Chemotherapy sequence in advanced pancreatic cancer – still a matter of debate?

Chemotherapy sequence in advanced pancreatic cancer – still a matter of debate? | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Chemotherapy sequence in advanced pancreatic cancer – still a matter of debate? Konstantin Schlick, Florian Huemer, Alexander Seymer, Lena Horvard, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4461811/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Managing advanced pancreatic ductal adenocarcinoma (aPDAC) is challenging, particularly in determining the optimal sequence of chemotherapy protocols. Despite a 5-year survival rate of only 3%, recent data from the US National Cancer Database indicate significant improvements in median overall survival (OS) for patients with metastatic pancreatic cancer over the past decade. This progress is attributed to enhanced chemotherapy regimens, the introduction of (new)-adjuvant chemotherapy, improved surgical techniques, and centralized treatment in high-volume centers. Methods: We conducted a retrospective cohort study at three Austrian academic centers, including patients with histologically confirmed primary locally advanced or metastatic PDAC who received first-line chemotherapy with either FOLFIRINOX (FFX) or gemcitabine + nab-paclitaxel (GN), followed by second-line treatments with GN or nanoliposomal irinotecan with fluorouracil + leucovorin (nal-IRI/5-FU) after progression. The study's primary endpoints were second progression-free survival (PFS2) and OS. Statistical analyses employed propensity score matching and inverse probability of treatment weighting (IPTW) to balance the groups and estimate the impact of the treatment sequences on outcomes. Results: Among 455 screened patients, 118 met the inclusion criteria, with 73 receiving FFX followed by GN and 45 receiving GN followed by nal-IRI/5-FU. The median OS was 15.4 months, and PFS2 was 11.5 months for the entire cohort. The GN-nal-IRI/5-FU sequence showed a trend toward improved OS compared to the FFX-GN sequence (HR = 0.57, p = 0.07), with comparable PFS2 between the two regimens (HR = 0.87, p = 0.58). Baseline characteristics differed significantly between the groups, necessitating the use of IPTW to ensure comparability. Discussion: This study is the largest to date comparing the efficacy of FFX followed by GN versus GN followed by nal-IRI/5-FU in aPDAC. The GN-nal-IRI/5-FU sequence demonstrated a potential survival benefit, although not statistically significant. The results suggest that both treatment sequences are viable, particularly where access to newer agents is limited. The study's retrospective nature and baseline differences between groups are acknowledged limitations. Conclusion: For patients suitable for triplet therapies, starting with NALIRIFOX or mFOLFIRINOX is supported by recent phase 3 trials. For those not fit for such intensive regimens, GN followed by nal-IRI/5-FU remains a valid strategy. Further prospective studies are needed to confirm these findings. Figures Figure 1 Figure 2 Figure 3 Background The management of patients with advanced pancreatic ductal adenocarcinoma (aPDAC) remains challenging, and the sequence of various chemotherapy protocols during the course of disease are a matter of debate among experts in the field. With a median 5-year survival rate of only three percent, metastatic pancreatic cancer has one of the lowest survival rates among all cancers [ 1 ]. Nevertheless, according to the US National Cancer Database the median overall survival has increase significantly within a decade between 2004–2007 vs 2017/2017 for patients undergoing resection(15.5m vs 25.3m) as well as for patients without surgery (7.2 vs 10.1m) [ 2 ]. This progress has been achieved by the improvement in chemotherapy regimens, the introduction of (new)-adjuvant chemotherapy, improved surgical techniques as well as centralization of treatment in high volume centers [ 3 , 4 ]. Concerning the advanced stage setting in particular improved response rates in advanced setting compared to gemcitabine (Gem) monotherapy with objectice response rate (ORR) of up to 15% have been observed with mFOLFIRINOX (a modified regimen of oxaliplatin, leucovorin, irinotecan, and fluorouracil; FFX) with an ORR in 32% of patients or gemcitabine + nab-paclitaxel (nanoparticle albumin-bound paclitaxel; GN) in 29% of patients as compared to gemcitabine monotherapy [ 5 , 6 ]. These regimens have resulted in a clinically and statistically meaningful overall survival (OS) benefit of 11.1 versus 6.8 months for FFX (HR of 0.57) and 8.5 versus 6.7 months for GN (HR of 0.72) [ 5 , 6 ]. Both therapy regimens serve as established standard first-line treatment options for patients with locally advanced or metastatic disease with ECOG-PS (ECOG-performance status) 0 or 1 [ 7 ]. However, there are reported differences in regard to application patterns of these two regimens between various countries: Recent assessments by American and Japanese groups analyzing treatment patterns have shown a consistent trend toward increased adoption of GN as the preferred first-line chemotherapy regimen. Over the recent years, the usage of GN has increased from approximately 40–57% %.[ 8 , 9 ]. In contrast, another multi-institutional large study from Canada showed a higher frequency of FFX application as first-line treatment (60%) [ 10 ]. Following disease progression during the first-line therapy, up to 45% of patients remain eligible for second-line chemotherapy [ 11 ]. Recent advances in the second-line setting of aPDAC, particularly with the introduction of nanoliposomal irinotecan with fluorouracil + leucovorin (nal-IRI/5-FU), have expanded the therapeutic armamentarium, resulting in further improvements in clinical outcome [ 12 ]. Another treatment option in this context involves chemotherapy protocols comprising oxaliplatin and fluorouracil; however, these have yielded conflicting outcome data [ 13 , 14 ]. As a result, nal-IRI/5-FU stands out as the only level 1A recommended second-line therapy according to NCCN and ESMO guidelines for patients experiencing progression during gemcitabine-based therapies [ 15 ]. In contrast to gemcitabine-based first-line treatment, there is considerably less evidence second-line treatments following FFX failure. Gemcitabine-based regimens are apparent options. A French nonrandomized prospective multicenter phase II trial investigated gemcitabine and nab-paclitaxel as second treatment line in patients who progressed to FFX therapy. The median overall survival was 8.8 months [ 16 ]. However, as of now, no prospective randomized head-to-head comparison between these two sequential strategies, FFX followed by second-line GN and patients with first-line GN followed by nal-IRI/5-FU, has been reported in the literature concerning response rates and survival outcomes. Therefore, we conducted a retrospective tri-center cohort study involving patients with aPADC undergoing above mentioned sequential strategies, in order to shed light on this clinically relevant question. Methods Study design: We conducted a retrospective cohort study, including all consecutive patients with histologically confirmed primary locally advanced or metastatic PDAC at three Austrian academic centers (Medical University of Graz, Paracelsus Medical University Salzburg and Medical University of Innsbruck) between August 2010 and October 2019. Per our inclusion criteria, only patients receiving palliative intended chemotherapy either with therapy sequence consisting of first-line treatment with FFX followed by GN as second-line therapy or with sequence GN followed by nal-IRI/5-FU after progression were used for the analyses (Fig. 1 ). No patients receiving adjuvant therapy in the past were included. (Abbr: FFX: FOLFIRINOX or mFOLFIRINOX, GN: Gemcitabine nab-Paclitaxel, nal-IRI/5-FU: nano-liposomal Irinotecan, PD1: first progress, PD2: second progress) Patients were identified using the respective in-house electronic healthcare databases. All eligible patients were aged 18 years or older, had histologically confirmed pancreatic ductal adenocarcinoma and/or radiologically confirmed advanced disease and received first line therapy (FFX or GN) and at least one cycle of the above mentioned second-line regimens (GN or nal-IRI/5-FU). The advanced disease stage was defined by either locally advanced and therefore inoperable