First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials
Journal
The Lancet Oncology
Journal Volume
18
Journal Issue
9
Date Issued
2017-09-01
Author(s)
Wasan, Harpreet S.
GRACE PEN-HSIU CHAO
Sharma, Navesh K.
Taieb, Julien
Heinemann, Volker
Ricke, Jens
Peeters, Marc
Findlay, Michael
Weaver, Andrew
Mills, Jamie
Wilson, Charles
ADRIAN RAUCHFLEISCH
Francis, Anne
Moschandreas, Joanna
Virdee, Pradeep S.
Dutton, Peter
Love, Sharon
Gebski, Val
Gray, Alastair
Bateman, Andrew
Blesing, Claire
BEI-EN CHANG
Chau, Ian
Cummins, Sebastian
Cunningham, David
Falk, Stephen
Hadaki, Maher
Hall, Marcia
Hickish, Tamas
Hornbuckle, Joanne
Lofts, Fiona
Lowndes, Sarah
Mayer, Astrid
Metcalfe, Matthew
Middleton, Gary
Montazeri, Amir
Muirhead, Rebecca
Polychronis, Andreas
Purcell, Colin
RICHARD PING CHENG
Sharma, Ricky A.
Sherwin, Liz
Smith, David
Soomal, Rubin
Swinson, Daniel
Walther, Axel
Wilson, Greg
Amin, Pradip
AN-BANG WANG
Balosso, Jacques
Beny, Alex
Bloomgarden D.
BEI-EN CHANG
Bruch, Harald Robert
Bui, James
Burge, Matthew
Cardaci, Giuseppe
Carlisle, James
Chai, Seungjean
Chen, Yi Jen
Chevallier, Patrick
Chuong, Michael
Clarke, Stephen
Coveler, Andrew
Craninx, Michael
Delanoit, Thierry
Deleporte A.
Eliadis, Paul
Facchini, Francis
Ferguson, Thomas
Ferrante, Michel
Frenette, Gary
Frick, Jacob
Ganju, Vinod
Garofalo, Michael
KAI-PING GRACE YAO
Gehbauer, Gerald
George, Benjamin
Geva, Ravit
Gordon, Michael
KAI-PING GRACE YAO
Gulec, Seza
Hannigan, James
van Hazel, Guy
Heching, Norman
Helmberger, Thomas
Hendlisz, Alain
Hendrickx, Koen
Holtzman, Matthew
I-RUE LAI
Jackson, Christopher
James, Philip
KATHERINE ANN KIM
Karapetis, Chris
KATHERINE ANN KIM
Ko, Yon Dschun
Kr?ning, Hendrik
Lammert, Frank
Liauw, Winston
Louafi S.
de Man M.
Margolis J.
Martin R.
Martoni A.
Marx G.
Matos M.
Monsaert E.
Moons V.
Nott L.
Nusch A.
O'Donnell A.
Ozer H.
Padia S.
Pavlakis N.
Perez D.
Pluntke S.
Polus M.
Powell A.
Pracht M.
Price T.
Ransom D.
Rebischung C.
Ridwelski K.
Riera-Knorrenschild J.
Riess H.
Rilling W.
Robinson B.
Rodr?guez J.
Sanchez F.
Sauerbruch T.
Savin M.
Scheidhauer K.
Schneiderman E.
Seeger G.
Segelov E.
Schmueli E.S.
Shani A.
Shannon J.
Shibata S.
Singhal N.
Smith D.
Smith R.
Stemmer S.
St?tzer O.
Strickland A.
Tatsch K.
Terrebonne E.
Tichler T.
Vehling-Kaiser U.
Vera-Garcia R.
Vogl T.
Walpole E.
Wang E.
Whiting S.
Wolf I.
Ades S.
Aghmesheh M.
Auber M.
Ayala H.
Boland P.
Bouche E.
Bowers C.
Bremer C.
Casado A.R.
Cooray P.
Crain M.
De Wit M.
Dowling K.
Durand A.
Faivre S.
Feeney K.
Ferru A.
Fragoso M.
Granetto C.
Hammel P.
Issacs R.
Iyer R.
Kim Y.H.
Lim L.
Liu J.H.
Masi G.
Mosconi S.
Numico G.
Ratner L.
Sae-Won H.
Singh M.
Stoltzfus P.
Tan I.
Trogu A.
Underhill C.
Westcott M.
