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In colorectal cancer (CRC), unresectable liver metastases are associated with a poor prognosis. The FOXFIRE (an open-label randomized phase III trial of 5-fluorouracil, oxaliplatin, and folinic acid +/- interventional radioembolization as first-line treatment for patients with unresectable liver-only or liver-predominant metastatic colorectal cancer), SIRFLOX (randomized comparative study of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma), and FOXFIRE-Global (assessment of overall survival of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma in a randomized clinical study) clinical trials were designed to evaluate the efficacy and safety of combining first-line chemotherapy with selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres, also called transarterial radioembolization.
The aim of this analysis is to prospectively combine clinical data from 3 trials to allow adequate power to evaluate the impact of chemotherapy with SIRT on overall survival.
Eligible patients are adults with histologically confirmed CRC and unequivocal evidence of liver metastases which are not treatable by surgical resection or local ablation with curative intent at the time of study entry. Patients may also have limited extrahepatic metastases. Final analysis will take place when all participants have been followed up for a minimum of 2 years.
Efficacy and safety estimates derived using individual participant data (IPD) from SIRFLOX, FOXFIRE, and FOXFIRE-Global will be pooled using 2-stage prospective meta-analysis. Secondary outcome measures include progression-free survival (PFS), liver-specific PFS, health-related quality of life, response rate, resection rate, and adverse event profile. The large study population will facilitate comparisons of low frequency adverse events and allow for more robust safety analyses. The potential treatment benefit in those patients who present with disease confined to the liver will be investigated using 1-stage IPD meta-analysis. Efficacy will be analyzed on an intention-to-treat basis.
This analysis will assess the impact of SIRT combined with chemotherapy on overall survival in the first-line treatment of metastatic CRC. If positive, the results will change the standard of care for this disease.
FOXFIRE ISRCTN Registry ISRCTN83867919; http://www.isrctn.com/ISRCTN83867919 (Archived by WebCite at http://www.webcitation.org/6oN7axrvA). SIRFLOX ClinicalTrials.gov NCT00724503; https://clinicaltrials.gov/ ct2/show/NCT00724503 (Archived by WebCite at http://www.webcitation.org/6oN7lEGbD). FOXFIRE-Global ClinicalTrials.gov NCT01721954; https://clinicaltrials.gov/ct2/show/NCT01721954 (Archived by WebCite at http://www.webcitation.org/ 6oN7vvQvG).
The 5-year overall survival (OS) of metastatic colorectal cancer (mCRC) patients, who constitute 21% of all CRC diagnoses, is approximately 13% [
Among the liver-directed therapies that may control liver metastases, selective internal radiation therapy (SIRT) is one option for patients with liver-only or liver-dominant disease [
The FOXFIRE (an open-label randomized phase III trial of 5-fluorouracil, oxaliplatin, and folinic acid +/- interventional radioembolization as first-line treatment for patients with unresectable liver-only or liver-predominant metastatic colorectal cancer), SIRFLOX (randomized comparative study of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma), and FOXFIRE-Global (assessment of overall survival of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma in a randomized clinical study) clinical trials were designed to study SIRT in combination with chemotherapy, specifically the modified fluorouracil, leucovorin, and oxaliplatin (FOLFOX) regimen, compared with FOLFOX alone as first-line therapy for mCRC [
The primary objective of the combined analysis is to report the planned meta-analysis (MA) of individual participant data (IPD) from the FOXFIRE, SIRFLOX, and FOXFIRE-Global studies for the primary endpoint, OS, and for secondary outcomes including PFS, liver-specific PFS, quality of life measures, response rate, resection rate, and adverse event profile. The IPD-MA will assess the treatment effects on clinical outcomes in the entire subject group and in key subgroups.
As the results on survival benefits for each of the 3 studies are still blinded, the statistical design is a prospective MA based on randomized IPD from the FOXFIRE, SIRFLOX, and FOXFIRE-Global clinical trials.