tumors or tumors initially presenting with distant metastases on imaging scans. Therapy response was assessed by objective response rate (ORR), that is, the composite of complete (CR) or partial remission (PR) and disease control rate (DCR: CR + PR + SD). The study was approved by the institutional review board of the leading center (Ethics Committee of the Medical University of Graz, Austria; document number 31–035 ex 18/19). Study outcomes: The primary end-points of our analysis were second progression-free survival (PFS2) and OS. PFS2 was defined as the time-duration from the first day of first-line chemotherapy until radiological progression of the underlying disease during the second line treatment, death from any cause during second-line, or censoring alive, whichever came first. If a patient could not receive second line for medical reason or refusal, she/he was not included in our analyses. OS was defined as the time from the first diagnosis until death from any cause or censoring alive in the pre-defined patient population. Statistical methods: Statistical analyses were conducted using R version 4.3.1 (R-Core Team, 2023) [ 17 ]. We utilized the Kruskal-Wallis rank-sum test, chi-square test, and Fisher’s exact test for bivariate association testing as appropriate. To equalize the two sequence groups, we estimated a propensity score model (PSM). Consistent with the literature, a standardized mean difference (SMD) of 0.2 or greater signifies an imbalance between groups [ 18 ]. Consequently, the PSM was computed as a multivariable binomial logistic model of sequence group assignment, with the propensity score representing the probability of a patient being a member of the GN-nal-IRI/5-FU sequence group, conditional on age, sex, ECOG, and CA 19.9. An inverse probability of treatment weight (IPTW) was calculated as the inverse of the propensity score [ 19 ] and used to balance both sequence groups [ 20 ]. We mitigated the impact of outliers in the IPTW by truncating the lowest and highest one percent of IPTW scores at the 1st and 99th percentile of the distribution, respectively. OS and PFS2 were estimated using Kaplan-Meier estimates, and the data was weighted with the trimmed IPTW. In addition to survival curves, a Schoenfeld test revealed no violations of the proportional hazard assumption, thereby justifying the use of a Cox regression model to estimate the impact of two treatment sequences on OS and PFS2. Subsequently, interaction terms for the treatment sequences with all independent variables were calculated to determine the hazard ratio for each independent variable. Results Cohort Description: A total of 587 patients diagnosed with PDAC were identified across three tertiary cancer centers (Medical University of Graz, Paracelsus Medical University Salzburg and Medical University of Innsbruck, all Austria). Among them, 455 patients with primary locally advanced (never resectable) or primary metastatic PDAC, receiving systemic therapy in palliative intent, were screened according to our inclusion criteria. Out of these, 297 (65.3%) patients received GN, and 158 (34.7%) were treated with FFX in their respective palliative first-line settings. Ultimately, 118 patients, treated with one of the two pre-specified therapy sequences, were included in our analysis. Among these, 73 (62%) received FFX followed by GN sequence, and 45 (38%) were given GN followed by nal-IRI/5-FU (Table 1 ). Table 1 Consort diagram The median age of the cohort was 65 years (range 44–79 years), with 40% being women. Most patients had ECOG PS of 0 or on 1, and the majority presented with synchronous metastatic disease (79%). For the entire study cohort (n = 118), the median OS and PFS2 were 15.4 months (95% CI = 12.2–19.6) and 11.5 months (95% CI = 9.2–13.5), respectively For more details, please refer to Table 2. Variable Overall FFX followed by GN GN followed by nal-IRI/5-FU p SMD n 118 73 45 Age at diagnosis (median [IQR]) 65.00 [55.25, 70.00] 61.00 [52.00, 67.00] 70.00 [64.00, 73.00] < 0.001 0.881 Sex = female (%) 48 (41) 28 (38) 20 (44) 0.565 0.124 ECOG (%) 0.005 0.583 0 65 (55) 48 (66) 17 (38) 1 51 (43) 24 (33) 27 (60) 2+ 2 (2) 1 (1) 1 (2) Metastatic tumor (%) 93 (79) 57 (78) 36 (80) 1.000 0.047 Grading (%) 0.493 0.269 I 7 (9) 3 (7) 4 (12) II 38 (48) 24 (53) 14 (41) III 34 (43) 18 (40) 16 (47) CA 19 − 9 in U/mL (median [IQR]) 1629.00 [187.50, 10165.65] 1918.80 [344.00, 12786.00] 533.10 [140.75, 3482.78] 0.065 0.385 Notes: Table 2: Patient baseline characteristics at diagnosis Chemotherapy sequence description: In the palliative first-line setting, patients had a median first-line treatment duration of 5.5 vs 4.8 months (p = 0.602). This difference was statistically not significant between the two groups. Concerning second-line therapy duration for patients progressing on FFX or GN, again was no statistically significant with a median treatment duration of 2.9 vs 2.1 months (p = 0.155). Outcome according to chemotherapy sequence: ORR, including complete response (CR) and partial response (PR), were 44% for FFX and 36% for GN for first-line treatment (ORR = 1.391, 95% CI = 0.594–3.328, p = 0.435), and 18% for GN and 25% for nal-IRI/5-FU for second-line therapy (OR = 0.657, 95% CI = 0.222-2.000, p = 0.446), respectively. CBR, including CR, PR and SD, were 74% for FFX and 72% for GN for first-line treatment (OR = 1.094, 95% CI = 0.422–2.765, p = 0.831), and 45% for GN and 47% for nal-IRI/5-FU for second-line therapy (OR = 0.907, 95% CI = 0.372–2.215, p = 0.838), respectively. See Table 3 . Table 3 Treatment response rates for first and second line by treatment-sequence First-Line Second-Line Characteristic FFX-GN N = 73 1 GN-nal-IRI/5-FU N = 45 1 p-value 2 FFX-GN N = 73 1 GN-nal-IRI/5-FU N = 45 1 p-value 2 Response 0.7 0.7 Complete response 0 (0%) 0 (0%) 0 (0%) 0 (0%) Partial response 31 (44%) 15 (36%) 12 (18%) 9 (25%) Stable disease 21 (30%) 15 (36%) 18 (27%) 8 (22%) Progressive disease 19 (27%) 12 (29%) 37 (55%) 19 (53%) Not evaluable 2 3 6 9 Notes: 1 n (%); 2 Fisher’s exact test There was no statistically significant difference in outcomes in terms of OS between the two therapy sequences: Median OS for the FFX-GN sequence was 13.5 months vs 16.8 months for GN-nal-IRI/5-FU (HR = 0.57, 95% CI = 0.31–1.04, p = 0.07). In terms of PFS2, both treatment groups were highly comparable with a median of 10.8 months for FFX-GN vs 11.7 months for GN-nal-IRI/5-FU (HR = 0.87, 95% CI = 0.55–1.40, p = 0.58). A Schoenfeld test supports the assumption of proportional hazards and therefore hazard ratios were based on Cox-regression applying inverse probability of treatment weight( IPTW). The relative efficacy of the two different treatments sequences was not statistically significantly different across several subgroups regarding OS and PFS2. Differences between sequence groups However, patients in the GN group exhibited significant differences from those in the FFX group in terms of several key baseline characteristics (Table 2). Specifically, FFX group patients were notably younger and had a superior ECOG PS. To address this potential confounding factor when comparing GN-nal-IRI/5-FU and FFX-GN, we devised a refined IPTW that incorporated variables such as age, gender, staging (locally advanced versus metastatic disease), and performance status. Applying the IPTW reduced the Standardized Mean Difference (SMD) for various variables, most prominently for age (from 0.88 to 0.04) and performance status (from 0.58 to 0.05). Consequently, we regard the baseline characteristics of both treatment sequences as comparable when using the IPTW. Discussion/Limitations To our best knowledge, this study represents the largest analysis reporting efficacy data including PFS2, ORR and OS on the two predominant sequence strategies in the treatment of PDAC patients: FFX followed by GN versus GN followed by nal-IRI/5-FU employed as palliative first and second-line treatments in aPDAC. Currently, the only approved second-line treatment with level IA, as per NCCN and ESMO [21, 22], is a combination of nal-IRI/5-FU which demonstrated superior overall survival (OS) compared to 5-FU and leucovorin in the NAPOLI-1 trial after gemcitabine-based first-line treatment. Despite FFX being one of the preferred first-line options, there is a lack of randomized controlled trials proving the efficacy of GN as a second-line option after FFX failure. The absence of head-to-head