Comparative efficacy of modified FOLFIRINOX, plus capecitabine and gemcitabine plus nab-paclitaxel as adjuvant treatment for resected : a Bayesian network meta-analysis

Victor Hugo Fonseca de Jesus and Rachel P Riechelmann

Medical Oncology Department, A.C. Camargo Cancer Center, Rua Prof. Antônio Prudente 211, São Paulo SP 01509-010, Brazil

Abstract

Background: There are no head-to-head comparisons evaluating the efficacy of the main polychemotherapy regimens used for patients with pancreatic cancer in the adjuvant set- ting. We aimed to describe the relative efficacy of modified FOLFIRINOX (mFOLFIRI- NOX), gemcitabine plus capecitabine (GEM-CAP) and gemcitabine plus nab-paclitaxel (GEM-NAB) in this setting using a Bayesian network approach.

Methods: We collected data from the ESPAC-4, PRODIGE 24 and APACT trials. Disease- free survival (DFS), according to the investigators, and overall survival (OS) for the three Review polychemotherapy regimens were compared using gemcitabine as the reference arm. We ran Markov chain Monte Carlo simulations with a fixed-effect model to generate the posterior distribution of the hazard ratios (HRs) using non-informative priors. Relative efficacy was measured by HRs, surface under cumulative ranking and rankograms.

Results: mFOLFIRINOX was the most likely to be the most effec- tive in the adjuvant setting (98.9% and 89.6% probability for DFS and OS, respectively). Correspondence to: Victor Hugo Fonseca de Jesus GEM-NAB marginally improved DFS (HR = 0.97, 95% credible interval (95% CrI) = 0.77– Email: [email protected] 1.21) and OS (HR = 0.98, 95% CrI = 0.76–1.25) when compared to GEM-CAP. However, ecancer 2021, 15:1276 GEM-NAB had the highest chances of being the second most active chemotherapy regi- https://doi.org/10.3332/ecancer.2021.1276 men (61.4% and 52.5% probability for DFS and OS, respectively), whereas GEM-CAP was Published: 16/08/2021 less likely to represent the second most active regimen (37.7% and 40.1% probability for Received: 23/10/2020 DFS and OS, respectively). Publication costs for this article were supported by Conclusion: For patients eligible and fit enough to undergo adjuvant treatment with ecancer (UK Charity number 1176307). mFOLFIRINOX, this constitutes the treatment of choice. For those with contraindications Copyright: © the authors; licensee to mFOLFIRINOX, while both GEM-NAB and GEM-CAP can be considered appropriate ecancermedicalscience. This is an Open Access alternatives, GEM-NAB is likely the most effective regimen. article distributed under the terms of the Creative Commons Attribution License (http:// Keywords: FOLFIRINOX, gemcitabine, capecitabine, nab-paclitaxel, adjuvant, pancreatic, creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and cancer reproduction in any medium, provided the original work is properly cited.

ecancer 2021, 15:1276; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2021.1276 1 weeks. For alltreatments, theplanned adjuvant treatment duration was 24 weeks. once a week for three every 4 weeks. Incontrol the of arms trials, patients the received gemcitabine 1,000mg/m once every 2 weeks. Inexperimental the ofarm the APACTpatients trial, received nab-paclitaxel 125mg/m citabine 1,000 mg/mcitabine ecancer 2021, 15:1276; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1276 [20] andthe APACT trials[21]. Meetingpresentation for the APACT trial original publicationsthe for ESPAC-4 the Data regardingand exclusion theinclusion criteria, thecharacteristics of thestudies’ populations andthetoxicity profile were extracted from Data extraction and collection Methods therapy regimens usingsingle-agent gemcitabine asthereference treatment. processdecision-making the [19].Our aim was torelativethe establish efficacy andto compare thetoxicity profile of eachof thesechemo- throughrandomised aretrials notavailable. An advantage of thisapproach isthat onecangenerate probabilistic results thatcan support methodology allows usto infer theprobable gains(e.g.,of inOS) anintervention over another when formal direct comparisons of therapies be ever pursuedin acontrolled setting. Thus, we analysedresults the of thesetrialsusingaBayesian network meta-analysis framework. This At thismoment, there are norandomisedtrials directly comparing thesethree chemotherapy regimens comparisons andsuch are unlikely to 24 (modified FOLFIRINOX) [17] andthe APACT (gemcitabine nab-paclitaxel plus (GEM-NAB))[18]. trials improved overall survival (OS) combinationwith chemotherapy: theESPAC-4 (gemcitabine pluscapecitabine(GEM-CAP)) [16],thePRODIGE disease. While two randomisedtrials showed nobenefitof addingerlotinib to gemcitabine [14,15],three randomised trialsdemonstrated randomised trials were designed to assess whether patients could benefit from treatment intensification in thesetting of less advanced With theriseof polychemotherapy regimensas FOLFIRINOX such andgemcitabine-based combinations inthemetastatic setting [11–13], (7.5% versus 14.0%). As aresult, gemcitabine becamethestandard chemotherapy regimen inthisscenario. that therewhile were nodifferences insurvival, gemcitabine was associated with lower rates of treatment-related seriousadverse events pancreaticlocalised cancer, respectively. Subsequently,two these drugs were compared intheESPAC-3trial [10]. The authors demonstrated InESPAC-1 thissense,the treatment modality isusedinisolation [6]. patients are candidates for curative-intent surgery [5].Moreover, for thosesubmitted to surgery, survival outcomes are dismal when this grow significantlytodecade inthe come. This highlethality rate ispartially related to thediseasestage at diagnosis.Only 15%–20%of the from developed [2,3]anddeveloping [4]countries suggest that theburden of pancreatic neoplasmsincancer epidemiology isexpected to same year,represented it seventh the commonmost ofcause cancer-related mortality, with 432,242estimated deaths. Furthermore, data Pancreatic cancer currently stands as the 14thmostcommon of type cancer worldwide, with 458,918 estimated cases in 2018 Background In theexperimental armof theESPAC-4 trial,patients received capecitabine1,660mg/m Treatment schedules received 5-Fluorouracil2,400 mg/m 2 once a week for three every 4 weeks. In thePRODIGE 24study, patients assignedto combination chemotherapy and the CONKO-001[7] andthe 2 (46-hour continuousinfusion), 150mg/m [18]. Additionally, updated survival data were extracted from recentpresentations for theESPAC-4 [16] andPRODIGE24 [17]trialsandfrom the2019 American Society of Medical Oncology Annual [8, 9]have establishedtherole of 5- andgemcitabine inthetreatment of 2 2 , 85mg/m for 21days followed by a7days’ rest plusgem- 2 andgemcitabine 1,000mg/m 2 andfolinic acid400mg/m 2 weekly for three every 4 [1]. In the 2 2 2

