Selective Internal Radiotherapy of the Liver: At the Crossroads of Interventional Oncology Research and National Health Service Commissioning
2014; Elsevier BV; Volume: 26; Issue: 12 Linguagem: Inglês
10.1016/j.clon.2014.09.009
ISSN1433-2981
AutoresRicky A. Sharma, Carole Cummins, A. Crellin,
Tópico(s)Pancreatic and Hepatic Oncology Research
ResumoInterventional oncology is a rapidly growing clinical specialty that has emerged from the interface between radiology and oncology [[1]Kenny L.M. Adam A. Radiation oncology and interventional oncology: time for a collaborative approach.Clin Oncol. 2013; 25: 515-518Abstract Full Text Full Text PDF Scopus (3) Google Scholar]. One example of a successful new technique to emerge from this new specialty is selective internal radiotherapy (SIRT), also termed radio-embolisation.SIRT is a technique that has been developed to target multiple sites of disease within the liver as a form of arterially delivered brachytherapy using yttrium 90 microspheres. In contrast to surgical resection and radiofrequency ablation, its use is not limited by the number or sites of malignant lesions within the liver [[2]Kennedy A. Nag S. Salem R. et al.Resin 90Y-microsphere brachytherapy for unresectable colorectal liver metastases: modern USA experience.Int J Radiat Oncol Biol Phys. 2006; 65: 412-425Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar]. There are two products available for carrying out SIRT, both of which contain the pure beta-emitter, yttrium 90: TheraSpheres® (BTG, Canada) are glass microspheres and SIR-Spheres® (Sirtex Medical, Australia) are resin microspheres.SIRT treatment involves two outpatient procedures. In the first procedure, trans-femoral catheterisation, hepatic angiography and coil embolisation of arteries that flow from the hepatic arterial vasculature to other organs (e.g. duodenum, stomach, anterior abdominal wall, gall bladder) is carried out. At the end of this procedure, a ‘surrogate’ scan is carried out after injection of technetium 99m-labelled macro-aggregated albumin to check the distribution of radioactivity. In the second procedure, millions of microspheres are injected under fluoroscopic guidance. Whereas the normal liver receives most of its blood supply from the portal venous system, primary and secondary malignancies within the liver obtain most blood from the hepatic artery. The microspheres are of a particular size to lodge in malignant vessels rather than normal arterioles.In this way, SIRT utilises the differential characteristics of normal tissue and tumour anatomy to provide a therapeutic window for this anatomically targeted form of radiotherapy. The result is delivery of greater than 120 Gy of radiation to tumour cells while sparing the normal liver parenchyma. In the treatment of metastatic colorectal cancer, small prospective studies and larger retrospective series would suggest that radiological response rates to SIRT may be as high as 50–90% in the first-line and second-line settings in combination with chemotherapy and 20–35% in the salvage setting in chemotherapy-refractory patients (reviewed in [[3]Nicolay N.H. Berry D.P. Sharma R.A. Liver metastases from colorectal cancer: radioembolization with systemic therapy.Nat Rev Clin Oncol. 2009; 6: 687-697Crossref PubMed Scopus (69) Google Scholar]).Building on phase I–II studies of SIRT in combination with radiosensitising chemotherapy [4Sharma R.A. Van Hazel G.A. Morgan B. et al.Radioembolization of liver metastases from colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil, and leucovorin chemotherapy.J Clin Oncol. 2007; 25: 1099-1106Crossref PubMed Scopus (251) Google Scholar, 5Van Hazel G. Blackwell A. Anderson J. et al.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: 78-85Crossref PubMed Scopus (351) Google Scholar], the FOXFIRE clinical trial was developed by the National Cancer Research Institute Colorectal Clinical Study Group and the trial sponsor, the University of Oxford. Funding was agreed with the Bobby Moore Fund of Cancer Research UK and Sirtex Medical in 2007. The FOXFIRE trial is testing the hypothesis that combining radiosensitising chemotherapy (oxaliplatin and infusional 5-fluorouracil) with SIRT using yttrium 90 resin microspheres as a first-line treatment for liver-dominant metastatic colorectal cancer will improve clinical outcomes when compared with first-line chemotherapy alone. As the first multicentre, phase III clinical trial of SIRT in the UK, FOXFIRE has resulted in the establishment of a national infrastructure for the safe delivery of SIRT to patients with cancer and ‘chemotherapy-only’ centres who deliver FOXFIRE chemotherapy and refer their patients to a specialist liver centre for the SIRT procedure. FOXFIRE has been a challenging clinical trial as it involves multiple disciplines that include interventional radiologists, oncologists, surgeons, medical physicists and nuclear medicine staff. Despite these early challenges, recruitment to the trial has been highly satisfactory over the past 2 years and the revised