Selective Internal Radiation Therapy (SIRT) with yttrium-90 resin microspheres plus standard systemic chemotherapy regimen of FOLFOX versus FOLFOX alone as first-line treatment of non-resectable liver metastases from colorectal cancer: the SIRFLOX study

Peter Gibbs, Val Gebski, Mark Van Buskirk, Kenneth Thurston, David N Cade, Guy A Van Hazel, SIRFLOX Study Group, Pradip Amin, Bruna Angelelli, Jacques Balosso, Alex Beny, Daniel Bloomgarden, Eveline Boucher, Michael Brown, Harald-Robert Bruch, James Bui, Matthew Burge, Giuseppe Cardaci, James Carlisle, Yi-Jen Chen, Patrick Chevallier, Stephen Clarke, Andrew Coveler, Michel Craninx, Thierry Delanoit, Amélie Deleporte, Paul Eliadis, Francis Facchini, Thomas Ferguson, Michel Ferrante, Michael Findlay, Gary Frenette, Jacob Frick, Vinod Ganju, Michael Garofalo, Karen Geboes, Gerald Gehbauer, Benjamin George, Ravit Geva, Michael Gordon, Seza Gulac, James Hannigan, Volker Heinemann, Thomas Helmberger, Matthew Holtzman, Richard Isaacs, Philip James, Andreas Kaubisch, Yon-Dschun Ko, Todd Kooy, Hendrik Kröning, Frank Lammert, Winston Liauw, Samy Louafi, Marc de Man, Jeffrey Margolis, Robert Martin, Gavin Marx, Marco Matos, Els Monsaert, Veerle Moons, Louise Nott, Arnd Nusch, Anne O'Donnell, Howard Ozer, Siddarth Padia, Nick Pavlakis, Marc Peeters, David Perez, Stefan Pluntke, Marc Polus, Alex Powell, Timothy Price, David Ransom, Christine Rebischung, Karsten Ridwelski, Hanno Riess, JorgeRamon Riera, Jens Ricke, William Rilling, Bridget Robinson, Javier Rodríguez, Tilmann Sauerbruch, Michael Savin, Klemens Scheidhauer, Elyse Schneiderman, Grant Seeger, Eva Segelov, EinatShaham Schmueli, Adi Shani, Jenny Shannon, Navesh Sharma, Stephen Shibata, Nimit Singhal, Denis Smith, Randall Smith, Salomon Stemmer, Oliver Stötzer, Andrew Strickland, Julien Taieb, Klaus Tatsch, Eric Terrebonne, Thomas Tilcher, Ursula Vehling-Kaiser, Ruth Vera-Garcia, Thomas Vogl, Euan Walpole, Eric Wang, Samuel Whiting, Ido Wolf, Peter Gibbs, Val Gebski, Mark Van Buskirk, Kenneth Thurston, David N Cade, Guy A Van Hazel, SIRFLOX Study Group, Pradip Amin, Bruna Angelelli, Jacques Balosso, Alex Beny, Daniel Bloomgarden, Eveline Boucher, Michael Brown, Harald-Robert Bruch, James Bui, Matthew Burge, Giuseppe Cardaci, James Carlisle, Yi-Jen Chen, Patrick Chevallier, Stephen Clarke, Andrew Coveler, Michel Craninx, Thierry Delanoit, Amélie Deleporte, Paul Eliadis, Francis Facchini, Thomas Ferguson, Michel Ferrante, Michael Findlay, Gary Frenette, Jacob Frick, Vinod Ganju, Michael Garofalo, Karen Geboes, Gerald Gehbauer, Benjamin George, Ravit Geva, Michael Gordon, Seza Gulac, James Hannigan, Volker Heinemann, Thomas Helmberger, Matthew Holtzman, Richard Isaacs, Philip James, Andreas Kaubisch, Yon-Dschun Ko, Todd Kooy, Hendrik Kröning, Frank Lammert, Winston Liauw, Samy Louafi, Marc de Man, Jeffrey Margolis, Robert Martin, Gavin Marx, Marco Matos, Els Monsaert, Veerle Moons, Louise Nott, Arnd Nusch, Anne O'Donnell, Howard Ozer, Siddarth Padia, Nick Pavlakis, Marc Peeters, David Perez, Stefan Pluntke, Marc Polus, Alex Powell, Timothy Price, David Ransom, Christine Rebischung, Karsten Ridwelski, Hanno Riess, JorgeRamon Riera, Jens Ricke, William Rilling, Bridget Robinson, Javier Rodríguez, Tilmann Sauerbruch, Michael Savin, Klemens Scheidhauer, Elyse Schneiderman, Grant Seeger, Eva Segelov, EinatShaham Schmueli, Adi Shani, Jenny Shannon, Navesh Sharma, Stephen Shibata, Nimit Singhal, Denis Smith, Randall Smith, Salomon Stemmer, Oliver Stötzer, Andrew Strickland, Julien Taieb, Klaus Tatsch, Eric Terrebonne, Thomas Tilcher, Ursula Vehling-Kaiser, Ruth Vera-Garcia, Thomas Vogl, Euan Walpole, Eric Wang, Samuel Whiting, Ido Wolf