The protocols of the FOXFIRE [
Characteristics of studies included in the meta-analysis: FOXFIRE [
FOXFIREa | SIRFLOXb | FOXFIRE-Globalc | |
Start of recruitment | Nov 13, 2009 | Oct 11, 2006 | May 20, 2013 |
End of recruitment | Oct 31, 2014 | Apr 25, 2013 | Dec 23, 2014 |
End of follow-up | Oct 31, 2016 | Apr 25, 2018 | Dec 23, 2019 |
Number of recruiting centers | 28 | 87 | 69 |
Primary objective | Overall survival | Progression-free survival | Overall survival |
Secondary objectives | Progression-free survival |
Overall survival |
Progression-free survival |
Sample size accrued | 364 | 530 | 209 |
Accrual period | November 2009–October 2014 | October 2006–April 2013 | May 2013–December 2014 |
Follow-up period | November 2014–October 2016 | April 2013–April 2018 | December 2014–December 2019 |
Randomization | 1:1 with minimization | 1:1 with minimization | 1:1 with minimization |
Minimization factors | Liver only versus extrahepatic metastases |
Liver only versus extrahepatic metastases |
Liver only versus extrahepatic metastases |
Recruiting countries/regions | United Kingdom (England, Northern Ireland, Scotland, Wales) | Australia, Europe, Israel, New Zealand, and United States | Australia, Europe, Israel, Korea, New Zealand, Singapore, Taiwan and United States |
aAn open-label randomized phase III trial of 5-fluorouracil, oxaliplatin, and folinic acid +/- interventional radioembolization as first-line treatment for patients with unresectable liver-only or liver-predominant metastatic colorectal cancer.
bRandomized comparative study of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma.
cAssessment of overall survival of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma in a randomized clinical study.
dComputed tomography.
Schema for the FOXFIRE, SIRFLOX, and FOXFIRE-Global trials.
All randomized patients from the SIRFLOX, FOXFIRE, and FOXFIRE-Global clinical trials will be included in the combined analysis.
Histologically confirmed CRC with liver-only or liver-dominant metastases not amenable to surgical resection, primary tumour in situ permitted (FOXFIRE); histologically confirmed CRC with liver-only or liver-dominant metastases (SIRFLOX); histologically confirmed adenocarcinoma of the colon or rectum with or without primary tumor in situ (FOXFIRE-Global)
Unequivocal and measurable computed tomography (CT) evidence of liver metastases not treatable by surgical resection or local ablation with curative intent at time of trial entry
Chemotherapy-naïve for mCRC, but previous adjuvant systemic chemotherapy for primary CRC or neoadjuvant chemoradiotherapy to the pelvis more than 6 months before recruitment is permitted (SIRFLOX, FOXFIRE-Global); eligible for systemic chemotherapy as first-line treatment for metastatic CRC (FOXFIRE)
Additional limited extrahepatic metastases in the lung or lymph nodes permitted (SIRFLOX, FOXFIRE-Global); patients are permitted to have limited extrahepatic disease (FOXFIRE)
Age ≥18 years
World Health Organization performance status of 0-1
Life expectancy >3 months
Adequate hematological, renal, and hepatic function
Female patients must be postmenopausal or using adequate contraception if premenopausal, and male patients must be using an appropriate method of contraception if with a premenopausal partner (FOXFIRE); female patients must either be postmenopausal, sterile (surgically or chemically or radiation-induced) or if sexually active using an acceptable method of contraception, and male patients must be surgically sterile or if sexually active and have a premenopausal partner must be using an acceptable method of contraception (SIRFLOX, FOXFIRE-Global)
Suitable for all aspects of treatment determined by clinical assessment undertaken by investigator
Willing and able to provide written informed consent
FOXFIRE-Global and SIRFLOX:
All imaging evidence used as part of the screening process must be within 28 days prior to randomization
Evidence of ascites, cirrhosis, portal hypertension; tumour involvement of, or thrombosis leading to occlusion of the main portal vein
Previous radiotherapy delivered to upper abdomen or upper lumbar spine (FOXFIRE); previous radiotherapy delivered to the upper abdomen (SIRFLOX); previous radiotherapy delivered to the liver (FOXFIRE-Global)
Nonmalignant disease that would render patient ineligible at the discretion of the investigator
Dose-limiting toxicity associated with previous 5-fluorouracil or oxaliplatin chemotherapy
Peripheral neuropathy higher than grade 1 (National Cancer Institute–Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 3)
Pregnant or breastfeeding
Previous chemotherapy for any malignancy; adjuvant chemotherapy for colorectal cancer is not an exclusion criterion provided that it was completed more than 6 months prior to entry into the study (SIRFLOX, FOXFIRE-Global). Previous chemotherapy for metastatic colorectal cancer; adjuvant chemotherapy for colorectal cancer is not an exclusion criterion provided that it was completed more than 6 months prior to entry into the study (FOXFIRE)