recruitment targets have been surpassed.Planned combined analyses of carefully designed clinical trials can permit greater statistical power. SIRFLOX is an industry-sponsored, randomised, multicentre trial with the same design as FOXFIRE. SIRFLOX has participating centres in Australia, New Zealand, Europe and the USA. As FOXFIRE and SIRFLOX use similar chemotherapy delivery regimens with regard to the sequencing of drugs and experimental intervention (SIRT), discussion between the trial development groups of the two trials led to the formulation of similar protocols and treatment paradigms [6Dutton S.J. Kenealy N. Love S.B. Wasan H.S. Sharma R.A. FOXFIRE Protocol Development Group and the NCRI Colorectal Clinical Study GroupFOXFIRE protocol: an open-label, randomised, phase III trial of 5-fluorouracil, oxaliplatin and folinic acid (OxMdG) with or without interventional selective internal radiation therapy (SIRT) as first-line treatment for patients with unresectable liver-only or liver-dominant metastatic colorectal cancer.BMC Cancer. 2014; 14: 497Crossref PubMed Scopus (59) Google Scholar, 7http://clinicaltrials.gov/show/NCT00724503.Google Scholar] in order to provide sufficient power for the prospective combined analysis of the two trials for overall survival. This collaboration will allow progression-free survival to be reported separately for SIRFLOX and FOXFIRE, anticipated in 2015 and 2016, respectively, and overall survival for at least 1022 participants (i.e. the combination of both trials) to be reported in 2017.FOXFIRE is the first clinical study of SIRT to be powered to address an overall survival end point and to include systematic evaluation of quality of life and healthcare economics [[6]Dutton S.J. Kenealy N. Love S.B. Wasan H.S. Sharma R.A. FOXFIRE Protocol Development Group and the NCRI Colorectal Clinical Study GroupFOXFIRE protocol: an open-label, randomised, phase III trial of 5-fluorouracil, oxaliplatin and folinic acid (OxMdG) with or without interventional selective internal radiation therapy (SIRT) as first-line treatment for patients with unresectable liver-only or liver-dominant metastatic colorectal cancer.BMC Cancer. 2014; 14: 497Crossref PubMed Scopus (59) Google Scholar]. In their procedure guidance published in July 2011 [[8]http://www.nice.org.uk/guidance/ipg401/resources/guidance-selective-internal-radiation-therapy-for-nonresectable-colorectal-metastases-in-the-liver-pdf.Google Scholar], the UK National Institute for Health and Care Excellence (NICE) stated that ‘Clinicians should offer eligible patients who have not been previously treated by chemotherapy entry into well-designed research studies such as the FOXFIRE trial (www.octo-oxford.org.uk/alltrials/trials/FOXFIRE)’. Indeed, the FOXFIRE trial has generated a quality-assured infrastructure within the UK for SIRT to be offered at specialist centres, which has increased the capability of these centres to take referrals from outside their local area and from abroad.In November 2013, National Health Service (NHS) England announced that SIRT would be its first procedure covered by the new NHS Commissioning through Evaluation (CtE) programme [[9]http://www.england.nhs.uk/2013/11/20/sirt-comm/.Google Scholar]. This programme links commissioning of interventions without a complete evidence base and not routinely funded by the NHS with collection of evidence to allow assessment of clinical and cost-effectiveness. In this programme, selected provider services are commissioned by NHS England and the evaluation is commissioned by NICE. Chosen interventions must show promise of improving patient outcomes to be offered to patients meeting explicit criteria in selected provider centres.In the case of SIRT commissioning, the evaluation is via an online registry with a mandatory minimum dataset of clinical and patient-reported information. Continued funding at each centre depends on complete data submission and is monitored throughout the commissioning period. A limited number of highly specialist providers have been selected in this programme, and the process is bound by contracts held with the central commissioning body.If successful, this type of commissioning model allows innovative treatments, for which there is an incomplete evidence base, to be tested within well-defined clinical parameters in a limited number of centres with explicit clinical end points. The CtE complements, but does not replace, randomised controlled trials (RCTs). Although the quality of comparative evidence provided by good-quality RCTs is preferable when obtainable, good-quality observational data from single-arm or controlled prospective cohorts can provide evidence on patient populations in which RCTs are not feasible and might, on the model of post-marketing observational safety studies of medicines, contribute to evidence on adverse events as well as procedural success. Although the aim within the CtE programme is also to collect control data, identification of appropriate controls is problematic.An additional aim of SIRT