comparisons between the two first and second line poly-chemotherapy strategies and the eligibility criteria for clinical trials limit the generalizability of trial results to diverse patient scenarios. In this study, we aimed at addressing this dearth of comparative data by conducting a propensity score matched comparative effectiveness analysis of real-world outcomes from 118 patients treated either with FFX followed by GN or GN followed by nal-IRI/5-FU. As we included PDAC patients that had been diagnosed between 2010 and 2019, application patterns changed in the three academic centers especially upon the approval of nal-IRI/5-FU in 2016. This resulted in a shift of prescriptions towards GN followed by nal-IRI/5-FU. Median OS showed only a trend towards improved survival for the therapy sequence GN followed by nal-IRI compared to FFX-GN (HR = 0.57, 95% CI = 0.31–1.04, p = 0.07). PFS2 outcomes were comparable between the two regimens (HR = 0.87, 95% CI = 0.54–1.41, p = 0.58). However, significant differences in baseline characteristics, such as age and performance status, were noted between the two sequence cohorts. To mitigate potential bias and account for non-random treatment assignment, a propensity score model using Inverse Probability of Treatment Weighting was employed. In the adjusted analysis, according to IPTW, both treatment groups can be considered comparable regarding baseline characteristics. Response for both therapy sequences were similar for first and second-line treatments between the two sequential systemic treatment approaches, indicating the suitability of both poly-chemotherapy strategies for patients requiring a therapeutic response, especially in regions where access to novel and costly antineoplastic agents may be limited. Although the study has limitations, including its retrospective nature and relatively low patient numbers in each sequence arm, it provides valuable insights into the real-world palliative therapy sequences for patients with advanced PC. Furthermore, one must keep in mind that, as patient inclusion started in August 2010, no information on BRCA status was available as a treatment decision tool at that time. Standard molecular testing in palliative first-line setting became routinely available in 2019. The rather large distribution between the two therapy sequences our rate from first- to second-line chemotherapy (FFX - >GN with around 50%) an GN -> Nalir-5-FU of over 80%) is interpreted with the rather long inclusion time frame of 9 years (2010–2019) and therefore lack of availability of Nalir-5-FU. Another limitation is the fact that novel data resulting from following two phase 3 trials could not be accounted for: On one hand, the results of this tri- centric retrospective analysis suggest that the GN- Nalir-5-FU sequence is not inferior in terms of OS/PFS2/ORR compared to FFX-GN, and may even be potentially superior in terms of OS (HR 0.57). On the other hand, the findings from NAPOLI-3 (comparing NALIRIFOX (liposomal irinotecan 50 mg/m 2 , oxaliplatin 60 mg/m 2 , leucovorin 400 mg/m 2 , and fluorouracil 2400 mg/m 2 ) to GN resulted in a median OS of 11.1 months in the NALIFIROX arm as compared with 9.2 months in the GN arm (HR 0.84 [95% CI 0.71–0.99]; p = 0.04) favor initiating treatment with the Naliri-containing triplet regimen compared to the NAPOLI-1 sequence. [23] In contrast, the results of the Asian GENERATE study showed a surprisingly median OS benefit of 17.0 months with GN compared to 14.0 months with modified FOLFIRINOX (HR1.29; 95% CI 0.98–1.70) in an Asian study population [24]. Conclusion In conclusion, in cases where patients are considered suitable candidates for a triplet therapy (NALIRIFOX or mFOLFIRINOX), treatment should start accordingly (NAPOLI-3, Prodige4) as there is no statistically significant evidence of disadvantage in this retrospectively collected therapy sequence, which consists of triplets followed by Gem-Nab. For those patients who are not deemed fit for triplet therapy, the treatment protocol involves Gem-Nab followed by nal-IRI/5-FU. Abbrevation aPDAC: advanced ductal adenocarcinoma of the pancreas CI: confidence intervall CR: complete remission DCR: disease control rate FFX: FOLFIRINOX GN: Gemcitabine nab-Paclitaxel HR: hazard ratio IPTW: inverse probability of treatment weight nal-IRI/5-FU: nano-liposomal Irinotecan OR: odds ratio ORR: objectice response rate OS: overall survival PD: progressive disease PD1: progressive disease 1 PD2: progressive disease 1 PFS: progression-free survival PFS2: second progression-free survival PR: partial remission PS: performance status PSM: propensitiy score model SD: stable disease SMD: standardized mean difference Declarations Author Contribution FH, LW, AS, KS and RH conceived and designed thestudy; AS interpreted the results; RG, AG,LH and ADcontributed to the writing of the manuscript; all authorscollected data and contributed patients, performed allstatistical analyses, wrote the first draft of the manuscript,agree with the manuscript’s results and conclusions References Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA: a cancer journal for clinicians. 2020;70(1):7-30. Underwood PW, Herremans KM, Neal D, Riner AN, Nassour I, Hughes SJ, Trevino JG. Changing Practice Patterns and Improving Survival for Patients with Pancreatic Ductal Adenocarcinoma. Cancers. 2023;15(18):4464. Polonski A, Izbicki JR, Uzunoglu FG. Centralization of Pancreatic Surgery in Europe. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 2019;23(10):2081-92. Conroy T, Castan F, Lopez A, Turpin A, Ben Abdelghani M, Wei AC, Mitry E, Biagi JJ, Evesque L, Artru P, et al. Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer: A Randomized Clinical Trial. JAMA oncology. 2022;8(11):1571-8. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. The New England journal of medicine. 2011;364(19):1817-25. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. The New England journal of medicine. 2013;369(18):1691-703. Ducreux M, Cuhna AS, Caramella C, Hollebecque A, Burtin P, Goéré D, Seufferlein T, Haustermans K, Van Laethem JL, Conroy T, et al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology. 2015;26 Suppl 5:v56-68. Abrams TA, Meyer G, Meyerhardt JA, Wolpin BM, Schrag D, Fuchs CS. Patterns of Chemotherapy Use in a U.S.-Based Cohort of Patients with Metastatic Pancreatic Cancer. The oncologist. 2017;22(8):925-33. Nagai K, Terashima T, Yamashita T, Kido H, Hayashi K, Sunagozaka H, Nakai R, Mizuno H, Hayakawa H, Nomura Y, et al. Dynamical changes of treatment patterns and outcomes of unresectable pancreatic cancer patients in real-life practice. Journal of Clinical Oncology. 2019;37(4_suppl):407-. Cheung WY, Zhang H, Tang PA, Spratlin JL, Lee-Ying RM, Goodwin RA, Meyers BM, Armstrong DE, Ramjeesingh R, Vickers MM. A real world multicenter study of first (1L) and second (2L) line treatment patterns and outcomes in advanced pancreatic cancer (APC). American Society of Clinical Oncology; 2018. Riedl JM, Posch F, Horvath L, Gantschnigg A, Renneberg F, Schwarzenbacher E, Moik F, Barth DA, Rossmann CH, Stotz M, et al. Gemcitabine/nab-Paclitaxel versus FOLFIRINOX for palliative first-line treatment of advanced pancreatic cancer: A propensity score analysis. European journal of cancer (Oxford, England : 1990). 2021;151:3-13. Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet (London, England). 2016;387(10018):545-57. Zaanan A, Trouilloud I, Markoutsaki T, Gauthier M, Dupont-Gossart AC, Lecomte T, Aparicio T, Artru P, Thirot-Bidault A, Joubert F, et al. FOLFOX as second-line chemotherapy in patients with pretreated metastatic pancreatic cancer from the FIRGEM study. BMC Cancer. 2014;14:441. Ghosn M, Farhat F, Kattan J, Younes F, Moukadem W, Nasr F, Chahine G. FOLFOX-6 combination as the first-line treatment of locally advanced and/or metastatic pancreatic cancer. American journal of clinical oncology. 2007;30(1):15-20. Tempero MA. NCCN Guidelines Updates: Pancreatic Cancer. Journal of the National Comprehensive Cancer Network : JNCCN. 2019;17(5.5):603-5. Hosein PJ, de Lima Lopes G, Jr., Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-Paclitaxel as second-line therapy in patients with advanced pancreatic cancer. American journal of clinical oncology. 2013;36(2):151-6. R Core Team (2023). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria. [23.02.2024]. Available from: . Zhang Z, Kim HJ, Lonjon G, Zhu Y. Balance diagnostics after propensity score matching. Ann Transl Med. 2019;7(1):16. Chesnaye NC, Stel VS, Tripepi G, Dekker FW, Fu EL, Zoccali C, Jager KJ. An introduction to inverse probability of treatment weighting in observational research. Clinical kidney journal. 2022;15(1):14-20. Xu S, Ross C, Raebel MA, Shetterly S, Blanchette C, Smith D. Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2010;13(2):273-7. NCCN. NCCN Guidelines Version 1.2024 Pancreatic Adenocarcinoma [Available from: https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Conroy T, Pfeiffer P, Vilgrain V, Lamarca A, Seufferlein T, O’Reilly E, Hackert T, Golan T, Prager G, Haustermans K. Pancreatic cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up☆. Annals of Oncology. 2023;34(11):987-1002. Wainberg ZA, Melisi D, Macarulla T, Pazo Cid R, Chandana SR, De La Fouchardière C, Dean A, Kiss I, Lee WJ, Goetze TO, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet (London, England). 2023;402(10409):1272-81. Ohba A, Ozaka M, Ogawa G, Okusaka T, Kobayashi S, Yamashita T, Ikeda M, Yasuda I, Sugimori K, Sasahira N. 1616O Nab-paclitaxel plus gemcitabine versus modified FOLFIRINOX or S-IROX in metastatic or recurrent pancreatic cancer (JCOG1611, GENERATE): A multicentred, randomized, open-label, three-arm, phase II/III trial. Annals of Oncology. 2023;34:S894. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4461811","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":308789086,"identity":"0474ef94-9c3a-4db9-a691-955c8f60ccc2","order_by":0,"name":"Konstantin Schlick","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIie3OMQrCMBiG4U86dMkBfgnYKyQEQoeKV4m4dnB0koJDlx5A8TKdzOIBHC0dXAtdHI2DgtPf0SEvZAh8DwkQi/1hqk3vCbYESivg3k4guhIqgQpEhLkLR3DEhEkgAJGbSCzEbNyqPJufHt3grshWHCmQ9vKoSJ9lacjdoBuewCZCkVvIEuQGzFhiv2Tu+2cgK5aYD5EE+/7YmiX6IIwMRJ+a0ubuSpumZYjydTeK3T4j7/vbcCmWdcU9k/xeidvHYrFYbEovE402NzAgaiMAAAAASUVORK5CYII=","orcid":"","institution":"Salzburger Landeskliniken","correspondingAuthor":true,"prefix":"","firstName":"Konstantin","middleName":"","lastName":"Schlick","suffix":""},{"id":308789087,"identity":"75879e1b-14d2-4ec6-b7a7-a9ee0bf9210d","order_by":1,"name":"Florian Huemer","email":"","orcid":"","institution":"Salzburger Landeskliniken","correspondingAuthor":false,"prefix":"","firstName":"Florian","middleName":"","lastName":"Huemer","suffix":""},{"id":308789088,"identity":"cb5058ce-ef0e-40a9-aabb-276965d7987e","order_by":2,"name":"Alexander Seymer","email":"","orcid":"","institution":"University of Salzburg","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Seymer","suffix":""},{"id":308789089,"identity":"1cc55960-f9ea-4a8e-8309-824dc4c7cd9f","order_by":3,"name":"Lena Horvard","email":"","orcid":"","institution":"Innsbruck Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lena","middleName":"","lastName":"Horvard","suffix":""},{"id":308789090,"identity":"2011becf-31a3-4efd-aa76-0aa5f26c7f55","order_by":4,"name":"Ronald heregger","email":"","orcid":"","institution":"Salzburger Landeskliniken","correspondingAuthor":false,"prefix":"","firstName":"Ronald","middleName":"","lastName":"heregger","suffix":""},{"id":308789091,"identity":"1aa31487-ad2d-4dad-a2b2-0cf2803e5cc5","order_by":5,"name":"Richard Greil","email":"","orcid":"","institution":"Salzburger Landeskliniken","correspondingAuthor":false,"prefix":"","firstName":"Richard","middleName":"","lastName":"Greil","suffix":""},{"id":308789092,"identity":"452e1e25-37ca-4e9b-b358-2bf0b38ecfce","order_by":6,"name":"Angela Djanani","email":"","orcid":"","institution":"Innsbruck Medical University","correspondingAuthor":false,"prefix":"","firstName":"Angela","middleName":"","lastName":"Djanani","suffix":""},{"id":308789093,"identity":"01c734bc-8aab-4d38-969b-b63b860e0a42","order_by":7,"name":"Armin Gerger","email":"","orcid":"","institution":"Medical University of Graz","correspondingAuthor":false,"prefix":"","firstName":"Armin","middleName":"","lastName":"Gerger","suffix":""},{"id":308789094,"identity":"2e98e69f-d453-4ca2-8a0b-ce7b6fcbf532","order_by":8,"name":"Lukas Weiss","email":"","orcid":"","institution":"Salzburger Landeskliniken","correspondingAuthor":false,"prefix":"","firstName":"Lukas","middleName":"","lastName":"Weiss","suffix":""},{"id":308789095,"identity":"cbd9a570-c08e-4af3-8896-91ac0fd082f8","order_by":9,"name":"Jakob Riedl","email":"","orcid":"","institution":"Medical University of Graz","correspondingAuthor":false,"prefix":"","firstName":"Jakob","middleName":"","lastName":"Riedl","suffix":""}],"badges":[],"createdAt":"2024-05-22 15:04:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4461811/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4461811/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57952695,"identity":"7924cdd3-c4fb-439b-bae5-b3ab2904ff35","added_by":"auto","created_at":"2024-06-07 22:58:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":152974,"visible":true,"origin":"","legend":"\u003cp\u003eDefinition of the two treatment sequences.\u003c/p\u003e\n\u003cp\u003e(Abbr: FFX: FOLFIRINOX or mFOLFIRINOX, GN: Gemcitabine nab-Paclitaxel, nal-IRI/5-FU: nano-liposomal Irinotecan, PD1: first progress, PD2: second progress)\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4461811/v1/21b68d095fc854ad023b7877.png"},{"id":57952696,"identity":"4b18ba94-c627-461c-88dd-d6ddbf601bde","added_by":"auto","created_at":"2024-06-07 22:58:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":441741,"visible":true,"origin":"","legend":"\u003cp\u003eAdjusted survival curves for OS (A) and PFS2 (B) by treatment sequence\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4461811/v1/1d375a8cad6eba93eb61b8e6.png"},{"id":57952694,"identity":"91e78b99-b432-4a8a-b7d2-810283f9a1e7","added_by":"auto","created_at":"2024-06-07 22:58:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":88831,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analysis of efficacy of GN-nal-IRI/5-Fu and FFX-GN towards overall survival and second progression free survival. Coefficients are interactions between treatment sequence and respective variable estimated in a cox-regression model applying IPTW.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4461811/v1/fb505ff436f6c2f72a0abb5b.png"},{"id":75336059,"identity":"8e5be594-48c5-4e45-a097-0cb231d901ee","added_by":"auto","created_at":"2025-02-03 13:24:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1289693,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4461811/v1/b30ffc11-855f-4203-88cc-7e1063991127.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Chemotherapy sequence in advanced pancreatic cancer – still a matter of debate?","fulltext":[{"header":"Background","content":"\u003cp\u003eThe management of patients with advanced pancreatic ductal adenocarcinoma (aPDAC) remains challenging, and the sequence of various chemotherapy protocols during the course of disease are a matter of debate among experts in the field. With a median 5-year survival rate of only three percent, metastatic pancreatic cancer has one of the lowest survival rates among all cancers [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Nevertheless, according to the US National Cancer Database the median overall survival has increase significantly within a decade between 2004\u0026ndash;2007 vs 2017/2017 for patients undergoing resection(15.5m vs 25.3m) as well as for patients without surgery (7.2 vs 10.1m) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis progress has been achieved by the improvement in chemotherapy regimens, the introduction of (new)-adjuvant chemotherapy, improved surgical techniques as well as centralization of treatment in high volume centers [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Concerning the advanced stage setting in particular improved response rates in advanced setting compared to gemcitabine (Gem) monotherapy with objectice response rate (ORR) of up to 15% have been observed with mFOLFIRINOX (a modified regimen of oxaliplatin, leucovorin, irinotecan, and fluorouracil; FFX) with an ORR in 32% of patients or gemcitabine\u0026thinsp;+\u0026thinsp;nab-paclitaxel (nanoparticle albumin-bound paclitaxel; GN) in 29% of patients as compared to gemcitabine monotherapy [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThese regimens have resulted in a clinically and statistically meaningful overall survival (OS) benefit of 11.1 versus 6.8 months for FFX (HR of 0.57) and 8.5 versus 6.7 months for GN (HR of 0.72) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBoth therapy regimens serve as established standard first-line treatment options for patients with locally advanced or metastatic disease with ECOG-PS (ECOG-performance status) 0 or 1 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, there are reported differences in regard to application patterns of these two regimens between various countries:\u003c/p\u003e \u003cp\u003eRecent assessments by American and Japanese groups analyzing treatment patterns have shown a consistent trend toward increased adoption of GN as the preferred first-line chemotherapy regimen. Over the recent years, the usage of GN has increased from approximately 40\u0026ndash;57% %.