Concurrent or prior history of cancer other than adequately treated nonmelanoma skin cancer or carcinoma in situ of the cervix (SIRFLOX, FOXFIRE-Global); other active malignancy within last 5 years excluding colorectal cancer and other nonmelanoma skin cancers (FOXFIRE)
SIRFLOX and FOXFIRE-Global:
Allergy to nonionic contrast agents
FOXFIRE only:
Liver metastases amenable to curative resection at time of study entry
Equivocal, immeasurable, or nonevaluable liver metastases
Unequivocal evidence of bone metastasis
All patients received first-line chemotherapy for mCRC. In FOXFIRE, the chemotherapy received was oxaliplatin, 5-fluorouracil, and leucovorin/folic acid in the OxMdG regime [
In all 3 trials, patients were assessed every 2 weeks during chemotherapy treatment. In SIRFLOX and FOXFIRE-Global, patients were assessed every 12 weeks during the postprogression follow-up period. FOXFIRE patients were assessed every 8 weeks following completion of treatment up to 18 months and then every 12 weeks thereafter. In all 3 trials, patients were followed until death or for a period of at least 2 years after randomization. Patients undergoing surgical resection after trial entry were also followed up until trial closure or until death.
Screening and follow-up assessments included clinical assessment and laboratory analyses, recording concurrent medications, CT scan of the chest/abdomen/pelvis with or without magnetic resonance imaging, recording adverse events, assessment for resection or ablation, and questionnaire-based assessments of quality of life.
The primary outcome of OS is the time from randomization to death from any cause, with patients still alive being censored at their last known follow-up date.
The secondary outcomes are PFS at any site, liver-specific PFS, health-related quality of life (HRQoL), response rate, resection rate, and the safety profiles. PFS is defined as the time from randomization to radiological progression according to Response Evaluation Criteria In Solid Tumors (RECIST version 1.0) or death from any cause, whichever is sooner. Patients who are not observed to progress or die during the course of the trial will be censored at last known progression-free follow-up date. Patients who withdraw from study treatment prior to documented progression will be censored at the time they commence nonstudy treatment. Patients who become eligible for resection will be considered as still being on study until progression is documented or last follow-up. Scans and tumor response will be centrally reviewed in FOXFIRE and SIRFLOX.
Liver-specific PFS is defined as the time from randomization to radiological progression in the liver (hepatic progression) according to RECIST version 1.0. Progression outside the liver (extrahepatic progression) and deaths prior to progression will be considered as competing risks for failure in the liver. Hepatic progression will be assumed to have occurred immediately before extrahepatic progression in patients who have identical hepatic and extrahepatic progression dates. Patients who withdraw from study treatment prior to any documented progression will be censored at the time they commence nonstudy treatment. Patients who become eligible for resection will be considered as still being on study until progression is documented or last follow-up.
HRQoL will be assessed using the EuroQol 5 dimensions questionnaire (EQ-5D). The EQ-5D comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each of the 5 dimensions is scored, generating a profile. A single index score or utility value, representing population-derived preferences for different health states, will be attached to each profile.
The response rate (objective response) is defined as the number of patients achieving a complete or partial response according to RECIST version 1.0 divided by the number of patients in each treatment arm. Early death by any cause and unknown responses will be included in the denominator. Response will be assessed over 2 time periods: within 12 months of randomization and over follow-up.
The resection rate in each treatment arm is defined as the number of patients undergoing resection of their liver metastases divided by the number of patients randomized in each arm. Patients undergoing treatment are assessed by an experienced liver multidisciplinary team or equivalent for eligibility for resection at the discretion of the treating physician.
The safety profile is assessed by the collection of adverse events (AEs) and serious adverse events (SAEs) at any time during treatment with grading using the NCI-CTCAE version 3.
For the primary combined OS analysis, the FOXFIRE study protocol details a calculated 1075 patients required using a protocol-specified hazard ratio (HR) of 0.8, a 36-month accrual period, and 18-month minimum follow-up with 2-sided 5% significance, 80% power, and allowing for noncompliance. A total of 710 deaths are expected. The required sample size had been previously calculated to be 1022 [
The final analysis will be undertaken when a minimum of 710 deaths overall and 463 deaths in the liver-only subgroup have been observed in the pooled dataset and there has been a minimum follow-up of 2 years since the last patient was randomized into the 3 trials.
