Radiofrequency ablation and chemotherapy versus chemotherapy alone for locally advanced pancreatic cancer (PELICAN): study protocol for a randomized controlled trial

M S Walma, S J Rombouts, L J H Brada, I H Borel Rinkes, K Bosscha, R C Bruijnen, O R Busch, G J Creemers, F Daams, R M van Dam, O M van Delden, S Festen, P Ghorbani, D J de Groot, J W B de Groot, N Haj Mohammad, R van Hillegersberg, I H de Hingh, M D'Hondt, E D Kerver, M S van Leeuwen, M S Liem, K P van Lienden, M Los, V E de Meijer, M R Meijerink, L J Mekenkamp, C Y Nio, I Oulad Abdennabi, E Pando, G A Patijn, M B Polée, J F Pruijt, G Roeyen, J A Ropela, M W J Stommel, J de Vos-Geelen, J J de Vries, E M van der Waal, F J Wessels, J W Wilmink, H C van Santvoort, M G Besselink, I Q Molenaar, Dutch Pancreatic Cancer Group, M S Walma, S J Rombouts, L J H Brada, I H Borel Rinkes, K Bosscha, R C Bruijnen, O R Busch, G J Creemers, F Daams, R M van Dam, O M van Delden, S Festen, P Ghorbani, D J de Groot, J W B de Groot, N Haj Mohammad, R van Hillegersberg, I H de Hingh, M D'Hondt, E D Kerver, M S van Leeuwen, M S Liem, K P van Lienden, M Los, V E de Meijer, M R Meijerink, L J Mekenkamp, C Y Nio, I Oulad Abdennabi, E Pando, G A Patijn, M B Polée, J F Pruijt, G Roeyen, J A Ropela, M W J Stommel, J de Vos-Geelen, J J de Vries, E M van der Waal, F J Wessels, J W Wilmink, H C van Santvoort, M G Besselink, I Q Molenaar, Dutch Pancreatic Cancer Group

Abstract

Background: Approximately 80% of patients with locally advanced pancreatic cancer (LAPC) are treated with chemotherapy, of whom approximately 10% undergo a resection. Cohort studies investigating local tumor ablation with radiofrequency ablation (RFA) have reported a promising overall survival of 26-34 months when given in a multimodal setting. However, randomized controlled trials (RCTs) investigating the effect of RFA in combination with chemotherapy in patients with LAPC are lacking.

Methods: The "Pancreatic Locally Advanced Unresectable Cancer Ablation" (PELICAN) trial is an international multicenter superiority RCT, initiated by the Dutch Pancreatic Cancer Group (DPCG). All patients with LAPC according to DPCG criteria, who start with FOLFIRINOX or (nab-paclitaxel/)gemcitabine, are screened for eligibility. Restaging is performed after completion of four cycles of FOLFIRINOX or two cycles of (nab-paclitaxel/)gemcitabine (i.e., 2 months of treatment), and the results are assessed within a nationwide online expert panel. Eligible patients with RECIST stable disease or objective response, in whom resection is not feasible, are randomized to RFA followed by chemotherapy or chemotherapy alone. In total, 228 patients will be included in 16 centers in The Netherlands and four other European centers. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, RECIST response, CA 19.9 and CEA response, toxicity, quality of life, pain, costs, and immunomodulatory effects of RFA.

Discussion: The PELICAN RCT aims to assess whether the combination of chemotherapy and RFA improves the overall survival when compared to chemotherapy alone, in patients with LAPC with no progression of disease following 2 months of systemic treatment.

Trial registration: Dutch Trial Registry NL4997 . Registered on December 29, 2015. ClinicalTrials.gov NCT03690323 . Retrospectively registered on October 1, 2018.

Keywords: Chemotherapy; Locally advanced pancreatic cancer; Overall survival; Radiofrequency ablation.

Conflict of interest statement

JWdG has received personal fees outside the submitted work from Bristol-Myers Squibb, Roche, Pierre-Fabre, Servier, MSD, and Novartis. RvH is a proctor for Intuitive, is part of the advisory board of Medtronics, and received an educational grant from Olympus outside the submitted work. IdH reports grants from Roche Pharmaceutical, QPS/RanD, and Medtronic, outside the submitted work. KvL reports personal fees and non-financial support from AngioDynamics, outside the submitted work. VEdM reports grants from Stichting Louise Vehmeijer and NWO and travel grants from Astellas and Neovii, outside the submitted work. MRM reports grants, personal fees, and non-financial support from Angiodynamics; grants and personal fees from Medtronic Covidien; and non-financial support from Cascination, outside the submitted work. NHM reports advisory board fees for her institution from BMS, Eli Lilly, Servier, and MSD. JdVG reports grants and non-financial support from Servier, outside the submitted work. JWW reports research grants from Servier, Halozyme, Novartis, Celgene, Astra Zeneca, Pfizer, Roche, Amgen, and Merck and a consulting/advisory role for Servier and Celgene. HCvS has received a research grant from the Dutch Cancer Society, during and outside the submitted work. MGB has received a research grant from the Dutch Cancer Society, during and outside the conduct of the study. IQM has received a research grant from the Dutch Cancer Society, during the conduct of the study. The other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Trial flow diagram
Fig. 2
Fig. 2
Schedule of enrolment, interventions, and assessments according to the SPIRIT guidelines

References

    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi: 10.3322/caac.21492.
    1. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378(9791):607–620. doi: 10.1016/S0140-6736(10)62307-0.
    1. Latenstein AEJ, van der Geest LGM, Bonsing BA, Groot Koerkamp B, Haj Mohammad N, de Hingh IHJT, de Meijer VE, Molenaar IQ, van Santvoort H, van Tienhoven G, Verheij J, Vissers PAJ, de Vos-Geelen J, Busch OR, van Eijck C, van Laarhoven H, Besselink MG, Wilmink JW, Dutch Pancreatic Cancer Group Nationwide trends in incidence, treatment and survival of pancreatic ductal adenocarcinoma. Eur J Cancer. 2020;125:83–93. doi: 10.1016/j.ejca.2019.11.002.
    1. Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403–2413. doi: 10.1200/JCO.1997.15.6.2403.
    1. Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, Zaniboni A, Ducreux M, Aitini E, Taïeb J, Faroux R, Lepere C, de Gramont A, GERCOR., GISCAD Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005;23(15):3509–3516. doi: 10.1200/JCO.2005.06.023.
    1. Lima CMR, Green MR, Rotche R, Miller WH, Jeffrey GM, Cisar LA, et al. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol. 2004;22(18):3776–3783. doi: 10.1200/JCO.2004.12.082.
    1. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–1825. doi: 10.1056/NEJMoa1011923.
    1. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–1703. doi: 10.1056/NEJMoa1304369.
    1. van Veldhuisen E, van den Oord C, Brada LJ, Walma MS, Vogel JA, Wilmink JW, et al. Locally advanced pancreatic cancer: work-up, staging, and local intervention strategies. Cancers (Basel) 2019;11:976. doi: 10.3390/cancers11070976.
    1. Philip PA, Lacy J, Portales F, Sobrero A, Pazo-Cid R, Manzano Mozo JL, Kim EJ, Dowden S, Zakari A, Borg C, Terrebonne E, Rivera F, Sastre J, Bathini V, López-Trabada D, Asselah J, Saif MW, Shiansong Li J, Ong TJ, Nydam T, Hammel P. Nab-paclitaxel plus gemcitabine in patients with locally advanced pancreatic cancer (LAPACT): a multicentre, open-label phase 2 study. Lancet Gastroenterol Hepatol. 2020;5(3):285–294. doi: 10.1016/S2468-1253(19)30327-9.
    1. Suker M, Beumer BR, Sadot E, Marthey L, Faris JE, Mellon EA, el-Rayes BF, Wang-Gillam A, Lacy J, Hosein PJ, Moorcraft SY, Conroy T, Hohla F, Allen P, Taieb J, Hong TS, Shridhar R, Chau I, van Eijck C, Koerkamp BG. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol. 2016;17(6):801–810. doi: 10.1016/S1470-2045(16)00172-8.
    1. Matsui Y, Nakagawa A, Kamiyama Y, Yamamoto K, Kubo N, Nakase Y. Selective thermocoagulation of unresectable pancreatic cancers by using radiofrequency capacitive heating. Pancreas. 2000;20(1):14–20. doi: 10.1097/00006676-200001000-00002.
    1. Mirza AN, Fornage BD, Sneige N, Kuerer HM, Newman LA, Ames FC, et al. Radiofrequency ablation of solid tumors. Cancer J. 2001;7:95–102.
    1. Girelli R, Frigerio I, Giardino A, Regi P, Gobbo S, Malleo G, Salvia R, Bassi C. Results of 100 pancreatic radiofrequency ablations in the context of a multimodal strategy for stage III ductal adenocarcinoma. Langenbeck’s Arch Surg. 2013;398(1):63–69. doi: 10.1007/s00423-012-1011-z.
    1. Girelli R, Frigerio I, Salvia R, Barbi E, Tinazzi Martini P, Bassi C. Feasibility and safety of radiofrequency ablation for locally advanced pancreatic cancer. Br J Surg. 2010;97(2):220–225. doi: 10.1002/bjs.6800.
    1. Fegrachi S, Walma MS, de Vries JJJ, van Santvoort HC, Besselink MG, von Asmuth EG, van Leeuwen MS, Borel Rinkes IH, Bruijnen RC, de Hingh IH, Klaase JM, Molenaar IQ, van Hillegersberg R. Safety of radiofrequency ablation in patients with locally advanced, unresectable pancreatic cancer: a phase II study. Eur J Surg Oncol. 2019;45(11):2166–2172. doi: 10.1016/j.ejso.2019.06.008.
    1. Cantore M, Girelli R, Mambrini A, Frigerio I, Boz G, Salvia R, Giardino A, Orlandi M, Auriemma A, Bassi C. Combined modality treatment for patients with locally advanced pancreatic adenocarcinoma. Br J Surg. 2012;99(8):1083–1088. doi: 10.1002/bjs.8789.
    1. Tempero MA, Malafa MP, Behrman SW, Benson AB, Casper ES, Chiorean EG, et al. Pancreatic adenocarcinoma, version 2.2014: featured updates to the NCCN guidelines. J Natl Compr Cancer Netw. 2014;12(8):1083–1093. doi: 10.6004/jnccn.2014.0106.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Tol JAMG, Gouma DJ, Bassi C, Dervenis C, Montorsi M, Adham M, et al. Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS) Surg (United States) 2014;156:591–600.
    1. Tol JAMG, Van Hooft JE, Timmer R, Kubben FJGM, Van Der Harst E, De Hingh IHJT, et al. Metal or plastic stents for preoperative biliary drainage in resectable pancreatic cancer. Gut. 2016;65(12):1981–1987. doi: 10.1136/gutjnl-2014-308762.
    1. Frericks BB, Ritz JP, Roggan A, Wolf KJ, Albrecht T. Multipolar radiofrequency ablation of hepatic tumors: initial experience. Radiology. 2005;237(3):1056–1062. doi: 10.1148/radiol.2373041104.
    1. Fegrachi S, Molenaar IQ, Klaessens JH, Besselink MG, Offerhaus JA, Van Hillegersberg R. Radiofrequency ablation of the pancreas with and without intraluminal duodenal cooling in a porcine model. J Surg Res. 2013;184(2):867–872. doi: 10.1016/j.jss.2013.04.068.
    1. Fegrachi S, Molenaar IQ, Klaessens JH, Besselink MG, Offerhaus JA, Van Hillegersberg R. Radiofrequency ablation of the pancreas: two-week follow-up in a porcine model. Eur J Surg Oncol. 2014;40(8):1000–1007. doi: 10.1016/j.ejso.2013.11.001.
    1. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, Haes JCJM, Kaasa S, Klee M, Osoba D, Razavi D, Rofe PB, Schraub S, Sneeuw K, Sullivan M, Takeda F. The European organization for research and treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365–376. doi: 10.1093/jnci/85.5.365.
    1. Fitzsimmons D, Johnson CD, George S, Payne S, Sandberg AA, Bassi C, Beger HG, Birk D, Büchler MW, Dervenis C, Fernandez Cruz L, Friess H, Grahm AL, Jeekel J, Laugier R, Meyer D, Singer MW, Tihanyi T. Development of a disease specific quality of life (QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the QLQ-C30 in patients with pancreatic cancer. Eur J Cancer. 1999;35(6):939–941. doi: 10.1016/S0959-8049(99)00047-7.
    1. Jun GT, Ward J, Clarkson PJ. Systems modelling approaches to the design of safe healthcare delivery: ease of use and usefulness perceived by healthcare workers. Ergonomics. 2010;53(7):829–847. doi: 10.1080/00140139.2010.489653.
    1. Bonnetain F, Bonsing B, Conroy T, Dousseau A, Glimelius B, Haustermans K, et al. Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN Initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials). Eur. J. Cancer. 2014;50(17):2983–93.
    1. Wente MN, Veit JA, Bassi C, Dervenis C, Fingerhut A, Gouma DJ, Izbicki JR, Neoptolemos JP, Padbury RT, Sarr MG, Yeo CJ, Büchler MW. Postpancreatectomy hemorrhage (PPH)-an International Study Group of Pancreatic Surgery (ISGPS) definition. Surgery. 2007;142(1):20–25. doi: 10.1016/j.surg.2007.02.001.
    1. Wente MN, Bassi C, Dervenis C, Fingerhut A, Gouma DJ, Izbicki JR, Neoptolemos JP, Padbury RT, Sarr MG, Traverso LW, Yeo CJ, Büchler MW. Delayed gastric emptying (DGE) after pancreatic surgery: a suggested definition by the International Study Group of Pancreatic Surgery (ISGPS) Surgery. 2007;142(5):761–768. doi: 10.1016/j.surg.2007.05.005.
    1. Bassi C, Marchegiani G, Dervenis C, Sarr M, Abu Hilal M, Adham M, et al. The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 years after. Surg (United States) 2017;161:584–591. doi: 10.1016/j.surg.2016.11.014.
    1. Koch M, Garden OJ, Padbury R, Rahbari NN, Adam R, Capussotti L, Fan ST, Yokoyama Y, Crawford M, Makuuchi M, Christophi C, Banting S, Brooke-Smith M, Usatoff V, Nagino M, Maddern G, Hugh TJ, Vauthey JN, Greig P, Rees M, Nimura Y, Figueras J, DeMatteo RP, Büchler MW, Weitz J. Bile leakage after hepatobiliary and pancreatic surgery: a definition and grading of severity by the International Study Group of Liver Surgery. Surgery. 2011;149(5):680–688. doi: 10.1016/j.surg.2010.12.002.
    1. Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346(jan08 15) 10.1136/bmj.e7586.