Review ecancer 2021, 15:1276; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1276 suggested modelconvergence for allcomparisons of HRs. the populations were homogenous enoughfor thetransitivity assumption to be valid. The assessment of theBrooks–Gelman–Rubin plots stagewith IIIdisease.Despite thesedifferences, we considered that, basedonthesimilar inclusionandexclusion criteria amongthetrials, marginsresection), (R1 a highratewith seenparticularlyESPAC-4 inthe trial.Moreover, patients intheESPAC-4 trialmore often presented ofdistribution the patients’ characteristicsacross trials. We noted significant differences intherate of microscopically involved resection Table 1describesthecharacteristicsof thestudies’ populations. Despite similar inclusionandexclusion criteria, we observed differences in APACT studiesexcluded patients with post-operative Carbohydrate antigen 19-9(CA 19-9)levels above 180and100UI/mL, respectively. Importantly, both ESPAC-4 and APACT mandated a CT scanat least3months before patient registration. Lastly, thePRODIGE 24andthe old or above were notin thePRODIGE included 24 study. Also, theESPAC-4 study allowed for theenrolment of patients ECOGwith PS2. performance status0 or (PS) 1at randomisation. However, slight differences amongthestudies’ protocols were noted. Patients aged 80 years to microscopically complete (R0)or incomplete (R1)resection. Also, patients shouldpresent anEastern Cooperative Oncology Group(ECOG) be 18 should trials in these included years oldor above, havepathological the diagnosisof adenocarcinoma ductal andhave beensubmitted The network isshown map inFigure 1.Overall,presented thestudies similar inclusionandexclusion criteria –Supplementary Results comparisons of categorical variables across studiesandthegraphics were usingthesoftware carriedout R version 3.6.0. test or chi-square test. Bayesian analyses were conducted usingthesoftware WinBUGS version 1.4.3(MRC Biostatistics Unit, Cambridge, UK). The treatments andthetotal number of cycles of theMCMC. We compared thedistributionof categorical variables across studies with Fisher’s exact the ratio between thenumber of cycles of theMCMCin treatmentwhich aspecific hadalog HR(effect size) more or lessthantheonesof other cumulative ranking (SUCRA)andplotted treatment ranks againsttheir probabilities usingrankograms [28]. These probabilities were calculated as case)in this hasa95%probability of belongingto suchaninterval [27]. To portray effectiveness, we ranked treatments according to surface under trials). Pairwise comparisons were summarisedusingHRs credible and95% intervals (95%CrIs). By definition, thetrue value of theparameter (HR gence was checked by inspectionof theBrooks–Gelman–Rubin plots [26].Gemcitabine was usedasthereference comparator (common to all thinning). We chosenon-informative priors sothat results of theanalyses would bedriven solely by thedata from thestudies.Parameter conver 40,000 iterations using three chains, we drew 120,000 samples from the posterior distribution (40,000 additional iterations for each chain without able intheSupplementary Material). Briefly, using non-informative priors (mean equalto 0and variance equalto 1,000)andafter aburn-inphaseof [25]. We usedaMarkov chainMonte Carlo(MCMC)method usingGibbs’ samplingalgorithm to perform network meta-analyses (codes are avail- on between-trial heterogeneity for pairwise comparisons. Thus, we employed a pragmatic approach in which we fit a fixed-effect model to the data the limited number of studiesandtheindirect nature of allthecomparisons between polychemotherapy regimens, there would benoinformation selog(HR), respectively. In theSupplementary Material, we have provided formulas andmodelspecifications inaccordance with Hu et al intervals (CIs) (95%CI).Before data manipulation, we usedtheapproach describedby Parmar et al criteria of the studies Before data analysis, we assessed the transitivity assumption by inspecting the characteristics of populationsthe and the inclusion and exclusion Statistical analysis on toxicity. Therefore, data ontoxicity are summarisedusingonly descriptive statistics. any severe or any grade 3–4adverse eventsacross three the studies was not available, we didnot perform a Bayesian network meta-analysis sensitivityspecified analysis of theprimary outcome of the APACT study (independently assessedDFS). Since comparable of depiction either from randomisation to death or disease progression. It was a secondary outcome of the ESPAC-4 and PRODIGE 24 trials, and it was a pre- free-survival (DFS)(relapse-free survivalESPAC-4) inthe intention-to-treatin the population. In allthree trials,it was defined asthetime It was theprimary outcome of theESPAC-4 andthePRODIGE24 trials. As asecondary outcome, we analysed investigator-assessed disease The primary outcome wasintent [22]. Data on time-to-event outcomes (DFS and OS) were extracted using hazard ratios (HRs) and their 95% confidence [23] to convert thesemeasures into log(HR) and Table 1.Patients . Given [24]. Given 3 -

Review Table 1.Characteristics of thestudies’ populations. ecancer 2021, 15:1276; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1276 chemotherapy regimen across linesrepresent studies.Solid direct comparisons. Dashed linesrepresent indirect comparisons. Figure 1.Network map.Eachnoderepresents a chemotherapy regimen. The nodesize reflects the total number of patients treated withaspecific ECOG PS R1resection R0resection Resection margin Female Male Sex Range Median Postoperative CA 19-9(UI/mL) Range Median Preoperative CA 19-9(UI/mL) Unknown 2 1 0 Range Median Age (years) a Gemcitabine N =366(%) 0.1–2448.3 0.9–10761 219 (59.8) 147 (40.2) 154 (42.1) 212 (57.9) 199 (54.4) 158 (43.2) 37–80 0 (0.0) 9 (2.4) 142.5 20.5 65 ESPAC-4 N =364(%) 0.8–76549 GEM-CAP 221 (60.7) 143 (39.3) 162 (44.5) 202 (55.5) 202 (55.5) 150 (41.2) 0.6–8112 12 (3.3) 39–81 0 (0.0) 154.5 17.6 65 Gemcitabine N =246(%) 112 (45.5) 134 (54.5) 111 (45.1) 135 (54.9) 115 (46.7) 127 (51.6) (30–81) 4 (1.6) 0 (0) 64 - - - - PRODIGE 24 FOLFIRINOX N =247(%) 148 (59.9) 105 (42.5) 142 (57.5) 123 (49.8) 122 (49.4) Modified 99 (40.1) (30–79) 2 (<1) 0 (0) 63 - - - -

Gemcitabine N =434(%) 100 (23.0) 334 (77.0) 181 (41.7) 253 (58.3) 166 (38.2) 268 (61.8) 38–86 0 (0.0) 0 (0.0) 12.9 64 - - - APACT N =432(%) GEM-NAB 105 (24.3) 327 (75.7) 204 (47.2) 228 (52.8) 180 (41.7) 252 (58.3) 34–83 0 (0.0) 0 (0.0) 14.31 64 - - - <0.001 <0.001 p value 0.894 - - - b b b 4

Review c b a ecancer 2021, 15:1276; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1276 binationchemotherapy experienced improved investigator-assessed DFS inboth PRODIGE 24and APACT. The relative efficacy interms of No significant difference inDFS according to theinvestigators was observed inESPAC-4 (p=0.069).Conversely, patients treated comwith - The mediandurationof follow-upthree inthe ranged studies from 33.6to 53.3months. Disease-free survival Based onchi-square test; only for categorical variables ECOG PS:Eastern Cooperative Oncology Group (ECOG) performance status Based onFisher’s exact test; only for categorical variables Unknown Yes No Venous resection IV III II I (AJCC 7thEdition) Tumour stage Unknown Yes No Perineural invasion Unknown Yes No Lymphovascular invasion Distal pancreatectomy resection Pylorus-preserving Total pancreatectomy Whipple resection Surgery Range Median Maximum tumour size (mm) Positive Negative Lymph nodes Unknown undifferentiated Poorly differentiated or differentiated Moderately Well differentiated Tumour grade Table 1.Characteristics of thestudies’ populations. 298 (81.4) 325 (88.8) 122 (33.3) 188 (51.4) 299 (81.7) 142 (38.8) 192 (52.5) 63 (17.2) 67 (18.3) 29 (7.9) 29 (7.9) 27 (7.4) 30 (8.2) 0–110 5 (1.4) 5 (1.3) 7 (1.9) 2 (0.5) 30 ------(Continued) 323 (88.7) 326 (89.6) 129 (35.4) 182 (50.0) 288 (79.1) 149 (40.9) 175 (48.1) 39 (10.7) 76 (20.9) 20 (5.5) 15 (4.1) 31 (8.5) 22 (6.0) 32 (8.8) 6–105 2 (0.5) 3 (0.8) 8 (2.2) 30 ------176 (71.5) 226 (91.9) 207 (84.1) 190 (77.2) 178 (72.4) 125 (50.8) 135 (54.9) 69 (28.0) 68 (27.6) 29 (11.8) 79 (32.1) 32 (13.0) 79 (32.1) 14 (5.7) 15 (6.1) 24 (9.8) 13 (5.3) 6–120 5 (2.0) 1 (0.4) 1 (<1) 30 - - - 192 (77.7) 226 (91.5) 205 (83.0) 202 (81.8) 124 (50.2) 188 (76.1) 154 (62.3) 53 (21.5) 26 (10.5) 35 (14.2) 70 (28.3) 59 (23.9) 38 (15.4) 55 (22.3) 12 (4.9) 16 (6.5) 18 (7.3) 8 (3.2) 1 (0.4) 2 (<1) 8–90 30 - - - Table 2describesthesurvival outcomes of thetrials. 117 (27.0) 241 (55.5) 312 (71.9) 122 (28.1) 55 (12.7) 21 (4.8) ------102 (23.6) 264 (61.1) 311 (72.0) 121 (28.0) 49 (11.3) 17 (3.9) ------<0.001 <0.001 <0.001 <0.001 - - - b b b c 5

Review than GEM-CAP (37.7%probability) to bethesecond bestchemotherapy regimen. FOLFIRINOXmodified activesingle most asthe chemotherapy agent (Table 4 ). Additionally, (61.4%probability) GEM-NAB was more likely activethe most chemotherapy amongthefour regimens intheadjuvant setting (Figure 2). The analysis of SUCRA for DFS alsodescribed DFSof chemotherapy each regimen isshownin ecancer 2021, 15:1276; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1276 agent gemcitabine across thethree trials. and APACT (median OS: 37.7 months) trials. However, there were no differences in the relapse-free survival for patients treated with single- = 22.7–28.4) comparedwhen totreated those regimensame the with inthePRODIGE 24(median OS:35.0months; 95%CI=28.7–43.9) Patients who were treated inthegemcitabinearm intheESPAC-4 trialexperienced numerically worse OS(median OS:26.0months; 95%CI There were significant differences in OS across trials for patients undergoing adjuvant treatment single-agentwith gemcitabine (Table ). 2 Outcomes of patients treated withsingle-agent gemcitabine across trials (40.1%) to bethesecond bestchemotherapy regimen. NOXactive asthesinglemost chemotherapy agent (Table 4). Additionally, GEM-NAB(52.5%probability) was more likely thanGEM-CAP chemotherapyfour amongthe regimensadjuvantin the setting (Figure 2). The analysis of SUCRA for OSalsodescribedmodifiedFOLFIRI - motherapy regimen isshown in In allthree trials,patients treated combinationwith chemotherapy experienced longer OS. The relative efficacy interms of OSof eachche- Overall survival CI, Confidence interval; NA,not reached a Table 2.Survival outcomes according to thetreatments across studies. Based onoriginalpublication (not onupdated analysis). For theESPAC-4, administrative censoring occurred at 5 years of follow-up (95% CI) HR (95% CI) Median OS–months OS (95% CI) HR (95% CI) Median follow-up –months (95% CI) Median DFS –months DFS Table 3. According to therankogram, modifiedFOLFIRINOX had89.6%probability of beingthemostactive Gemcitabine (22.7–28.4) (11.7–15.5) N =366 26.0 13.4 1.0 1.0 (39.7–45.5) ESPAC-4 43.2 Table 3. According to therankogram, modifiedFOLFIRINOX hada98.9%probability of being a (0.70–0.99) (23.3–31.2) (0.73–1.00) (12.2–16.9) GEM-CAP N =364 0.84 27.7 0.85 14.2 Gemcitabine (28.7–43.9) (11.7–15.2) N =246 35.0 12.8 1.0 1.0 PRODIGE 24 (30.3–36.0) 33.6 FOLFIRINOX (0.48–0.86) (0.46–0.73) (17.7–27.6) (41.8–NA) Modified N =247 0.64 54.4 0.58 21.6

Gemcitabine N =434 37.7 13.7 53.0 1.0 1.0 - - APACT (0.69–0.97) (0.69–0.97) GEM-NAB N =432 41.8 0.82 0.82 16.6 53.3 - - 6

Review ecancer 2021, 15:1276; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1276 in which thecoefficient of theHR(log HR) for onespecificchemotherapy regimen was greater orlesser thanthose ofthe other chemotherapy regimens. chemotherapy regimen interms of DFS andOS. These rankograms are created by assessingthroughout thecycles from theMCMCrelative frequency Figure 2.Rankograms for DFS andOSshow theprobability that eachchemotherapy regimen has of beingthefirst, second, third and fourth best Table 3.HRs and95%CrIs for DFS andOS. FOLFIRINOX Modified GEM-NAB GEM-CAP Gemcitabine FOLFIRINOX Modified GEM-NAB GEM-CAP Gemcitabine Gemcitabine Gemcitabine (0.48–0.86) (0.69–0.97) (0.71–1.00) (0.46–0.73) (0.70–0.97) (0.73–0.99) 0.65 0.82 0.84 0.58 0.82 0.85 (0.54–1.07) (0.76–1.25) (0.52–0.90) (0.77–1.21) GEM-CAP GEM-CAP 0.77 0.98 0.69 0.97 DFS OS (0.56–1.10) (0.53–0.94) GEM-NAB GEM-NAB 0.79 0.72 FOLFIRINOX FOLFIRINOX Modified Modified

