,P.001).Thus,Gem-NabP became a second standard of care option for metastatic PDAC.The combination did re-sult in the need for dose reductions in NabP for 41%of pa-tients,mostly due to neurotoxicity,and in GEM for 47%of patients,mostly due to

20、neutropenia and leukopenia.This regimen allowed for an alternate front-line combination to FOLFIRINOX.Both combination regimens(FOLFIRINOX and GEM+NabP)are incorporated currently in the front-line treatment of locally advanced and metastatic PDAC.1,2 At our institution,GEM-NabP is often prescribed i

21、n an every two-week schedule for tolerability and patient convenience allowing for decreased infusion times and follow-up visits.The purpose of this retrospective analysis was to review the safety and efficacy of this every two-week regimen while characterizing our dosing practices in metastatic PDA

22、C patients.2|MATERIALS AND METHODSOur study was a single institution,retrospective chart review of patients with metastatic PDAC who received GEM-NabP front-line or second-line.Adult metastatic PDAC patients who initiated this regimen from June 1,2013 to July 1,2017 were included.Patients must have

23、received this treat-ment at our center along with radiographic follow-up every 8-12 weeks at our center.Patients who received recom-mendations from our center but received therapy elsewhere were excluded.Patients with unresectable locally advanced disease were excluded.OS was our primary objective.S

24、econdary objectives were PFS and disease stability/regres-sion(disease control)vs progression on first radiographic evaluation.Any response or stable disease by radiology re-view was classified as disease control.Toxicity was evalu-ated based on the need for dose delays/reductions or when patients w

25、ere admitted.The reasons for dose delays and admissions were collected.Common Terminology Criteria for Adverse Effects(CTCAE)version 49 was utilized to de-termine adverse effect grade retrospectively when toxicities Conclusion:Our analysis revealed safety with every two-week low dose GEM-NabP while

26、maintaining efficacy.Patient schedule convenience should factor into meta-static incurable malignancies.We suggest the use of every two-week GEM-NabP particularly in patients desiring a modified schedule.K E Y W O R D Scarcinoma,pancreatic ductal,gemcitabine,nab-paclitaxel,pancreatic neoplasms5408|R

27、OGERS Et al.requiring dose delays/reductions or requiring admission occurred.Data collection included patient demographics(age,gender,race,ECOG performance status)and tumor charac-teristics(metastatic disease sites,primary tumor location).Treatment factors collected were GEM-NabP starting date,start

28、ing dose,and chemotherapy schedule.Patients who initiated a 3week on 1week off schedule were reviewed whether the schedule was modified to an every two-week schedule.Patients who received GEM-NabP second-line had their first-line regimen documented and whether they received therapy in the third-line

29、 setting.Additionally,date of progression,date of death or last follow-up,and the inci-dence and reason for dose delays and/or adjustments were included.2.1|EthicsOur institutional review board approved our study.A waiver of consent was granted given the minimal risk of a retrospec-tive evaluation.2

30、.2|Statistical analysisStatistical analysis was performed using descriptive statis-tics.Continuous variables were described using median and range while categorical data were summarized using frequen-cies and percentages.Chi-squared test/Fishers exact test and Wilcoxon rank sum test were used to eva

31、luate the association between response and patient characteristics.The Kaplan-Meier method was used to estimate survival outcomes,the log rank test and univariable Cox models were applied to evaluate the association between survival outcomes and co-variates.OS,the primary objective,was calculated as

32、 the time between treatment start to death or last follow-up date.PFS was defined as the time between treatment start date to treatment discontinuation for progressive disease,perfor-mance status decline,toxicity,patient preference,or death/last follow-up.Disease control was defined as any response

33、plus stable disease at first radiographic scan.3|RESULTS3.1|First-line GEM-NabP resultsOne hundred and forty patients received GEM-NabP in the front-line setting.Median age was 67 yo with just over half(58.6%)male.Most patients(71.4%)were Caucasian and had an ECOG performance status of 0-1(65%).Pati

34、ent character-istics and demographics are listed in Table1.Primary tumor location most often was in the head of the pancreas,and half of patients had metastatic disease to more than one organ.Most common organs involved were liver,peritoneum,and lung.Other sites include adenopathies,bone,ascites,adr

35、enal,pleura,ovaries,breast,and spleen.Median dosing of GEM was 600mg/m2(range:400mg/m2 to 750mg/m2)given over 10mg/m2/minute+NabP at 125mg/m2(range:65mg/m2 to 200mg/m2)given over 30minutes.Of note,our institu-tions standard of care practice is to administer GEM at a fixed-dose rate(10mg/m2/min)to ma

36、ximize GEM phospho-rylation as described in the E6201 trial10 while our institution additionally reduces the GEM dose to 600mg/m2 or 750mg/m2.The majority of our patients(86%)received GEM-NabP every two-weeks.Patients(13.5%;n=19)that started ther-apy on a three weeks on one week off regimen were mos