commissioning via CtE is to measure effectiveness through the collection of quality of life data. Whereas research trials can incorporate detailed quality of life and health economics analyses, for example FOXFIRE has incorporated three quality of life instruments and a bespoke health economics questionnaire to provide information about potential health economic benefits for patients treated with SIRT [[6]Dutton S.J. Kenealy N. Love S.B. Wasan H.S. Sharma R.A. FOXFIRE Protocol Development Group and the NCRI Colorectal Clinical Study GroupFOXFIRE protocol: an open-label, randomised, phase III trial of 5-fluorouracil, oxaliplatin and folinic acid (OxMdG) with or without interventional selective internal radiation therapy (SIRT) as first-line treatment for patients with unresectable liver-only or liver-dominant metastatic colorectal cancer.BMC Cancer. 2014; 14: 497Crossref PubMed Scopus (59) Google Scholar], the CtE programme is constrained by what is feasible and practical in the NHS in a limited period of time (2–3 years). In the case of SIRT commissioning, health-related quality of life is being measured by asking patients to complete the EQ5D-5L questionnaire at baseline and every 3 months. It was decided that the collection of full cost-effectiveness data was not feasible in this programme.Importantly, commissioning of 10 centres by NHS England and one centre by the NHS in Scotland has improved equity of access to SIRT and it has raised awareness of this novel therapy among oncologists, other referring doctors and the general public.In summary, the evidence base for interventional oncology is currently dominated by single-arm studies reporting technical success or clinical efficacy [[10]Franklin J.M. Gebski V. Poston G.J. Sharma R.A. Clinical trials of interventional oncology—moving from efficacy to outcomes.Nature Rev Clin Oncol. 2014; (in press)Google Scholar]. This has successfully resulted in the development of new techniques, but is not sufficient to change clinical practice uniformly across healthcare systems. SIRT is an example of clinical research where trialists have incorporated measures of overall survival, cost-effectiveness and patient-reported outcomes trial design, in order to provide robust evidence for changing clinical practice. More recently, a registry-based model of funding for SIRT has emerged as an alternative means of deriving cohort data and now exists in parallel with research studies currently ongoing. This is an exciting time for interventional oncology research and commissioning. Interventional oncology is a rapidly growing clinical specialty that has emerged from the interface between radiology and oncology [[1]Kenny L.M. Adam A. Radiation oncology and interventional oncology: time for a collaborative approach.Clin Oncol. 2013; 25: 515-518Abstract Full Text Full Text PDF Scopus (3) Google Scholar]. One example of a successful new technique to emerge from this new specialty is selective internal radiotherapy (SIRT), also termed radio-embolisation. SIRT is a technique that has been developed to target multiple sites of disease within the liver as a form of arterially delivered brachytherapy using yttrium 90 microspheres. In contrast to surgical resection and radiofrequency ablation, its use is not limited by the number or sites of malignant lesions within the liver [[2]Kennedy A. Nag S. Salem R. et al.Resin 90Y-microsphere brachytherapy for unresectable colorectal liver metastases: modern USA experience.Int J Radiat Oncol Biol Phys. 2006; 65: 412-425Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar]. There are two products available for carrying out SIRT, both of which contain the pure beta-emitter, yttrium 90: TheraSpheres® (BTG, Canada) are glass microspheres and SIR-Spheres® (Sirtex Medical, Australia) are resin microspheres. SIRT treatment involves two outpatient procedures. In the first procedure, trans-femoral catheterisation, hepatic angiography and coil embolisation of arteries that flow from the hepatic arterial vasculature to other organs (e.g. duodenum, stomach, anterior abdominal wall, gall bladder) is carried out. At the end of this procedure, a ‘surrogate’ scan is carried out after injection of technetium 99m-labelled macro-aggregated albumin to check the distribution of radioactivity. In the second procedure, millions of microspheres are injected under fluoroscopic guidance. Whereas the normal liver receives most of its blood supply from the portal venous system, primary and secondary malignancies within the liver obtain most blood from the hepatic artery. The microspheres are of a particular size to lodge in malignant vessels rather than normal arterioles. In this way, SIRT utilises the differential characteristics of normal tissue and tumour anatomy to provide a therapeutic window for this anatomically targeted form of radiotherapy. The result is delivery of greater than 120 Gy of radiation to tumour cells while sparing the normal liver parenchyma. In the treatment of metastatic colorectal cancer, small prospective studies and larger retrospective series would suggest that radiological response rates to SIRT may be as high as 50–90% in the first-line and second-line settings in combination with chemotherapy and 20–35% in the salvage setting in chemotherapy-refractory patients (reviewed in [[3]Nicolay N.H. Berry D.P. Sharma R.A. Liver metastases from colorectal cancer: radioembolization with systemic therapy.Nat Rev Clin Oncol. 