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn contrast, another multi-institutional large study from Canada showed a higher frequency of FFX application as first-line treatment (60%) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFollowing disease progression during the first-line therapy, up to 45% of patients remain eligible for second-line chemotherapy [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecent advances in the second-line setting of aPDAC, particularly with the introduction of nanoliposomal irinotecan with fluorouracil\u0026thinsp;+\u0026thinsp;leucovorin (nal-IRI/5-FU), have expanded the therapeutic armamentarium, resulting in further improvements in clinical outcome [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Another treatment option in this context involves chemotherapy protocols comprising oxaliplatin and fluorouracil; however, these have yielded conflicting outcome data [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. As a result, nal-IRI/5-FU stands out as the only level 1A recommended second-line therapy according to NCCN and ESMO guidelines for patients experiencing progression during gemcitabine-based therapies [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn contrast to gemcitabine-based first-line treatment, there is considerably less evidence second-line treatments following FFX failure. Gemcitabine-based regimens are apparent options. A French nonrandomized prospective multicenter phase II trial investigated gemcitabine and nab-paclitaxel as second treatment line in patients who progressed to FFX therapy. The median overall survival was 8.8 months [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, as of now, no prospective randomized head-to-head comparison between these two sequential strategies, FFX followed by second-line GN and patients with first-line GN followed by nal-IRI/5-FU, has been reported in the literature concerning response rates and survival outcomes.\u003c/p\u003e \u003cp\u003eTherefore, we conducted a retrospective tri-center cohort study involving patients with aPADC undergoing above mentioned sequential strategies, in order to shed light on this clinically relevant question.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eStudy design:\u003c/p\u003e \u003cp\u003e We conducted a retrospective cohort study, including all consecutive patients with histologically confirmed primary locally advanced or metastatic PDAC at three Austrian academic centers (Medical University of Graz, Paracelsus Medical University Salzburg and Medical University of Innsbruck) between August 2010 and October 2019.\u003c/p\u003e \u003cp\u003ePer our inclusion criteria, only patients receiving palliative intended chemotherapy either with therapy sequence consisting of first-line treatment with FFX followed by GN as second-line therapy or with sequence GN followed by nal-IRI/5-FU after progression were used for the analyses (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNo patients receiving adjuvant therapy in the past were included.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e(Abbr: FFX: FOLFIRINOX or mFOLFIRINOX, GN: Gemcitabine nab-Paclitaxel, nal-IRI/5-FU: nano-liposomal Irinotecan, PD1: first progress, PD2: second progress)\u003c/p\u003e \u003cp\u003ePatients were identified using the respective in-house electronic healthcare databases. All eligible patients were aged 18 years or older, had histologically confirmed pancreatic ductal adenocarcinoma and/or radiologically confirmed advanced disease and received first line therapy (FFX or GN) and at least one cycle of the above mentioned second-line regimens (GN or nal-IRI/5-FU).\u003c/p\u003e \u003cp\u003eThe advanced disease stage was defined by either locally advanced and therefore inoperable tumors or tumors initially presenting with distant metastases on imaging scans.\u003c/p\u003e \u003cp\u003eTherapy response was assessed by objective response rate (ORR), that is, the composite of complete (CR) or partial remission (PR) and disease control rate (DCR: CR\u0026thinsp;+\u0026thinsp;PR\u0026thinsp;+\u0026thinsp;SD).\u003c/p\u003e \u003cp\u003e The study was approved by the institutional review board of the leading center (Ethics Committee of the Medical University of Graz, Austria; document number 31\u0026ndash;035 ex 18/19).\u003c/p\u003e \u003cp\u003eStudy outcomes:\u003c/p\u003e \u003cp\u003eThe primary end-points of our analysis were second progression-free survival (PFS2) and OS.\u003c/p\u003e \u003cp\u003ePFS2 was defined as the time-duration from the first day of first-line chemotherapy until radiological progression of the underlying disease during the second line treatment, death from any cause during second-line, or censoring alive, whichever came first.\u003c/p\u003e \u003cp\u003eIf a patient could not receive second line for medical reason or refusal, she/he was not included in our analyses. OS was defined as the time from the first diagnosis until death from any cause or censoring alive in the pre-defined patient population.\u003c/p\u003e \u003cp\u003eStatistical methods:\u003c/p\u003e \u003cp\u003eStatistical analyses were conducted using R version 4.3.1 (R-Core Team, 2023) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. We utilized the Kruskal-Wallis rank-sum test, chi-square test, and Fisher\u0026rsquo;s exact test for bivariate association testing as appropriate. To equalize the two sequence groups, we estimated a propensity score model (PSM). Consistent with the literature, a standardized mean difference (SMD) of 0.2 or greater signifies an imbalance between groups [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Consequently, the PSM was computed as a multivariable binomial logistic model of sequence group assignment, with the propensity score representing the probability of a patient being a member of the GN-nal-IRI/5-FU sequence group, conditional on age, sex, ECOG, and CA 19.9.\u003c/p\u003e \u003cp\u003eAn inverse probability of treatment weight (IPTW) was calculated as the inverse of the propensity score [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] and used to balance both sequence groups [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. We mitigated the impact of outliers in the IPTW by truncating the lowest and highest one percent of IPTW scores at the 1st and 99th percentile of the distribution, respectively. OS and PFS2 were estimated using Kaplan-Meier estimates, and the data was weighted with the trimmed IPTW.\u003c/p\u003e \u003cp\u003eIn addition to survival curves, a Schoenfeld test revealed no violations of the proportional hazard assumption, thereby justifying the use of a Cox regression model to estimate the impact of two treatment sequences on OS and PFS2. Subsequently, interaction terms for the treatment sequences with all independent variables were calculated to determine the hazard ratio for each independent variable.