37、tly(n=12)converted to an every two-week regimen due to tox-icity(most frequently neutropenia).Outcomes are listed in Table2.The overall population median OS was 7.5months.In patients with an ECOG of 0 or 1,median OS was 12.7months and 9.6months,respec-tively(Figure1).Overall median PFS of the entire

38、 population was 2.8months.In patients with an ECOG of 0 or 1,median PFS was 5.3months and 2.8months,respectively(Figure2).Patients with an ECOG of 2 had a median OS and median PFS of 5.3months and 1.8months,respectively(Figure1 and 2).Disease stability/regression(disease-control)on first scan was 48

39、.6%.Disease progression was the main reason for patients to stop GEM-NabP(n=105;75%).Other rea-sons that were termed progression were patient choice/loss to follow up(n=8),performance status decline due to can-cer or noncancer complication(n=18),or toxicity(n=6).Three patients were transitioned to c

40、apecitabine maintenance(n=2)or had yet to progress on GEM-NabP(n=1)at the time of data collection.Toxicity reasons for stopping GEM-NabP were pneumonitis(n=3),persistent myelosuppres-sion(n=2),and myalgias(n=1).No patient deaths were attributed to GEM-NabP toxicity.For those patients with recorded d

41、eath dates,the cause of death was attributed to cancer progression due to no further standard treatment op-tions,performance status decline,organ dysfunction not suit-able for treatment,complications from cancer(ie,pulmonary embolism,gastrointestinal bleed,hepatic failure,respiratory failure),noncan

42、cer related comorbidity(ie,cerebrovascular accident,renal failure),or as a result of the patients decision to stop therapy.Forty-six percent(n=64;45.7%)received second-line therapy following progression.Most patients received a fluoropyrimidine-based combination therapy in the sec-ond-line setting(F

43、OLFIRINOX;5-FU plus oxaliplatin;5-FU plus irinotecan/liposomal irinotecan).Those with gemcit-abine-based therapy in the second-line setting generally uti-lized triplet combination by adding on an additional agent(capecitabine or cisplatin)to GEM-NabP.Approximately|5409ROGERS Et al.TABLE 1 Overall Pa

44、tient CharacteristicsCharacteristicsFirst Line-GEM-NabPN(%)N=140Second-Line GEM-NabPN(%)N=95MPACT First-Line GEM-NabPN(%)N=431AgeMedian=67 yoMedian=59 yoMedian=62 yoRange=37-83 yoRange=20-78 yoRange=27-86 yo65 yo=40%65 yo=67(70%)65 yo=60%65 yo=28(30%)65 yo=177(41%)GenderMale82(58.6%)50(52.6%)245(57%

45、)Female58(41.4%)45(47.4%)186(43%)Pancreatic mass locationHead65(46.4%)47(49.5%)191(44%)Body41(29.3%)32(33.7%)132(31%)Tail33(23.6%)16(16.8%)105(24%)Undefined1(0.7%)3(1%)EthnicityCaucasian100(71.4%)68(71.6%)378(88%)African American15(10.7%)11(11.6%)16(4%)Hispanic5(3.6%)5(5.3%)25(6%)Arabic11(7.9%)3(3.2

46、%)Middle Eastern4(2.9%)3(3.2%)Other5(3.6%)2(2.1%)12(3%)NR3(3%)ECOG Performance Status021(15%)17(20.7%)NR170(50%)61(74.4%)NR226(18.6%)4(4.9%)NR31(0.7%)NRNR22(15.7%)13NRKarnofsky Performance status score100NRNR69(16%)90NRNR179(42%)80NRNR149(35%)70NRNR30(7%)60NRNR2(1%)Level of carbohydrate antigen 19-9

47、a Normal(or=35 U/mL)24(17.1%)14(14.7%60(16%)or=59 ULN64(45.7%)33(34.7%)197(52%)Carbohydrate antigen 19-9 U/mla Median156311452293.7Range1 1,381,0001 275,6001.9-6,159,233Metastatic disease sitesDiffuse71(50.7%)42(44.2%)338(92%)Single site69(49.3%)53(55.8%)33(8%)Site of metastatic diseaseLiver90(64%)6

48、0(63.2%)365(85%)Lung41(29%)27(28.4%)153(35%)Peritoneum40(29%)25(26%)60(14%)Abbreviations:ECOG,Eastern cooperative oncology group;NR,not reported;yo,years old.aCarbohydrate antigen 19-9 level at the start of GEM-NabP.TABLE 1(Continued)|5411ROGERS Et al.Outcomes are listed in Table2.The overall popula

49、tion median OS was 7.6months.In patients with an ECOG of 0 or 1,median OS was 8months and 7.3months,respectively.The overall population median PFS was 2.5months.In pa-tients with an ECOG of 0 or 1,median PFS was 3.5months and 2.4months,respectively.Patients with an ECOG of 2 had a median OS of 6.1mo

50、nths and median PFS of 2.6months,respectively.Disease stability/regression(disease-control)on first scan was 40%.The main reason for discontinuation of GemNabP was disease progression(n=89;94%).Other reasons were cancer complication(n=2),patients request(n=2),and progressive myelosuppression with an