The independent data and safety monitoring committee (IDSMC) consisted of the same representatives for the FOXFIRE, SIRFLOX, and FOXFIRE-Global clinical trials. Formal interim monitoring of the accumulating data was performed at regular intervals (approximately every 6 months) by the IDSMC for each trial separately. This information included results from other relevant trials but not the analysis of primary or secondary objectives or outcomes by treatment groups apart from the prespecified interim analyses. As part of the review, the IDSMC was asked to justify continued recruitment of further patients or further follow-up. The IDSMC advised on the frequency of future reviews of the data on the basis of accrual and event rates.
The IDSMC reviewed the combined safety data from FOXFIRE and SIRFLOX at the interim analyses. The following planned interim analyses were undertaken using combined data from the FOXFIRE and SIRFLOX trials:
Analysis of toxicity and safety: 8 months after at least 80 patients were randomized in total (a minimum of 40 per trial)
Analysis of toxicity and safety: 8 months after at least 300 patients were randomized in total (a minimum of 120 patients per trial)
The 3 clinical trials that constitute this MA were conducted in accordance with the Declaration of Helsinki and current Good Clinical Practice guidelines, and all participating centers obtained the relevant ethics committee approval before patient enrollment. FOXFIRE was approved by the National Research Ethics Service Committee South Central – Berkshire Research Ethics Committee reference 09/H0505/1 and sponsored by the University of Oxford. SIRFLOX and FOXFIRE-Global were approved by the relevant ethics committees for each center and sponsored by Sirtex Technology Pty Ltd.
Summaries of baseline factors, including minimization factors, and percentages of missing data will be reported. Losses to follow-up will be reported for each trial and combined. Median follow-up time will be calculated using the reverse Kaplan-Meier method. Dose of trial-specific treatment delivered and treatment received subsequent-to-trial treatment will be described.
All efficacy analyses will be performed on an intention-to-treat (ITT) basis. OS and PFS estimates will be obtained using Kaplan-Meier survival curves, unadjusted log-rank tests, and survival models. A 2-stage inverse-variance weighted IPD-MA will be performed for both OS and PFS, with the first stage consisting of trial-specific analyses to obtain efficacy estimates (HRs) and the second stage being a pooled analysis of the separate trial-specific HRs. As a sensitivity analysis, a 1-stage IPD-MA using regression models stratified by study will be performed to confirm the results obtained from the 2-stage IPD-MA. For each outcome, multivariable models will be used in the 1-stage IPD-MA to account for baseline covariates.
Liver-specific PFS will be analyzed using cumulative incidence curves, Gray’s test, and competing risks regression. This analysis will be performed on the pooled dataset with models stratified by trial. For OS, PFS, and liver-specific PFS, the potential treatment benefit in those patients who present with disease confined to the liver will be investigated. This prespecified subgroup analysis will be performed on the pooled dataset. The analysis strategy will include calculating HR for the effect of treatment in the liver-only subgroup using survival models stratified by trial.
A separate landmark analysis of OS will start at the 15-month time point (after randomization) and therefore exclude those who have died/withdrawn within 15 months of randomization. This time point has previously been considered of value in clinical trials of the treatment of mCRC [
The EQ-5D data will be merged across all 3 trials and summary data prepared on the mean EQ-5D utility score in each trial arm by time period, with appropriate tests for difference. Resection rate and response rate will be analyzed using chi-square tests and odds ratios (ORs) for the individual trials and a 2-stage IPD-MA.
Safety analyses will be performed on patients who received at least 1 dose of chemotherapy in either arm and on an as-treated basis (safety population). AEs experienced up to 28 days after the end of trial treatment or 7 months postrandomization, whichever was earlier, will be included. Descriptive summaries of the frequency and severity of AEs and the numbers of patients experiencing AEs of grade 3 or higher between treatment arms will be presented overall and by system organ class. The Medical Dictionary for Regulatory Activities version 16.1 is used to categorize the AEs. Univariate comparisons will be made.
All hypothesis tests will be 2-sided. A significance level of .05 will be used to indicate statistical significance. No missing data imputation is intended. Missing days in dates may be appropriately imputed.