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eCohort Description:\u003c/p\u003e\n\u003cp\u003eA total of 587 patients diagnosed with PDAC were identified across three tertiary cancer centers (Medical University of Graz, Paracelsus Medical University Salzburg and Medical University of Innsbruck, all Austria). Among them, 455 patients with primary locally advanced (never resectable) or primary metastatic PDAC, receiving systemic therapy in palliative intent, were screened according to our inclusion criteria. Out of these, 297 (65.3%) patients received GN, and 158 (34.7%) were treated with FFX in their respective palliative first-line settings. Ultimately, 118 patients, treated with one of the two pre-specified therapy sequences, were included in our analysis. Among these, 73 (62%) received FFX followed by GN sequence, and 45 (38%) were given GN followed by nal-IRI/5-FU (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eConsort diagram\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/122228_c8a1650c59388082/122228_custom_files/img1717524209.png\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eThe median age of the cohort was 65 years (range 44\u0026ndash;79 years), with 40% being women. Most patients had ECOG PS of 0 or on 1, and the majority presented with synchronous metastatic disease (79%). For the entire study cohort (n\u0026thinsp;=\u0026thinsp;118), the median OS and PFS2 were 15.4 months (95% CI\u0026thinsp;=\u0026thinsp;12.2\u0026ndash;19.6) and 11.5 months (95% CI\u0026thinsp;=\u0026thinsp;9.2\u0026ndash;13.5), respectively\u003c/p\u003e\n\u003cp\u003eFor more details, please refer to Table 2.\u0026nbsp;\u003c/p\u003e\n\u003ctable id=\"Taba\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOverall\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFFX followed by GN\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGN followed by nal-IRI/5-FU\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSMD\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge at diagnosis\u003c/p\u003e\n \u003cp\u003e(median [IQR])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65.00 [55.25, 70.00]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61.00 [52.00, 67.00]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70.00 [64.00, 73.00]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.881\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex\u0026thinsp;=\u0026thinsp;female (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48 (41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.565\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.124\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eECOG (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.583\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65 (55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48 (66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51 (43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMetastatic tumor (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e93 (79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57 (78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.047\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrading (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.493\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.269\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38 (48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34 (43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 in U/mL\u003c/p\u003e\n \u003cp\u003e(median [IQR])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1629.00 [187.50, 10165.65]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1918.80 [344.00, 12786.00]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e533.10 [140.75, 3482.78]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.065\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.385\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eNotes:\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003eTable 2: Patient baseline characteristics at diagnosis\u003c/p\u003e\n\u003cp\u003eChemotherapy sequence description:\u003c/p\u003e\n\u003cp\u003eIn the palliative first-line setting, patients had a median first-line treatment duration of 5.5 vs 4.8 months (p\u0026thinsp;=\u0026thinsp;0.602). This difference was statistically not significant between the two groups.\u003c/p\u003e\n\u003cp\u003eConcerning second-line therapy duration for patients progressing on FFX or GN, again was no statistically significant with a median treatment duration of 2.9 vs 2.1 months (p\u0026thinsp;=\u0026thinsp;0.155).\u003c/p\u003e\n\u003cp\u003eOutcome according to chemotherapy sequence:\u003c/p\u003e\n\u003cp\u003eORR, including complete response (CR) and partial response (PR), were 44% for FFX and 36% for GN for first-line treatment (ORR\u0026thinsp;=\u0026thinsp;1.391, 95% CI\u0026thinsp;=\u0026thinsp;0.594\u0026ndash;3.328, p\u0026thinsp;=\u0026thinsp;0.435), and 18% for GN and 25% for nal-IRI/5-FU for second-line therapy (OR\u0026thinsp;=\u0026thinsp;0.657, 95% CI\u0026thinsp;=\u0026thinsp;0.222-2.000, p\u0026thinsp;=\u0026thinsp;0.446), respectively. CBR, including CR, PR and SD, were 74% for FFX and 72% for GN for first-line treatment (OR\u0026thinsp;=\u0026thinsp;1.094, 95% CI\u0026thinsp;=\u0026thinsp;0.422\u0026ndash;2.765, p\u0026thinsp;=\u0026thinsp;0.831), and 45% for GN and 47% for nal-IRI/5-FU for second-line therapy (OR\u0026thinsp;=\u0026thinsp;0.907, 95% CI\u0026thinsp;=\u0026thinsp;0.372\u0026ndash;2.215, p\u0026thinsp;=\u0026thinsp;0.838), respectively. See Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTreatment response rates for first and second line by treatment-sequence\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eFirst-Line\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eSecond-Line\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFFX-GN\u003c/p\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;73\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGN-nal-IRI/5-FU\u003c/p\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;45\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep-value\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFFX-GN\u003c/p\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;73\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGN-nal-IRI/5-FU\u003c/p\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;45\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep-value\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eResponse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eComplete response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePartial response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 (44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (18%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStable disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProgressive disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (29%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37 (55%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (53%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot evaluable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"7\"\u003e\n \u003cp\u003eNotes: \u003csup\u003e1\u003c/sup\u003e n (%); \u003csup\u003e2\u003c/sup\u003e Fisher\u0026rsquo;s exact test\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003eThere was no statistically significant difference in outcomes in terms of OS between the two therapy sequences: Median OS for the FFX-GN sequence was 13.5 months vs 16.8 months for GN-nal-IRI/5-FU (HR\u0026thinsp;=\u0026thinsp;0.57, 95% CI\u0026thinsp;=\u0026thinsp;0.31\u0026ndash;1.04, p\u0026thinsp;=\u0026thinsp;0.07). In terms of PFS2, both treatment groups were highly comparable with a median of 10.8 months for FFX-GN vs 11.7 months for GN-nal-IRI/5-FU (HR\u0026thinsp;=\u0026thinsp;0.87, 95% CI\u0026thinsp;=\u0026thinsp;0.55\u0026ndash;1.40, p\u0026thinsp;=\u0026thinsp;0.58).\u003cp\u003e\u003c/p\u003e\n\u003cp\u003eA Schoenfeld test supports the assumption of proportional hazards and therefore hazard ratios were based on Cox-regression applying inverse probability of treatment weight( IPTW). The relative efficacy of the two different treatments sequences was not statistically significantly different across several subgroups regarding OS and PFS2.\u003c/p\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eDifferences between sequence groups\u003c/h2\u003e\n \u003cp\u003eHowever, patients in the GN group exhibited significant differences from those in the FFX group in terms of several key baseline characteristics (Table 2). Specifically, FFX group patients were notably younger and had a superior ECOG PS. To address this potential confounding factor when comparing GN-nal-IRI/5-FU and FFX-GN, we devised a refined IPTW that incorporated variables such as age, gender, staging (locally advanced versus metastatic disease), and performance status. Applying the IPTW reduced the Standardized Mean Difference (SMD) for various variables, most prominently for age (from 0.88 to 0.04) and performance status (from 0.58 to 0.05). Consequently, we regard the baseline characteristics of both treatment sequences as comparable when using the IPTW.