FOXFIRE trial investigators, SIRFLOX trial investigators, FOXFIRE-Global trial investigators, SIRFLOX trial investigators, FOXFIRE-Global trial investigators, FOXFIRE-Global trial investigators
Abstract
© 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license Background Data suggest selective internal radiotherapy (SIRT) in third-line or subsequent therapy for metastatic colorectal cancer has clinical benefit in patients with colorectal liver metastases with liver-dominant disease after chemotherapy. The FOXFIRE, SIRFLOX, and FOXFIRE-Global randomised studies evaluated the efficacy of combining first-line chemotherapy with SIRT using yttrium-90 resin microspheres in patients with metastatic colorectal cancer with liver metastases. The studies were designed for combined analysis of overall survival. Methods FOXFIRE, SIRFLOX, and FOXFIRE-Global were randomised, phase 3 trials done in hospitals and specialist liver centres in 14 countries worldwide (Australia, Belgium, France, Germany, Israel, Italy, New Zealand, Portugal, South Korea, Singapore, Spain, Taiwan, the UK, and the USA). Chemotherapy-naive patients with metastatic colorectal cancer (WHO performance status 0 or 1) with liver metastases not suitable for curative resection or ablation were randomly assigned (1:1) to either oxaliplatin-based chemotherapy (FOLFOX: leucovorin, fluorouracil, and oxaliplatin) or FOLFOX plus single treatment SIRT concurrent with cycle 1 or 2 of chemotherapy. In FOXFIRE, FOLFOX chemotherapy was OxMdG (oxaliplatin modified de Gramont chemotherapy; 85 mg/m 2 oxaliplatin infusion over 2 h, L-leucovorin 175 mg or D,L-leucovorin 350 mg infusion over 2 h, and 400 mg/m 2 bolus fluorouracil followed by a 2400 mg/m 2 continuous fluorouracil infusion over 46 h). In SIRFLOX and FOXFIRE-Global, FOLFOX chemotherapy was modified FOLFOX6 (85 mg/m 2 oxaliplatin infusion over 2 h, 200 mg leucovorin, and 400 mg/m 2 bolus fluorouracil followed by a 2400 mg/m 2 continuous fluorouracil infusion over 46 h). Randomisation was done by central minimisation with four factors: presence of extrahepatic metastases, tumour involvement of the liver, planned use of a biological agent, and investigational centre. Participants and investigators were not masked to treatment. The primary endpoint was overall survival, analysed in the intention-to-treat population, using a two-stage meta-analysis of pooled individual patient data. All three trials have completed 2 years of follow-up. FOXFIRE is registered with the ISRCTN registry, number ISRCTN83867919. SIRFLOX and FOXFIRE-Global are registered with ClinicalTrials.gov, numbers NCT00724503 (SIRFLOX) and NCT01721954 (FOXFIRE-Global). Findings Between Oct 11, 2006, and Dec 23, 2014, 549 patients were randomly assigned to FOLFOX alone and 554 patients were assigned FOLFOX plus SIRT. Median follow-up was 43·3 months (IQR 31·6–58·4). There were 411 (75%) deaths in 549 patients in the FOLFOX alone group and 433 (78%) deaths in 554 patients in the FOLFOX plus SIRT group. There was no difference in overall survival (hazard ratio [HR] 1·04, 95% CI 0·90–1·19; p=0·61). The median survival time in the FOLFOX plus SIRT group was 22·6 months (95% CI 21·0–24·5) compared with 23·3 months (21·8–24·7) in the FOLFOX alone group. In the safety population containing patients who received at least one dose of study treatment, as treated, the most common grade 3–4 adverse event was neutropenia (137 [24%] of 571 patients receiving FOLFOX alone vs 186 (37%) of 507 patients receiving FOLFOX plus SIRT). Serious adverse events of any grade occurred in 244 (43%) of 571 patients receiving FOLFOX alone and 274 (54%) of 507 patients receiving FOLFOX plus SIRT. 10 patients in the FOLFOX plus SIRT group and 11 patients in the FOLFOX alone group died due to an adverse event; eight treatment-related deaths occurred in the FOLFOX plus SIRT group and three treatment-related deaths occurred in the FOLFOX alone group. Interpretation Addition of SIRT to first-line FOLFOX chemotherapy for patients with liver-only and liver-dominant metastatic colorectal cancer did not improve overall survival compared with that for FOLFOX alone. Therefore, early use of SIRT in combination with chemotherapy in unselected patients with metastatic colorectal cancer cannot be recommended. To further define the role of SIRT in metastatic colorectal cancer, careful patient selection and studies investigating the role of SIRT as consolidation therapy after chemotherapy are needed. Funding Bobby Moore Fund of Cancer Research UK, Sirtex Medical.
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journal article