Abstract

Background: In colorectal cancer (CRC), unresectable liver metastases are linked to poor prognosis. Systemic chemotherapy with regimens such as FOLFOX (combination of infusional 5-fluorouracil, leucovorin and oxaliplatin) is the standard first-line treatment. The SIRFLOX trial was designed to assess the efficacy and safety of combining FOLFOX-based chemotherapy with Selective Internal Radiation Therapy (SIRT or radioembolisation) using yttrium-90 resin microspheres (SIR-SpheresR; Sirtex Medical Limited, North Sydney, Australia).

Methods/design: SIRFLOX is a randomised, multicentre trial of mFOLFOX6 chemotherapy+/-SIRT as first-line treatment of patients with liver-only or liver-predominant metastatic CRC (mCRC). The trial aims to recruit adult chemotherapy-naive patients with proven liver metastases with or without limited extra-hepatic disease, a life expectancy of >=3 months and a WHO performance status of 0-1. Patients will be randomised to receive either mFOLFOX6 or SIRT+mFOLFOX6 (with a reduced dose of oxaliplatin in cycles 1-3 following SIRT). Patients in both arms can receive bevacizumab at investigator discretion. Protocol chemotherapy will continue until there is unacceptable toxicity, evidence of tumour progression, complete surgical resection or ablation of cancerous lesions, or the patient requests an end to treatment. The primary endpoint of the SIRFLOX trial is progression-free survival (PFS). Secondary endpoints include: PFS in the liver; tumour response rate (liver and any site); site of tumour progression; health-related quality of life; toxicity and safety; liver resection rate; and overall survival. Assuming an increase in the median PFS from 9.4 months to 12.5 months with the addition of SIRT to mFOLFOX6, recruiting >=450 patients will be sufficient for 80% power and 95% confidence.

Discussion: The SIRFLOX trial will establish the potential role of SIRT+standard systemic chemotherapy in the first-line management of mCRC with non-resectable liver metastases.

Trial registration: SIRFLOX ClinicalTrials.gov identifier: NCT00724503. Registered 25 July 2008.

Figures

Figure 1
Figure 1
Overview of SIRFLOX study design. Figure footnote: * Bevacizumab, at the investigator’s discretion, but not until cycle 4.
Figure 2
Figure 2
Treatment received as part of the SIRFLOX study. Figure footnote: ‡Bevacizumab can be added at the investigator’s discretion starting at cycle 1 (or according to the institutional protocol). †Bevacizumab can be added at the investigator’s discretion but should not be initiated until cycle 4 (or according to the institutional protocol). If leucovorin is not available, levofolinic acid can be used at a dose of 100 mg/m2. If a centre considers leucovorin 400 mg/m2 the standard dose, then this will be allowed at the investigator’s discretion. LV = Leucovorin; 5-FU =5-Fluorouracil.