7

Review ecancer 2021, 15:1276; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1276 the cumulative cold-induced peripheral neuropathy (particularly relevant inregions with long winters). recommended ment a fluoropyrimidinewith in patients severewith deficiency DPD isassociated with aprohibitively highriskof severe toxicity andisnot irinotecanto seem besufficient to decreaserisk of the severe toxicity even in patients homozygouswith UGT1A polymorphism[32],treat- African-Americansor Asian patients) [31]are atan increased riskof toxicity when treated with irinotecan. While adjustments inthedoseof those while diphosphateuridine with glucoronosyltransferase 1A (UGT1A) (present polymorphisms inat least20%of and15%of Caucasians (presentofin 8% African-Americanofand 3–5% patients) Caucasian [30] are atincreased riskof toxicity when treated with fluoropyrimidines age groupas they were notPRODIGE inthe included 24 trial.Moreover, patients dihydropyrimidinewith dehydrogenase (DPD) deficiency are older80 than years atis currentlydiagnosis [29]andit unknown whether thischemotherapy regimen issafe enough for patients inthis this rate islikely to beeven higher amongreal-world patients. Also, 33%of allpatients diagnosed localisedpancreaticwith cancer intheUSA patient population enrolled inthePRODIGE24 trial,roughly one-third could not complete theplanned12cycles of modified FOLFIRINOX; However, somepatients will not beoptimal candidates to adjuvant treatment with modifiedFOLFIRINOX. Notably, amongthehighly selected with resected pancreatic cancer who are fitenoughto undergo adjuvant chemotherapy with thisregimen. while long-term survival outcomes of thistrialare expected, we believe that FOLFIRINOX iscurrently thestandard of care for allthepatients are inline the onesfoundwith in aprevious Bayesian network meta-analysis includingpatients with more advancedsaid, disease[27].That chanceand 89.6% ofactivemost beingthe chemotherapy regimen interms of investigator-assessed DFS andOS,respectively. These results and had aratherstudies selected patient population in terms of age and post-operative CA 19-9levels, modifiedFOLFIRINOX had98.9% vanttreatment of pancreaticadenocarcinoma. ductal WhilePRODIGE the 24hadalower medianfollow-upcompared to theother two In our study,FOLFIRINOX modified waschemotherapy the regimen mostlikely to represent thebestcurrently available option intheadju- Discussion compared to theother studies. Thus, indirect comparisons of toxicities across trialsshouldbeinterpreted caution. with we evaluate onlysingle-agent the gemcitabineofarms ratestrials, the of grade 3–4haematological toxicities were higher inthe APACT when of grade 3–4diarrhoea.GEM-CAP was theregimen commonlymost which ledto hand-foot syndrome. However, it is worth noting that when grade 3–4 anaemia, neutropenia and peripheral neuropathy. Patients who received modified FOLFIRINOX presented the highest frequency fatigue,diarrhoea andperipheral neuropathy. By indirectcomparison, patients treated experienced GEM-NAB with thehighestrates of vomiting,diarrhoea andperipheral neuropathy. In the APACT trial,GEM-NAB was associated with higher frequency of grade 3–4 anaemia, rhoea andhand-foot syndrome. In PRODIGEFOLFIRINOX24, modified was associated with increased rates of grade 3–4fatigue, nausea, increased riskof grade 3–4toxicity. In ESPAC-4,GEM-CAP was associated with numerically increased rates of grade 3–4neutropenia, diar Table 5describesthetoxicity patterns observed inthethree studies.In combination allstudies, chemotherapy was associated with an Toxicity [33]. Additionally, other limitations associated theuseofwith FOLFIRINOX theneedfor include apermanent catheter and Table 4.SUCRA for DFS andOS. Gemcitabine GEM-CAP GEM-NAB Modified FOLFIRINOX Chemotherapy 0.010 0.454 0.540 0.996 DFS 0.013 0.487 0.546 0.955 OS 8 -