Data from the final data lock will become available in January 2017. Data analysis will take place in 2017 with results being disseminated via peer-reviewed journals in 2017 and 2018.
Optimizing outcomes of treatment in patients with nonresectable liver metastases was identified in an international consensus expert statement as a key clinical need to be addressed [
This prospective MA of 3 phase III studies will provide comprehensive evidence of the safety and potential efficacy of SIRT in the first-line setting for patients with liver metastases from mCRC. The results of the SIRFLOX trial published so far have suggested that the addition of SIRT to chemotherapy can improve liver-specific PFS [
Although the SIRFLOX trial reported that liver-specific PFS was longer in the SIRT arm than in the control arm, the PFS at any site was similar between the SIRT arm and the control arm [
It is generally accepted that successful resection of liver metastases correlates with improved overall survival, particularly in the context of neoadjuvant or adjuvant chemotherapy [
The use of an IPD rather than an aggregate data approach to systematic review and MA of randomized controlled trials enables the standardization of outcomes across trials and detailed data checking, providing a more in-depth exploration and more robust MA results [
The results from the combined analysis of the SIRFLOX, FOXFIRE, and FOXFIRE-Global trials will provide valuable clinical information on the efficacy and toxicity profile of SIRT combined with chemotherapy as a first-line regimen for liver metastases from mCRC that will guide clinicians in the use of this technology to treat their patients. The IPD-MA will allow comparisons of less common AEs that would not be possible in a smaller population. Furthermore, this prospective MA provides sufficient power to determine whether SIRT provides a significant survival benefit for patients with metastases confined to the liver and no clinically detectable extrahepatic disease, an important research question among clinicians treating mCRC. When reported, the results of this combined analysis will define the use of SIRT in the treatment of mCRC.
adverse event
colorectal cancer
computed tomography
EuroQol 5 dimensions questionnaire
modified fluorouracil, leucovorin, and oxaliplatin regimen
An open-label randomized phase III trial of 5-fluorouracil, oxaliplatin, and folinic acid +/- interventional radioembolization as first-line treatment for patients with unresectable liver-only or liver-predominant metastatic colorectal cancer
Assessment of overall survival of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma in a randomized clinical study
hazard ratio
health-related quality of life
independent data and safety monitoring committee
individual participant data
Individual participant data meta-analysis
intention-to-treat
meta-analysis
metastatic colorectal cancer
National Cancer Institute–Common Terminology Criteria for Adverse Events
odds ratio
overall survival
progression-free survival
Response Evaluation Criteria In Solid Tumors
serious adverse events
Randomized comparative study of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma
selective internal radiation therapy
The FOXFIRE trial was developed by the National Cancer Research Institute Colorectal Clinical Study Group and is sponsored by the University of Oxford. It is supported by the Bobby Moore Fund of Cancer Research United Kingdom (Clinical Trials Awards and Advisory Committee reference number CRUK/A16630), an educational grant from Sirtex Medical Ltd, and by the National Institute for Health Research Biomedical Research Center Oxford. The SIRFLOX and FOXFIRE-Global studies are sponsored by Sirtex Technology Pty Ltd.
The FOXFIRE Trial Management and Quality Assurance Group: Adil Al-Nahhas, Dave Berry, Ian Chau, Luise Dunham, David Kerr, Nas Khan, Val Lewington, Rachel Midgley, Bruno Morgan, Sarah Pearson, Anne Roberts, Will Steward, Paul Tait, Greg Wilson, Andy Wotherspoon.
FOXFIRE Health Economists: Alastair Gray, Jane Wolstenholme.
The FOXFIRE Study Group: Richard Adams, Andrew Bateman, Claire Blesing, Ewan Brown, Ian Chau, Sebastian Cummins, David Cunningham, Stephen Falk, Maher Hadaki, Marcia Hall, Tamas Hickish, Joanne Hornbuckle, Fiona Lofts, Sarah Lowndes, Astrid Mayer, Matthew Metcalfe, Gary Middleton, Jamie Mills, Amir Montazeri, Rebecca Muirhead, Andreas Polychronis, Colin Purcell, Paul Ross, Liz Sherwin, David Smith, Rubin Soomal, Daniel Swinson, Axel Walther, Andrew Weaver, Charles Wilson, Greg Wilson. We would also like to thank the University of Oxford statisticians Susan Dutton and Peter Dutton for their contributions to the FOXFIRE study.