    1. Poon RT, Ng KK, Lam CM, Ai V, Yuen J, Fan ST, Wong J. Learning curve for radiofrequency ablation of liver tumors. Ann Surg. 2004;239(4):441–449. doi: 10.1097/01.sla.0000118565.21298.0a.
    1. De Wilde RF, Besselink MGH, Van Der Tweel I, De Hingh IHJT, Van Eijck CHJ, Dejong CHC, et al. Impact of nationwide centralization of pancreaticoduodenectomy on hospital mortality. Br J Surg. 2012;99(3):404–410. doi: 10.1002/bjs.8664.
    1. Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O’Dwyer P, Haller D, Catalano P, Cella D, Benson AB., III Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27(23):3778–3785. doi: 10.1200/JCO.2008.20.9007.
    1. Little RJA, Wang Y. Pattern-mixture models for multivariate incomplete data with covariates. Biometrics. 1996;52(1):98–111.
    1. Hackert T, Sachsenmaier M, Hinz U, Schneider L, Michalski CW, Springfeld C, Strobel O, Jäger D, Ulrich A, Büchler MW. Locally advanced pancreatic cancer: neoadjuvant therapy with folfirinox results in resectability in 60% of the patients. Ann Surg. 2016;264(3):457–461. doi: 10.1097/SLA.0000000000001850.
    1. Rangelova E, Wefer A, Persson S, Valente R, Tanaka K, Orsini N, et al. Surgery improves survival after neoadjuvant therapy for borderline and locally advanced pancreatic cancer. Ann Surg. 2021;273(3):579–86.
    1. Giardino A, Girelli R, Frigerio I, Regi P, Cantore M, Alessandra A, Lusenti A, Salvia R, Bassi C, Pederzoli P. Triple approach strategy for patients with locally advanced pancreatic carcinoma. Hpb. 2013;15(8):623–627. doi: 10.1111/hpb.12027.
    1. Marthey L, Sa-Cunha A, Blanc JF, Gauthier M, Cueff A, Francois E, Trouilloud I, Malka D, Bachet JB, Coriat R, Terrebonne E, de la Fouchardière C, Manfredi S, Solub D, Lécaille C, Thirot Bidault A, Carbonnel F, Taieb J. FOLFIRINOX for locally advanced pancreatic adenocarcinoma: results of an AGEO Multicenter Prospective Observational Cohort. Ann Surg Oncol. 2015;22(1):295–301. doi: 10.1245/s10434-014-3898-9.
    1. Suker M, Koerkamp BG, Coene PP, van der Harst E, Bonsing BA, Vahrmeijer AL, Mieog JSD, Swijnenburg RJ, Dwarkasing RS, Roos D, van Eijck CHJ. Yield of staging laparoscopy before treatment of locally advanced pancreatic cancer to detect occult metastases. Eur J Surg Oncol. 2019;45(10):1906–1919. doi: 10.1016/j.ejso.2019.06.004.
    1. Rombouts SJ, Walma MS, Vogel JA, van Rijssen LB, Wilmink JW, Mohammad NH, van Santvoort HC, Molenaar IQ, Besselink MG. Systematic review of resection rates and clinical outcomes after FOLFIRINOX-based treatment in patients with locally advanced pancreatic cancer. Ann Surg Oncol. 2016;23(13):4352–4360. doi: 10.1245/s10434-016-5373-2.
    1. Gemenetzis G, Groot VP, Blair AB, Laheru DA, Zheng L, Narang AK, et al. Survival in locally advanced pancreatic cancer after neoadjuvant therapy and surgical resection. Ann Surg. 2019; 10.1097/SLA.0000000000002753. Available from: ; . epublished
    1. Maggino L, Malleo G, Marchegiani G, Viviani E, Nessi C, Ciprani D, Esposito A, Landoni L, Casetti L, Tuveri M, Paiella S, Casciani F, Sereni E, Binco A, Bonamini D, Secchettin E, Auriemma A, Merz V, Simionato F, Zecchetto C, D’Onofrio M, Melisi D, Bassi C, Salvia R. Outcomes of primary chemotherapy for borderline resectable and locally advanced pancreatic ductal adenocarcinoma. JAMA Surg. 2019;154(10):932–942. doi: 10.1001/jamasurg.2019.2277.
    1. Walma MS, Brada LJ, Patuleia SIS, Blomjous JG, Bollen TL, Bosscha K, et al. Treatment strategies and clinical outcomes in consecutive patients with locally advanced pancreatic cancer: a multicenter prospective cohort. Eur J Surg Oncol. 2021;47:699–707. doi: 10.1016/j.ejso.2020.11.137.
    1. Strijker M, Mackay TM, Bonsing BA, Bruno MJ, van Eijck CHJ, de Hingh IHJT, Koerkamp BG, van Laarhoven H, Molenaar IQ, van Santvoort H, van Tienhoven G, Wilmink JW, Zeverijn S, Busch OR, Besselink MG, Dutch Pancreatic Cancer Group Establishing and coordinating a nationwide multidisciplinary study group: lessons learned by the Dutch Pancreatic Cancer Group. Ann Surg. 2020;271(4):e102–e104. doi: 10.1097/SLA.0000000000003779.

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