Review ecancer 2021, 15:1276; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1276 Table 5. Toxicity patterns of studies’ treatments. Grades 3–4 All grades Thrombosis All grades Alopecia Grades 3–4 All grades Peripheral neuropathy Grades 3–4 All grades Hand-foot syndrome Grades 3–4 All grades Mucositis Grades 3–4 All grades Diarrhoea Grades 3–4 All grades Vomiting Grades 3–4 All grades Nausea Grades 3–4 All grades Fatigue Non-haematological Grades 3–4 All grades Lymphopenia Grades 3–4 All grades Thrombocytopenia Grade 3–4 Febrile neutropenia Grades 3–4 All grades Neutropenia Grades 3–4 All grades Anaemia Haematological All Grade 3–4 Gemcitabine N =366(%) 196 (53.6) 89 (24.3) 19 (5.2) 11 (3.0) 14 (3.8) 9 (2.5) 0 (0.0) 6 (1.6) 7 (1.9) ------ESPAC-4 N =359(%) GEM-CAP 137 (38.2) 226 (63.0) 26 (7.2) 19 (5.3) 20 (5.6) 8 (2.2) 9 (2.5) 8 (2.2) 8 (2.2) ------Gemcitabine N =243(%) 118 (49.0) 187 (77.6) 117 (48.3) 122 (50.4) 154 (63.6) 216 (89.3) 128 (52.9) 47 (19.5) 36 (14.9) 70 (29.0) 133 (5.2) 63 (26.0) 21 (8.7) 11 (4.6) 11 (4.5) 10 (4.1) 19 (79) 1 (0.4) 2 (0.8) 0 (0.0) 0 (0.0) 9 (3.7) 3 (1.2) 2 (0.8) 7 (2.9) 6 (2.5) 0 (0) PRODIGE 24 Modified FOL N =238(%) 145 (61.2) 200 (84.4) 108 (45.6) 187 (78.9) 199 (84.0) 111 (47.0) 157 (66.5) 200 (84.7) 180 (75.9) FIRINOX 64 (27.0) 80 (33.8) 44 (18.6) 26 (11.0) 87 (36.9) 67 (28.4) 14 (5.9) 12 (5.1) 22 (9.3) 12 (5.1) 13 (5.5) 6 (2.5) 1 (0.4) 6 (2.5) 3 (1.3) 3 (1.3) 7 (3.0) 8 (3.4) - Gemcitabine N =423(%) 184 (43.5) 286 (67.6) 13 (3.1) 21 (5.0) 33 (7.8) 0 (0.0) 4 (0.9) ------APACT N =429(%) GEM-NAB 212 (49.4) 371 (86.5) 64 (14.9) 63 (14.7) 22 (5.1) 43 (10) 4 (0.9) ------9

Review survival benefit.Furthermore, of thelack seemly significantdifferences inmedianrelapse-free survival across thesingle-agentgemcitabine ies. This might have favoured the modifiedFOLFIRINOX and arms GEM-NAB when compared to GEM-CAP, at leastin terms of absolute PRODIGE24and APACT trials. That isinline ofthe distribution with known prognostic factors, asECOG such andstage, across thesestud- Patients treated with single-agent gemcitabinein theESPAC-4 trialexperienced numerically worse OS when compared to thosein the NOX isnot feasible. offer similar anti-tumour activitypancreatic inlocalised cancer, further theuseof supporting adjuvant GEM-NABincasemodified FOLFIRI- said, despite thelimitedsize sample andsomemethodological issues,theresults of SWOG S1505suggest that FOLFIRINOX andGEM-NAB FOLFIFIRINOX to perioperativein the resectable GEM-NAB disease setting, no significant differences in DFS and OS times were found. That of significant improvement inDFS. Additionally, in therecently presented SWOG S1505 trial [46], which compared perioperative modified both thePRODIGE 24andtheESPAC-4 trials.Interestingly, inthelatter study, theOSbenefits were considered significant despite thelack many expertsin pancreatic cancer important asthemost indicator of outcome quality [45]. Accordingly, OS was the primary outcome for Another argument that the useof supports in the adjuvant GEM-NAB setting is the significant OS benefit. This outcome is perceived by ment that likely influenced outcomes [21]. the APACT trialshowed that there were significant discordances inthenumber of DFS events between independent andinvestigator assess- verytofrom distinguish difficult post-operative alterations basedonly onradiological grounds [43,44]. Accordingly, arecent analysis from for theindependent reviewers [41,42]. These data seemparticularly important for patients with locoregional recurrences, which might be pancreaticcancer relapseis often (symptoms) suspected basedonclinical or laboratory (CA 19-9levels) information, which isnot available APACT investigatorsindependentlythe chose reviewed DFSas theprimary outcome inanattempt to improve reproducibility. Nonetheless, ered positive or negative iscomplex andshouldnotrely solely onthestatistical significance of thetest for theprimary outcome [40].The to meet the primary endpoint of DFS as assessed by the independent review. We believe that the conclusion as to whether a trial is consid- Despite theseresults,one might say thatshould not GEM-NAB beconsidered atreatment option inthissetting since the APACT trialsfailed graphical reasons. Europe currentdata similarsupport survival rates for patients stagewith I–IIpancreatic cancer who undergo resection intheUnited States andin ences in the chances of experiencing chemotherapy-related toxicity between North Americans andEuropeans, itisimportant to state that patients might face even moretoin trying complete difficulties adjuvant chemotherapy GEM-CAP.with However, despite potential differ Americans comparedwhen to Europeans Table 2.Furthermore, retrospective data fromX-ACTthe study incolon cancer suggest worse tolerance to fluoropyrimidine amongNorth therapy completion amongpatients treated GEM-CAPwith intheESPAC-4 study was thelowest amongthethree –Supplementary studies Also, in the real world, the useof GEM-CAP has been shown to be challenging given its toxicity profile [37].Likewise, the rate of chemo- terms of both investigator-assessed DFS and OS. GEM-CAP had a slightly worse performance than GEM-NAB in terms of survival outcomes. In this sense, we showed thatis likely GEM-NAB associated with the highest probability of being the best gemcitabine-based treatment in The useof gemcitabine-baseddoublets could match theneedfor lesstoxic or non-fluoropyrimidine-based regimens intheadjuvant setting. could beguidedby themolecular characteristics of thetumour. therapy for pancreaticcancer, compelling emerging data suggest thechoice of fluoropyrimidine-based or gemcitabine-based chemotherapy this treatment interaction gene expression profile (and therefore, low levels of GATA6 expression) [35]andrecent data in themetastatic setting the effects support of Also, pre-clinical datahave shownthat gemcitabine treatment might be more active againsttumours with basal-like (or quasi-mesenchymal) survival when compared to those high-levelwith tumours [34]. The samephenomenon was not seenfor thosetreated with gemcitabine. trial showed that patients who hadtumours lowwith orlevels medium of GATA6 expression who were treated with 5-Fluorouracil had worse randomised trialintheadjuvant settinghas beenspecifically designedto assessthishypothesis, aretrospective analysis from theESPAC-3 embryogenesis andlow levels of GATA6 are associated basa ecancer 2021, 15:1276; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1276 [39], which suggest that potential differences in survival outcomes across these trials are probably not secondary to ethnic or geo- [36]. Thus, while GATA6 expression andgene expression profiling are not currently usedto tailor adjuvant chemo- [38]. Becauseonly European patients were includedintheESPAC-4, non-European Western 10 -

Review ecancer 2021, 15:1276; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1276 meta-analysis. The authors would like to thank FernandoVinicius Calsavara (chief statistician) for reviewing the WinGUBS codes for Bayesian the network Acknowledgment elmann: methodology, writing and visualisation. Victor Hugo Fonseca de Jesus: conceptualisation, methodology, data curation, data analyses, writing and visualisation; Rachel Pimenta Riech- Authors’ contributions This study hadnofundingsource. Funding source received consultancy fees from Astra Zeneca in thepast12months. months. United Medical isthecompany responsible for andsaleof thedistribution nab-paclitaxel inBrazil. Rachel Pimenta Riechelmann Victor Hugo Fonseca de Jesus received honoraria from United Medical andhadtravel expenses paidby United Medical inthepast12 Conflicts of interest preferred adjuvant therapy, particularly to thosepatients who have contraindications for fluoropyrimidines. chemotherapythis regimen. For those contraindicationswith or who are not fitenoughfor modifiedFOLFIRINOX, might GEM-NAB bethe ModifiedFOLFIRINOX standard isthe of care fortreatment the of pancreatic cancer intheadjuvantsetting for patients fitenoughto receive Conclusion studies. reviewer-assessed andinvestigator-assessed DFSs. Furthermore, we present updated results for survival analysis from two of thethree approachbilistic thatprocess.decision-making aid the can Moreover, we usedmatched outcomes, considering differences inindependent effectiveness ofchemotherapy these regimens. Withmethodology, this we were ableto rank theefficacy of theseregimens usingaproba- risks of toxicities.Our study alsohasmerits. As far as we know, thisisthefirstBayesian network meta-analysis evaluating thecomparative 3–4 or severe adverse events.However, we displayeddata the from thestudiesina way that readers canhave anideaof thecomparative adjuvantsetting. Furthermore, inconsistenciesdescriptionsin the of thetoxicities prevented usfrom makingindirectcomparisons of grade those expertisewith in pancreatic cancer thatare these clinically themost relevant chemotherapy regimens tested inrandomised trialsinthe for patients resectedwith pancreaticcancer. Nevertheless,fromapart S-1 which isusedalmostexclusively in is largelyAsia, it known by Our study haslimitations. We didnot carrya systematic out search for allthearticles comparing different adjuvant chemotherapy regimens as characteristics of thepost-progression therapy. arms inthesetrialssuggests that factorsfrom apart theadjuvant chemotherapy regimen might have played apartindetermining OS,such 11

Review

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Review ecancer 2021, 15:1276; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1276 Supplementary tables Supplementary material a Supplementary Table2. Treatment compliance. c b a Supplementary Table 1.Inclusion andexclusion criteria. In cycle 6,59%of patients onGemcitabine plusNab-Paclitaxel received Nab-Paclitaxel CT without evidence of disease Defined asnocancer cells within 1mmof allresection margins Clear CT scanof chest,abdomen,andpelvisrequired within 3months before randomization No Yes completion (%) Treatment Nab-Paclitaxel Irinotecan Oxaliplatin 5-Fluorouracil Capecitabine Gemcitabine Dose intensity –% Comorbidity Previous treatment Post-operative tumor marker (U/mL) Exclusion Organ function Performance status (ECOG) Extent of resection Histology Age (years) Inclusion Staging Time from surgery (weeks) Gemcitabine 127 (34.7) 239 (65.3) N =366 93.0 - - - - - ESPAC-4 Gemcitabine plus Capecitabine 169 (46.4) 195 (53.6) N =364 - chemotherapy Radiotherapy or No restriction renal andhepatic functions Adequate haematologic, 0–2 R0 Ductal adenocarcinoma ≥18 Non-metastatic - 78.0 83.0 a - - - - or R1 ESPAC-4 Gemcitabine 192 (79.0) 54 (21.0) N =246 ------PRODIGE 24 congestive heartfailure artery diseaseor Symptomatic coronary chemotherapy Radiotherapy or >180 renal andhepatic functions Adequate haematologic, 0 and1 Ductal adenocarcinoma 18–79 Non-metastatic 3–12 R0 a FOLFIRINOX or R1 158 (66.4) Modified 89 (33.6) N =247 PRODIGE 24 ------

b Gemcitabine 123 (29.1) 300 (70.9) N =423 91.2 ------chemotherapy Radiotherapy or >100 - 0 and1 I or II Ductal adenocarcinoma ≥18 <12 R0 or R1 c APACT Gemcitabine plus Nab-Paclitaxel APACT 283 (66.0) 146 (34.0) N =429 75.1 80.0 - - - - a 15