The SIRFLOX and FOXFIRE-Global Study Group: Steven Ades, Morteza Aghmesheh, Pradip Amin, Bruna Angelelli, Miklos Auber, Jacques Balosso, Alex Beny, Daniel Bloomgarden, Patrick Boland, Eveline Boucher, Christoph Bremer, Michael Brown, Harald-Robert Bruch, James Bui, Matthew Burge, Giuseppe Cardaci, James Carlisle, Ruiz Casado, Yi-Jen Chen, Patrick Chevallier, Michael Chuong, Stephen Clarke, Prasad Cooray, Andrew Coveler, Michel Craninx, Thierry Delanoit, Amélie Deleporte, Kyran Dowling, Aurelie Durand, Paul Eliadis, Francis Facchini, Kynan Feeney, Thomas Ferguson, Michel Ferrante, Aurelie Ferru, Michael Findlay, Maria Fragoso, Gary Frenette, Jacob Frick, Vinod Ganju, Michael Garofalo, Karen Geboes, Gerald Gehbauer, Benjamin George, Ravit Geva, Michael Gordon, Cristina Granetto, Kate Gregory, Seza Gulec, Pascal Hammel, James Hannigan, Norman Heching, Volker Heinemann, Thomas Helmberger, Alain Hendlisz, Koen Hendrickx, Matthew Holtzman, Ayala Hubert, Richard Isaacs, Christopher Jackson, Philip James, Adeel Kaiser, Chris Karapetis, Andreas Kaubisch, Yeul Hong Kim, Yon-Dschun Ko, Todd Kooy, Hendrik Kröning, Frank Lammert, Jin Tung Liang, Winston Liauw, Lionel Lim, Yoo Joo Lim, Jin Hwang Liu, Samy Louafi, Marc de Man, Jeffrey Margolis, Robert Martin, Andrea Martoni, Gavin Marx, Marco Matos, Els Monsaert, Veerle Moons, Stefania Mosconi, Louise Nott, Arnd Nusch, Anne O’Donnell, Howard Ozer, Siddarth Padia, Nick Pavlakis, Marc Peeters, David Perez, Stefan Pluntke, Marc Polus, Alex Powell, Marc Pracht, Timothy Price, Jorge Ramon, David Ransom, Christine Rebischung, Jens Ricke, Karsten Ridwelski, Hanno Riess, Jorge Ramon Riera, William Rilling, Bridget Robinson, Javier Rodríguez, Federico Sanchez, Tilmann Sauerbruch, Michael Savin, Klemens Scheidhauer, Elyse Schneiderman, Grant Seeger, Eva Segelov, Einat Shaham Schmueli, Adi Shani, Jenny Shannon, Navesh Sharma, Stephen Shibata, Nimit Singhal, Denis Smith, Randall Smith, Salomon Stemmer, Oliver Stötzer, Andrew Strickland, Julien Taieb, Iain Tan, Klaus Tatsch, Eric Terrebonne, Thomas Tichler, Antonio Trogu, Craig Underhill, Daniel Van Daele, Ursula Vehling-Kaiser, Ruth Vera-Garcia, Caterina Vivaldi, Thomas Vogl, Euan Walpole, Eric Wang, Mark Westcott, Samuel Whiting, Ido Wolf.
The authors acknowledge Bruce Gray for his involvement in the development of the initial SIRFLOX protocol and the editorial assistance provided by Martin Gilmour and Thierry Deltheil of ESP Bioscience (Crowthorne, United Kingdom) during the preparation of this manuscript.
RAS and HSW conceived the FOXFIRE study and secured the funding for the investigator-initiated study. SBL and JM provided statistical advice. All authors read and approved the final draft of the manuscript for submission. PG, VG, and GVH were substantially involved in the conception and design of the SIRFLOX and FOXFIRE-Global studies. EAF coordinated the FOXFIRE study during the patient follow-up period. All authors were involved in critically reviewing the manuscript for important intellectual content, and all authors read and approved the final draft of the manuscript for submission.
RAS has received research funding, honoraria, and consultancy fees from Sirtex Medical Ltd. PG has received honoraria from Sirtex for participation in advisory boards and for giving presentations. VG and GVH have received compensation for participation in advisory committees from Sirtex. PSV, JM, HSW, EAF, and SBL declare no competing interests.