2009; 6: 687-697Crossref PubMed Scopus (69) Google Scholar]). Building on phase I–II studies of SIRT in combination with radiosensitising chemotherapy [4Sharma R.A. Van Hazel G.A. Morgan B. et al.Radioembolization of liver metastases from colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil, and leucovorin chemotherapy.J Clin Oncol. 2007; 25: 1099-1106Crossref PubMed Scopus (251) Google Scholar, 5Van Hazel G. Blackwell A. Anderson J. et al.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: 78-85Crossref PubMed Scopus (351) Google Scholar], the FOXFIRE clinical trial was developed by the National Cancer Research Institute Colorectal Clinical Study Group and the trial sponsor, the University of Oxford. Funding was agreed with the Bobby Moore Fund of Cancer Research UK and Sirtex Medical in 2007. The FOXFIRE trial is testing the hypothesis that combining radiosensitising chemotherapy (oxaliplatin and infusional 5-fluorouracil) with SIRT using yttrium 90 resin microspheres as a first-line treatment for liver-dominant metastatic colorectal cancer will improve clinical outcomes when compared with first-line chemotherapy alone. As the first multicentre, phase III clinical trial of SIRT in the UK, FOXFIRE has resulted in the establishment of a national infrastructure for the safe delivery of SIRT to patients with cancer and ‘chemotherapy-only’ centres who deliver FOXFIRE chemotherapy and refer their patients to a specialist liver centre for the SIRT procedure. FOXFIRE has been a challenging clinical trial as it involves multiple disciplines that include interventional radiologists, oncologists, surgeons, medical physicists and nuclear medicine staff. Despite these early challenges, recruitment to the trial has been highly satisfactory over the past 2 years and the revised recruitment targets have been surpassed. Planned combined analyses of carefully designed clinical trials can permit greater statistical power. SIRFLOX is an industry-sponsored, randomised, multicentre trial with the same design as FOXFIRE. SIRFLOX has participating centres in Australia, New Zealand, Europe and the USA. As FOXFIRE and SIRFLOX use similar chemotherapy delivery regimens with regard to the sequencing of drugs and experimental intervention (SIRT), discussion between the trial development groups of the two trials led to the formulation of similar protocols and treatment paradigms [6Dutton S.J. Kenealy N. Love S.B. Wasan H.S. Sharma R.A. FOXFIRE Protocol Development Group and the NCRI Colorectal Clinical Study GroupFOXFIRE protocol: an open-label, randomised, phase III trial of 5-fluorouracil, oxaliplatin and folinic acid (OxMdG) with or without interventional selective internal radiation therapy (SIRT) as first-line treatment for patients with unresectable liver-only or liver-dominant metastatic colorectal cancer.BMC Cancer. 2014; 14: 497Crossref PubMed Scopus (59) Google Scholar, 7http://clinicaltrials.gov/show/NCT00724503.Google Scholar] in order to provide sufficient power for the prospective combined analysis of the two trials for overall survival. This collaboration will allow progression-free survival to be reported separately for SIRFLOX and FOXFIRE, anticipated in 2015 and 2016, respectively, and overall survival for at least 1022 participants (i.e. the combination of both trials) to be reported in 2017. FOXFIRE is the first clinical study of SIRT to be powered to address an overall survival end point and to include systematic evaluation of quality of life and healthcare economics [[6]Dutton S.J. Kenealy N. Love S.B. Wasan H.S. Sharma R.A. FOXFIRE Protocol Development Group and the NCRI Colorectal Clinical Study GroupFOXFIRE protocol: an open-label, randomised, phase III trial of 5-fluorouracil, oxaliplatin and folinic acid (OxMdG) with or without interventional selective internal radiation therapy (SIRT) as first-line treatment for patients with unresectable liver-only or liver-dominant metastatic colorectal cancer.BMC Cancer. 