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion/Limitations","content":"\u003cp\u003eTo our best knowledge, this study represents the largest analysis reporting efficacy data including PFS2, ORR and OS on the two predominant sequence strategies in the treatment of PDAC patients: FFX followed by GN versus GN followed by nal-IRI/5-FU employed as palliative first and second-line treatments in aPDAC. Currently, the only approved second-line treatment with level IA, as per NCCN and ESMO [21, 22], is a combination of nal-IRI/5-FU which demonstrated superior overall survival (OS) compared to 5-FU and leucovorin in the NAPOLI-1 trial after gemcitabine-based first-line treatment.\u003c/p\u003e\n\u003cp\u003eDespite FFX being one of the preferred first-line options, there is a lack of randomized controlled trials proving the efficacy of GN as a second-line option after FFX failure. The absence of head-to-head comparisons between the two first and second line poly-chemotherapy strategies and the eligibility criteria for clinical trials limit the generalizability of trial results to diverse patient scenarios.\u003c/p\u003e\n\u003cp\u003eIn this study, we aimed at addressing this dearth of comparative data by conducting a propensity score matched comparative effectiveness analysis of real-world outcomes from 118 patients treated either with FFX followed by GN or GN followed by nal-IRI/5-FU.\u003c/p\u003e\n\u003cp\u003eAs we included PDAC patients that had been diagnosed between 2010 and 2019, application patterns changed in the three academic centers especially upon the approval of nal-IRI/5-FU in 2016. This resulted in a shift of prescriptions towards GN followed by nal-IRI/5-FU.\u003c/p\u003e\n\u003cp\u003eMedian OS showed only a trend towards improved survival for the therapy sequence GN followed by nal-IRI compared to FFX-GN (HR\u0026thinsp;=\u0026thinsp;0.57, 95% CI\u0026thinsp;=\u0026thinsp;0.31\u0026ndash;1.04, p\u0026thinsp;=\u0026thinsp;0.07). PFS2 outcomes were comparable between the two regimens (HR\u0026thinsp;=\u0026thinsp;0.87, 95% CI\u0026thinsp;=\u0026thinsp;0.54\u0026ndash;1.41, p\u0026thinsp;=\u0026thinsp;0.58). However, significant differences in baseline characteristics, such as age and performance status, were noted between the two sequence cohorts.\u003c/p\u003e\n\u003cp\u003eTo mitigate potential bias and account for non-random treatment assignment, a propensity score model using Inverse Probability of Treatment Weighting was employed. In the adjusted analysis, according to IPTW, both treatment groups can be considered comparable regarding baseline characteristics. Response for both therapy sequences were similar for first and second-line treatments between the two sequential systemic treatment approaches, indicating the suitability of both poly-chemotherapy strategies for patients requiring a therapeutic response, especially in regions where access to novel and costly antineoplastic agents may be limited.\u003c/p\u003e\n\u003cp\u003eAlthough the study has limitations, including its retrospective nature and relatively low patient numbers in each sequence arm, it provides valuable insights into the real-world palliative therapy sequences for patients with advanced PC. Furthermore, one must keep in mind that, as patient inclusion started in August 2010, no information on BRCA status was available as a treatment decision tool at that time. Standard molecular testing in palliative first-line setting became routinely available in 2019.\u003c/p\u003e\n\u003cp\u003eThe rather large distribution between the two therapy sequences our rate from first- to second-line chemotherapy (FFX - \u0026gt;GN with around 50%) an GN -\u0026gt; Nalir-5-FU of over 80%) is interpreted with the rather long inclusion time frame of 9 years (2010\u0026ndash;2019) and therefore lack of availability of Nalir-5-FU.\u003c/p\u003e\n\u003cp\u003eAnother limitation is the fact that novel data resulting from following two phase 3 trials could not be accounted for:\u003c/p\u003e\n\u003cp\u003eOn one hand, the results of this tri- centric retrospective analysis suggest that the GN- Nalir-5-FU sequence is not inferior in terms of OS/PFS2/ORR compared to FFX-GN, and may even be potentially superior in terms of OS (HR 0.57). On the other hand, the findings from NAPOLI-3 (comparing NALIRIFOX (liposomal irinotecan 50 mg/m\u003csup\u003e2\u003c/sup\u003e, oxaliplatin 60 mg/m\u003csup\u003e2\u003c/sup\u003e, leucovorin 400 mg/m\u003csup\u003e2\u003c/sup\u003e, and fluorouracil 2400 mg/m\u003csup\u003e2\u003c/sup\u003e) to GN resulted in a median OS of 11.1 months in the NALIFIROX arm as compared with 9.2 months in the GN arm (HR 0.84 [95% CI 0.71\u0026ndash;0.99]; p\u0026thinsp;=\u0026thinsp;0.04) favor initiating treatment with the Naliri-containing triplet regimen compared to the NAPOLI-1 sequence. [23]\u003c/p\u003e\n\u003cp\u003eIn contrast, the results of the Asian GENERATE study showed a surprisingly median OS benefit of 17.0 months with GN compared to 14.0 months with modified FOLFIRINOX (HR1.29; 95% CI 0.98\u0026ndash;1.70) in an Asian study population [24].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, in cases where patients are considered suitable candidates for a triplet therapy (NALIRIFOX or mFOLFIRINOX), treatment should start accordingly (NAPOLI-3, Prodige4) as there is no statistically significant evidence of disadvantage in this retrospectively collected therapy sequence, which consists of triplets followed by Gem-Nab. For those patients who are not deemed fit for triplet therapy, the treatment protocol involves Gem-Nab followed by nal-IRI/5-FU.\u003c/p\u003e"},{"header":"Abbrevation","content":"\u003cp\u003eaPDAC: advanced ductal adenocarcinoma of the pancreas\u003c/p\u003e \u003cp\u003eCI: confidence intervall\u003c/p\u003e \u003cp\u003eCR: complete remission\u003c/p\u003e \u003cp\u003eDCR: disease control rate\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eFFX: FOLFIRINOX\u003c/h2\u003e \u003cp\u003eGN: Gemcitabine nab-Paclitaxel\u003c/p\u003e \u003cp\u003eHR: hazard ratio\u003c/p\u003e \u003cp\u003eIPTW: inverse probability of treatment weight\u003c/p\u003e \u003cp\u003enal-IRI/5-FU: nano-liposomal Irinotecan\u003c/p\u003e \u003cp\u003eOR: odds ratio\u003c/p\u003e \u003cp\u003eORR: objectice response rate\u003c/p\u003e \u003cp\u003eOS: overall survival\u003c/p\u003e \u003cp\u003ePD: progressive disease\u003c/p\u003e \u003cp\u003ePD1: progressive disease 1\u003c/p\u003e \u003cp\u003ePD2: progressive disease 1\u003c/p\u003e \u003cp\u003ePFS: progression-free survival\u003c/p\u003e \u003cp\u003ePFS2: second progression-free survival\u003c/p\u003e \u003cp\u003ePR: partial remission\u003c/p\u003e \u003cp\u003ePS: performance status\u003c/p\u003e \u003cp\u003ePSM: propensitiy score model\u003c/p\u003e \u003cp\u003eSD: stable disease\u003c/p\u003e \u003cp\u003eSMD: standardized mean difference\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eFH, LW, AS, KS and RH conceived and designed thestudy; AS interpreted the results; RG, AG,LH and ADcontributed to the writing of the manuscript; all authorscollected data and contributed patients, performed allstatistical analyses, wrote the first draft of the manuscript,agree with the manuscript\u0026rsquo;s results and conclusions\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA: a cancer journal for clinicians. 2020;70(1):7-30.\u003c/li\u003e\n\u003cli\u003eUnderwood PW, Herremans KM, Neal D, Riner AN, Nassour I, Hughes SJ, Trevino JG. Changing Practice Patterns and Improving Survival for Patients with Pancreatic Ductal Adenocarcinoma. Cancers. 2023;15(18):4464.\u003c/li\u003e\n\u003cli\u003ePolonski A, Izbicki JR, Uzunoglu FG. Centralization of Pancreatic Surgery in Europe. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 2019;23(10):2081-92.\u003c/li\u003e\n\u003cli\u003eConroy T, Castan F, Lopez A, Turpin A, Ben Abdelghani M, Wei AC, Mitry E, Biagi JJ, Evesque L, Artru P, et al. Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer: A Randomized Clinical Trial. JAMA oncology. 2022;8(11):1571-8.\u003c/li\u003e\n\u003cli\u003eConroy T, Desseigne F, Ychou M, Bouch\u0026eacute; O, Guimbaud R, B\u0026eacute;couarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardi\u0026egrave;re C, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. The New England journal of medicine. 2011;364(19):1817-25.\u003c/li\u003e\n\u003cli\u003eVon Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. The New England journal of medicine. 2013;369(18):1691-703.\u003c/li\u003e\n\u003cli\u003eDucreux M, Cuhna AS, Caramella C, Hollebecque A, Burtin P, Go\u0026eacute;r\u0026eacute; D, Seufferlein T, Haustermans K, Van Laethem JL, Conroy T, et al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology. 2015;26 Suppl 5:v56-68.\u003c/li\u003e\n\u003cli\u003eAbrams TA, Meyer G, Meyerhardt JA, Wolpin BM, Schrag D, Fuchs CS. Patterns of Chemotherapy Use in a U.S.-Based Cohort of Patients with Metastatic Pancreatic Cancer. The oncologist. 2017;22(8):925-33.\u003c/li\u003e\n\u003cli\u003eNagai K, Terashima T, Yamashita T, Kido H, Hayashi K, Sunagozaka H, Nakai R, Mizuno H, Hayakawa H, Nomura Y, et al. Dynamical changes of treatment patterns and outcomes of unresectable pancreatic cancer patients in real-life practice. Journal of Clinical Oncology. 2019;37(4_suppl):407-.\u003c/li\u003e\n\u003cli\u003eCheung WY, Zhang H, Tang PA, Spratlin JL, Lee-Ying RM, Goodwin RA, Meyers BM, Armstrong DE, Ramjeesingh R, Vickers MM. A real world multicenter study of first (1L) and second (2L) line treatment patterns and outcomes in advanced pancreatic cancer (APC). American Society of Clinical Oncology; 2018.\u003c/li\u003e\n\u003cli\u003eRiedl JM, Posch F, Horvath L, Gantschnigg A, Renneberg F, Schwarzenbacher E, Moik F, Barth DA, Rossmann CH, Stotz M, et al. Gemcitabine/nab-Paclitaxel versus FOLFIRINOX for palliative first-line treatment of advanced pancreatic cancer: A propensity score analysis. European journal of cancer (Oxford, England : 1990). 2021;151:3-13.\u003c/li\u003e\n\u003cli\u003eWang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet (London, England). 2016;387(10018):545-57.\u003c/li\u003e\n\u003cli\u003eZaanan A, Trouilloud I, Markoutsaki T, Gauthier M, Dupont-Gossart AC, Lecomte T, Aparicio T, Artru P, Thirot-Bidault A, Joubert F, et al. FOLFOX as second-line chemotherapy in patients with pretreated metastatic pancreatic cancer from the FIRGEM study. BMC Cancer. 2014;14:441.\u003c/li\u003e\n\u003cli\u003eGhosn M, Farhat F, Kattan J, Younes F, Moukadem W, Nasr F, Chahine G. FOLFOX-6 combination as the first-line treatment of locally advanced and/or metastatic pancreatic cancer. American journal of clinical oncology. 2007;30(1):15-20.\u003c/li\u003e\n\u003cli\u003eTempero MA. NCCN Guidelines Updates: Pancreatic Cancer. Journal of the National Comprehensive Cancer Network : JNCCN. 2019;17(5.5):603-5.\u003c/li\u003e\n\u003cli\u003eHosein PJ, de Lima Lopes G, Jr., Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I, Montero AJ, Merchan JR, Rocha Lima CM. A phase II trial of nab-Paclitaxel as second-line therapy in patients with advanced pancreatic cancer. American journal of clinical oncology. 2013;36(2):151-6.\u003c/li\u003e\n\u003cli\u003eR Core Team (2023). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria. [23.02.2024]. Available from: \u0026lt;https://www.R-project.org/\u0026gt;.\u003c/li\u003e\n\u003cli\u003eZhang Z, Kim HJ, Lonjon G, Zhu Y. Balance diagnostics after propensity score matching. Ann Transl Med. 2019;7(1):16.\u003c/li\u003e\n\u003cli\u003eChesnaye NC, Stel VS, Tripepi G, Dekker FW, Fu EL, Zoccali C, Jager KJ. An introduction to inverse probability of treatment weighting in observational research. Clinical kidney journal. 2022;15(1):14-20.\u003c/li\u003e\n\u003cli\u003eXu S, Ross C, Raebel MA, Shetterly S, Blanchette C, Smith D. Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2010;13(2):273-7.\u003c/li\u003e\n\u003cli\u003eNCCN. NCCN Guidelines Version 1.2024 Pancreatic Adenocarcinoma [Available from: https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf.\u003c/li\u003e\n\u003cli\u003eConroy T, Pfeiffer P, Vilgrain V, Lamarca A, Seufferlein T, O\u0026rsquo;Reilly E, Hackert T, Golan T, Prager G, Haustermans K. Pancreatic cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up☆. Annals of Oncology. 2023;34(11):987-1002.\u003c/li\u003e\n\u003cli\u003eWainberg ZA, Melisi D, Macarulla T, Pazo Cid R, Chandana SR, De La Fouchardi\u0026egrave;re C, Dean A, Kiss I, Lee WJ, Goetze TO, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet (London, England). 2023;402(10409):1272-81.\u003c/li\u003e\n\u003cli\u003eOhba A, Ozaka M, Ogawa G, Okusaka T, Kobayashi S, Yamashita T, Ikeda M, Yasuda I, Sugimori K, Sasahira N. 1616O Nab-paclitaxel plus gemcitabine versus modified FOLFIRINOX or S-IROX in metastatic or recurrent pancreatic cancer (JCOG1611, GENERATE): A multicentred, randomized, open-label, three-arm, phase II/III trial. Annals of Oncology. 2023;34:S894.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4461811/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4461811/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eManaging advanced pancreatic ductal adenocarcinoma (aPDAC) is challenging, particularly in determining the optimal sequence of chemotherapy protocols. Despite a 5-year survival rate of only 3%, recent data from the US National Cancer Database indicate significant improvements in median overall survival (OS) for patients with metastatic pancreatic cancer over the past decade. This progress is attributed to enhanced chemotherapy regimens, the introduction of (new)-adjuvant chemotherapy, improved surgical techniques, and centralized treatment in high-volume centers.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003e We conducted a retrospective cohort study at three Austrian academic centers, including patients with histologically confirmed primary locally advanced or metastatic PDAC who received first-line chemotherapy with either FOLFIRINOX (FFX) or gemcitabine\u0026thinsp;+\u0026thinsp;nab-paclitaxel (GN), followed by second-line treatments with GN or nanoliposomal irinotecan with fluorouracil\u0026thinsp;+\u0026thinsp;leucovorin (nal-IRI/5-FU) after progression. The study's primary endpoints were second progression-free survival (PFS2) and OS. Statistical analyses employed propensity score matching and inverse probability of treatment weighting (IPTW) to balance the groups and estimate the impact of the treatment sequences on outcomes.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eAmong 455 screened patients, 118 met the inclusion criteria, with 73 receiving FFX followed by GN and 45 receiving GN followed by nal-IRI/5-FU. The median OS was 15.4 months, and PFS2 was 11.5 months for the entire cohort. The GN-nal-IRI/5-FU sequence showed a trend toward improved OS compared to the FFX-GN sequence (HR\u0026thinsp;=\u0026thinsp;0.57, p\u0026thinsp;=\u0026thinsp;0.07), with comparable PFS2 between the two regimens (HR\u0026thinsp;=\u0026thinsp;0.87, p\u0026thinsp;=\u0026thinsp;0.58). Baseline characteristics differed significantly between the groups, necessitating the use of IPTW to ensure comparability.\u003c/p\u003e\u003ch2\u003eDiscussion:\u003c/h2\u003e \u003cp\u003e This study is the largest to date comparing the efficacy of FFX followed by GN versus GN followed by nal-IRI/5-FU in aPDAC. The GN-nal-IRI/5-FU sequence demonstrated a potential survival benefit, although not statistically significant. The results suggest that both treatment sequences are viable, particularly where access to newer agents is limited. The study's retrospective nature and baseline differences between groups are acknowledged limitations.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eFor patients suitable for triplet therapies, starting with NALIRIFOX or mFOLFIRINOX is supported by recent phase 3 trials. For those not fit for such intensive regimens, GN followed by nal-IRI/5-FU remains a valid strategy. Further prospective studies are needed to confirm these findings.\u003c/p\u003e","manuscriptTitle":"Chemotherapy sequence in advanced pancreatic cancer – still a matter of debate?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-07 22:58:06","doi":"10.21203/rs.3.rs-4461811/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"eefc09c4-3d30-47b0-a6d5-2e3db1e76442","owner":[],"postedDate":"June 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-03T13:23:36+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-07 22:58:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4461811","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4461811","identity":"rs-4461811","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}