Review ecancer 2021, 15:1276; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1276 } for(k in1:nt){SUCRA[k]<-sum(cumeffectiveness[k,1:(nt-1)])/(nt-1) for(k in1:nt){for(j in1:nt){cumeffectiveness[k,j]<-sum(effectiveness[k,1:j])}} in1:nt){effectiveness[k,j]<-equals(rk[k],j)}}for(j # Defining SUCRA best[k]<-equals(rk[k],1) rk[k]<- rank(d[],k) for(k in1:nt){ # Defining ranks (rk) } d[k] ~dnorm(0,.001) for (kin2:nt){ d[1]<-0 # Give priors to log hazard ratios (lhr) md[i] <-d[t[i]] -d[b[i]] # Defining the fixed-effect modelfor the log hazard ratios (lhr) lhr[i]~dnorm(md[i],prec[i]) prec[i]<- 1/(se[i]*se[i]) for(i in1:ndp){ { model # Defining the modelfor log-hazard ratios (lhr) # MODEL for OS Codes for the WinBUGS 16

Review ecancer 2021, 15:1276; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1276 lhr[i]~dnorm(md[i],prec[i]) prec[i]<- 1/(se[i]*se[i]) for(i in1:ndp){ { model # Defining the modelfor log-hazard (lhr) # MODEL FOR DFS list(d=c(NA,0.5,0.5,0.5)) list(d=c(NA,0,0,0) list(d=c(NA,-0.5,-0.5,-0.5)) # three chains initials # Entering initial values inthemodel ######### 7)) list(ndp=3, nt=4,se=c(0.088424645,0.088788212,0.14876180 t=c(2,3,4),b=c(1,1,1),lhr=c(-0.174353387,-0.198450939,-0.446287103), ######### data # Entering the data in the model(observed data) } } } HR[c,k] <-exp(lhzr[c,k]) lhzr[c,k] <-d[k] -d[c] for (kin(c+1):nt){ for (c in1:nt-1){ # Construct hazard allpairwiselog ratios (lhr) andhazard ratios (HR) 17

Review } } } HR[c,k] <-exp(lhzr[c,k]) lhzr[c,k] <-d[k] -d[c] for (kin(c+1):nt){ for (c in1:nt-1){ # Construct hazard all pairwiselog ratios (lhr) andhazard ratios (HR) } for(k in1:nt){SUCRA[k]<-sum(cumeffectiveness[k,1:(nt-1)])/(nt-1) for(k in1:nt){for(j in1:nt){cumeffectiveness[k,j]<-sum(effectiveness[k,1:j])}} in1:nt){effectiveness[k,j]<-equals(rk[k],j)}}for(j # Defining SUCRA best[k]<-equals(rk[k],1) rk[k]<- rank(d[],k) for(k in1:nt){ # Defining ranks (rk) } d[k] ~dnorm(0,.001) for (kin2:nt){ d[1]<-0 # Give priors to log hazard ratios (lhr) md[i] <-d[t[i]] -d[b[i]] # Defining the fixed-effect modelfor the log hazard ratios (lhr) ecancer 2021, 15:1276; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1276 18

Review to sampling error [1].In other words: approachin which wea fixed-effect fit tomodel data. the In setting, this any difference between thelog hazard ratios isbelieved to bedue needs to berecorded asprecision (precisioninversebeing the of the variance). As stated intheMethods section, we employed apragmatic where ecancer 2021, 15:1276; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1276 where whereerrorsampling the ε The formula below specifiestheBayesian model: Formulas list(d=c(NA,0.5,0.5,0.5)) list(d=c(NA,0,0,0) list(d=c(NA,-0.5,-0.5,-0.5)) # three chains initials # Entering initial values inthemodel ######### list(ndp=3, nt=4,se=c(0.08028335,0.08409595,0.11781073)) t=c(2,3,4),b=c(1,1,1),lhr=c(-0.1625189,-0.1984509,-0.5447272), ######### data # Entering the data in the model(observed data) be describedas: References mean 0and variance 1000 was chosen.Further information found canbe onthepaper by Hu et al[2] 2. 1. Hu D, O’Connor AM, Wang C,Sargeant JM, Winder CB.How to Conduct aBayesian Network Meta-Analysis. Front Vet Sci. 2020;7:271. parison. First ed:Nova Science; 2014.p.157-70. Wang S, Hawkins H. Indrotuction. In: Biondi-Zoccai G,editor. Network Meta-Analysis: Evidence Synthesis with Mixed Treatment Com- d lhr bi are defined asbasicparameters andd i represents log trial-specific hazard ratio andV i isnormally distributed 0 and mean with variance equalto the within-trial variance. This fixed-effect modelcan ti are defined parameters. asfunctional For thebasicparameters, anon-informative prior with i represents the within-trial variance. It is worth noting that in WinBUGS variance lhr lhr θ i i =d ~N(θ i =θ+ε ti -d i ,V bi i i ) 19

Review