References

    1. Welch JP, Donaldson GA. The clinical correlation of an autopsy study of recurrent colorectal cancer. Ann Surg. 1979;189:496–502. doi: 10.1097/00000658-197904000-00027.
    1. Abbas S, Lam V, Hollands M. Ten-year survival after liver resection for colorectal metastases: systematic review and meta-analysis. ISRN Oncol. 2011;2011:763245.
    1. Adam R. Developing strategies for liver metastases from colorectal cancer. Semin Oncol. 2007;34:S7–S11. doi: 10.1053/j.seminoncol.2007.01.003.
    1. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230:309–318. doi: 10.1097/00000658-199909000-00004.
    1. Choti MA, Sitzmann JV, Tiburi MF, Sumetchotimetha W, Rangsin R, Schulick RD, Lillemoe KD, Yeo CJ, Cameron JL. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg. 2002;235:759–766. doi: 10.1097/00000658-200206000-00002.
    1. Stangl R, Altendorf-Hofmann A, Charnley RM, Scheele J. Factors influencing the natural history of colorectal liver metastases. Lancet. 1994;343:1405–1410. doi: 10.1016/S0140-6736(94)92529-1.
    1. Rothbarth J, van de Velde CJ. Treatment of liver metastases of colorectal cancer. Ann Oncol. 2005;16(Suppl 2):ii144–ii149.
    1. Berber E, Pelley R, Siperstein AE. Predictors of survival after radiofrequency thermal ablation of colorectal cancer metastases to the liver: a prospective study. J Clin Oncol. 2005;23:1358–1364. doi: 10.1200/JCO.2005.12.039.
    1. Navarra G, Ayav A, Weber JC, Jensen SL, Smadga C, Nicholls JP, Habib NA, Jiao LR. Short- and-long term results of intraoperative radiofrequency ablation of liver metastases. Int J Colorectal Dis. 2005;20:521–528. doi: 10.1007/s00384-005-0743-4.
    1. Van Cutsem E, Nordlinger B, Adam R, Kohne CH, Pozzo C, Poston G, Ychou M, Rougier P, European Colorectal Metastases Treatment G Towards a pan-European consensus on the treatment of patients with colorectal liver metastases. Eur J Cancer. 2006;42:2212–2221. doi: 10.1016/j.ejca.2006.04.012.
    1. de Jong MC, Pulitano C, Ribero D, Strub J, Mentha G, Schulick RD, Choti MA, Aldrighetti L, Capussotti L, Pawlik TM. Rates and patterns of recurrence following curative intent surgery for colorectal liver metastasis: an international multi-institutional analysis of 1669 patients. Ann Surg. 2009;250:440–448.
    1. Piedbois P, Rougier P, Buyse M, Pignon J, Ryan L, Hansen R, Zee B, Weinerman B, Pater J, Leichman C, Macdonald J, Benedetti J, Lokich J, Fryer J, Brufman G, Isacson R, Laplanche A, Levy E, Meta-analysis Group In Cancer Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol. 1998;16:301–308.
    1. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000;343:905–914. doi: 10.1056/NEJM200009283431302.
    1. Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22:23–30. doi: 10.1200/JCO.2004.09.046.
    1. Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229–237. doi: 10.1200/JCO.2004.05.113.
    1. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–2342. doi: 10.1056/NEJMoa032691.
    1. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–2019. doi: 10.1200/JCO.2007.14.9930.
    1. Folprecht G, Grothey A, Alberts S, Raab HR, Kohne CH. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol. 2005;16:1311–1319. doi: 10.1093/annonc/mdi246.
    1. Adam R, Delvart V, Pascal G, Valeanu A, Castaing D, Azoulay D, Giacchetti S, Paule B, Kunstlinger F, Ghemard O, Levi F, Bismuth H. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg. 2004;240:644–657. doi: 10.1097/01.sla.0000145964.08365.01.
    1. Louvet C, de Gramont A. Colorectal cancer: integrating oxaliplatin. Curr Treat Options Oncol. 2003;4:405–411. doi: 10.1007/s11864-003-0041-8.
    1. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB, 3rd, Eastern Cooperative Oncology Group Study E Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25:1539–1544. doi: 10.1200/JCO.2006.09.6305.
    1. Van Hazel G, Blackwell A, Anderson J, Price D, Moroz P, Bower G, Cardaci G, Gray B. Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer. J Surg Oncol. 2004;88:78–85. doi: 10.1002/jso.20141.
    1. Sharma RA, Van Hazel GA, Morgan B, Berry DP, Blanshard K, Price D, Bower G, Shannon JA, Gibbs P, Steward WP. Radioembolization of liver metastases from colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil, and leucovorin chemotherapy. J Clin Oncol. 2007;25:1099–1106. doi: 10.1200/JCO.2006.08.7916.
    1. Gray B, Van Hazel G, Hope M, Burton M, Moroz P, Anderson J, Gebski V. Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol. 2001;12:1711–1720. doi: 10.1023/A:1013569329846.
    1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–216. doi: 10.1093/jnci/92.3.205.
    1. Kosmider S, Tan TH, Yip D, Dowling R, Lichtenstein M, Gibbs P. Radioembolization in combination with systemic chemotherapy as first-line therapy for liver metastases from colorectal cancer. J Vasc Interv Radiol. 2011;22:780–786. doi: 10.1016/j.jvir.2011.02.023.