2014; 14: 497Crossref PubMed Scopus (59) Google Scholar]. In their procedure guidance published in July 2011 [[8]http://www.nice.org.uk/guidance/ipg401/resources/guidance-selective-internal-radiation-therapy-for-nonresectable-colorectal-metastases-in-the-liver-pdf.Google Scholar], the UK National Institute for Health and Care Excellence (NICE) stated that ‘Clinicians should offer eligible patients who have not been previously treated by chemotherapy entry into well-designed research studies such as the FOXFIRE trial (www.octo-oxford.org.uk/alltrials/trials/FOXFIRE)’. Indeed, the FOXFIRE trial has generated a quality-assured infrastructure within the UK for SIRT to be offered at specialist centres, which has increased the capability of these centres to take referrals from outside their local area and from abroad. In November 2013, National Health Service (NHS) England announced that SIRT would be its first procedure covered by the new NHS Commissioning through Evaluation (CtE) programme [[9]http://www.england.nhs.uk/2013/11/20/sirt-comm/.Google Scholar]. This programme links commissioning of interventions without a complete evidence base and not routinely funded by the NHS with collection of evidence to allow assessment of clinical and cost-effectiveness. In this programme, selected provider services are commissioned by NHS England and the evaluation is commissioned by NICE. Chosen interventions must show promise of improving patient outcomes to be offered to patients meeting explicit criteria in selected provider centres. In the case of SIRT commissioning, the evaluation is via an online registry with a mandatory minimum dataset of clinical and patient-reported information. Continued funding at each centre depends on complete data submission and is monitored throughout the commissioning period. A limited number of highly specialist providers have been selected in this programme, and the process is bound by contracts held with the central commissioning body. If successful, this type of commissioning model allows innovative treatments, for which there is an incomplete evidence base, to be tested within well-defined clinical parameters in a limited number of centres with explicit clinical end points. The CtE complements, but does not replace, randomised controlled trials (RCTs). Although the quality of comparative evidence provided by good-quality RCTs is preferable when obtainable, good-quality observational data from single-arm or controlled prospective cohorts can provide evidence on patient populations in which RCTs are not feasible and might, on the model of post-marketing observational safety studies of medicines, contribute to evidence on adverse events as well as procedural success. Although the aim within the CtE programme is also to collect control data, identification of appropriate controls is problematic. An additional aim of SIRT commissioning via CtE is to measure effectiveness through the collection of quality of life data. Whereas research trials can incorporate detailed quality of life and health economics analyses, for example FOXFIRE has incorporated three quality of life instruments and a bespoke health economics questionnaire to provide information about potential health economic benefits for patients treated with SIRT [[6]Dutton S.J. Kenealy N. Love S.B. Wasan H.S. Sharma R.A. FOXFIRE Protocol Development Group and the NCRI Colorectal Clinical Study GroupFOXFIRE protocol: an open-label, randomised, phase III trial of 5-fluorouracil, oxaliplatin and folinic acid (OxMdG) with or without interventional selective internal radiation therapy (SIRT) as first-line treatment for patients with unresectable liver-only or liver-dominant metastatic colorectal cancer.BMC Cancer. 2014; 14: 497Crossref PubMed Scopus (59) Google Scholar], the CtE programme is constrained by what is feasible and practical in the NHS in a limited period of time (2–3 years). In the case of SIRT commissioning, health-related quality of life is being measured by asking patients to complete the EQ5D-5L questionnaire at baseline and every 3 months. It was decided that the collection of full cost-effectiveness data was not feasible in this programme. Importantly, commissioning of 10 centres by NHS England and one centre by the NHS in Scotland has improved equity of access to SIRT and it has raised awareness of this novel therapy among oncologists, other referring doctors and the general public. In summary, the evidence base for interventional oncology is currently dominated by single-arm studies reporting technical success or clinical efficacy [[10]Franklin J.M. Gebski V. Poston G.J. Sharma R.A. Clinical trials of interventional oncology—moving from efficacy to outcomes.Nature Rev Clin Oncol. 2014; (in press)Google Scholar]. This has successfully resulted in the development of new techniques, but is not sufficient to change clinical practice uniformly across healthcare systems. SIRT is an example of clinical research where trialists have incorporated measures of overall survival, cost-effectiveness and patient-reported outcomes trial design, in order to provide robust evidence for changing clinical practice. More recently, a registry-based model of funding for SIRT has emerged as an alternative means of deriving cohort data and now exists in parallel with research studies currently ongoing. This is an exciting time for interventional oncology research and commissioning. The FOXFIRE trial is sponsored by the University of Oxford and is funded the Bobby Moore Fund of Cancer Research UK (CTAAC reference number: CRUK/A16630 ), an educational grant from Sirtex Medical Ltd and the NIHR Biomedical Research Centre Oxford .
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