    1. Hendlisz A, Van den Eynde M, Peeters M, Maleux G, Lambert B, Vannoote J, De Keukeleire K, Verslype C, Defreyne L, Van Cutsem E, Delatte P, Delaunoit T, Personeni N, Paesmans M, Van Laethem JL, Flamen P. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol. 2010;28:3687–3694. doi: 10.1200/JCO.2010.28.5643.
    1. Bester L, Meteling B, Pocock N, Pavlakis N, Chua TC, Saxena A, Morris DL. Radioembolization versus standard care of hepatic metastases: comparative retrospective cohort study of survival outcomes and adverse events in salvage patients. J Vasc Interv Radiol. 2012;23:96–105. doi: 10.1016/j.jvir.2011.09.028.
    1. Seidensticker R, Denecke T, Kraus P, Seidensticker M, Mohnike K, Fahlke J, Kettner E, Hildebrandt B, Dudeck O, Pech M, Amthauer H, Ricke J. Matched-pair comparison of radioembolization plus best supportive care versus best supportive care alone for chemotherapy refractory liver-dominant colorectal metastases. Cardiovasc Intervent Radiol. 2012;35:1066–1073. doi: 10.1007/s00270-011-0234-7.
    1. Khushalani NI, Leichman CG, Proulx G, Nava H, Bodnar L, Klippenstein D, Litwin A, Smith J, Nava E, Pendyala L, Smith P, Greco W, Berdzik J, Douglass H, Leichman L. Oxaliplatin in combination with protracted-infusion fluorouracil and radiation: report of a clinical trial for patients with esophageal cancer. J Clin Oncol. 2002;20:2844–2850. doi: 10.1200/JCO.2002.12.032.
    1. Freyer G, Bossard N, Romestaing P, Mornex F, Chapet O, Trillet-Lenoir V, Gerard JP. Addition of oxaliplatin to continuous fluorouracil, l-folinic acid, and concomitant radiotherapy in rectal cancer: the Lyon R 97–03 phase I trial. J Clin Oncol. 2001;19:2433–2438.
    1. Aschele C, Friso ML, Pucciarelli S, Lonardi S, Sartor L, Fabris G, Urso ED, Del Bianco P, Sotti G, Lise M, Monfardini S. A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer. Ann Oncol. 2005;16:1140–1146. doi: 10.1093/annonc/mdi212.
    1. Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002;87:393–399. doi: 10.1038/sj.bjc.6600467.
    1. Cersosimo RJ. Oxaliplatin-associated neuropathy: a review. Ann Pharmacother. 2005;39:128–135. doi: 10.1345/aph.1E319.
    1. Van Cutsem E, Rivera F, Berry S, Kretzschmar A, Michael M, DiBartolomeo M, Mazier MA, Canon JL, Georgoulias V, Peeters M, Bridgewater J, Cunningham D, BEAT investigators Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol. 2009;20:1842–1847. doi: 10.1093/annonc/mdp233.
    1. Nasti G, Ottaiano A, Berretta M, Delrio P, Izzo F, Cassata A, Romano C, Facchini G, Scala D, Mastro A, Romano G, Perri F, Iaffaioli RV. Pre-operative chemotherapy for colorectal cancer liver metastases: an update of recent clinical trials. Cancer Chemother Pharmacol. 2010;66:209–218. doi: 10.1007/s00280-010-1297-x.
    1. Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29:2011–2019. doi: 10.1200/JCO.2010.33.5091.
    1. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–671. doi: 10.1200/JCO.2008.20.8397.
    1. Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP, MRC COIN Trial Investigators Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011;377:2103–2114. doi: 10.1016/S0140-6736(11)60613-2.
    1. Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, Sigurdsson F, Kure E, Ikdahl T, Skovlund E, Fokstuen T, Hansen F, Hofsli E, Birkemeyer E, Johnsson A, Starkhammar H, Yilmaz MK, Keldsen, Erdal AB, Dajani O, Dahl O, Christoffersen T'. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012;30:1755–1762. doi: 10.1200/JCO.2011.38.0915.
    1. Zhou SW, Huang YY, Wei Y, Jiang ZM, Zhang YD, Yang Q, Xie DR. No survival benefit from adding cetuximab or panitumumab to oxaliplatin-based chemotherapy in the first-line treatment of metastatic colorectal cancer in KRAS wild type patients: a meta-analysis. PLoS One. 2012;7:e50925. doi: 10.1371/journal.pone.0050925.
    1. Peeters M, Price T. Biologic therapies in the metastatic colorectal cancer treatment continuum–applying current evidence to clinical practice. Cancer Treat Rev. 2012;38:397–406. doi: 10.1016/j.ctrv.2011.08.002.
    1. Chu E. An update on the current and emerging targeted agents in metastatic colorectal cancer. Clin Colorectal Cancer. 2012;11:1–13. doi: 10.1016/j.clcc.2011.05.005.
    1. Schwarz RE, Berlin JD, Lenz HJ, Nordlinger B, Rubbia-Brandt L, Choti MA. Systemic cytotoxic and biological therapies of colorectal liver metastases: expert consensus statement. HPB. 2013;15:106–115. doi: 10.1111/j.1477-2574.2012.00558.x.
    1. Clary BM, Grothey A, Kopetz S, Marsh RD. Systemic cytotoxic and biologic therapies for colorectal cancer liver metastases: expert consensus statement. HPB. 2013;15:116–118. doi: 10.1111/j.1477-2574.2012.00598.x.
Pre-publication history
    1. The pre-publication history for this paper can be accessed here:

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir