Where should SIR-Spheres® microspheres be optimally used in the treatment paradigms for unresectable liver tumours?
In the recently published study; "Yttrium-90 Radioembolization in Intrahepatic Cholangiocarcinoma: A Multicenter Retrospective Analysis" 1, designed to report outcomes of yttrium-90 (90Y) radioembolization in patients with unresectable ICC, survival estimates from SIRT were found to be superior to best supportive care.
Although the study included an aim to detail and compare the adverse event rate and severity of complications between the two current methods of delivery of SIRT, there were no significant differences between the delivery methods across the study criteria.
The study also found that overall survival for those treated with SIRT was in line with the results of other local therapy options.
The purpose of the observational retrospective study was to observe treatment outcomes in terms of adverse events, response rate, survival after first diagnosis, and survival after 90Y radioembolization in a large international cohort.
In the study, radioembolization was observed to be well tolerated in patients with a good performance status, which is in line with the current literature.
Fewer than 10% of patients experienced new grade 3/4 laboratory toxicity, compared with as many as 70% in currently used chemotherapy regimens. This confirmed previous estimates.
The survival estimates in the study were superior to published estimates of patients undergoing best supportive care only 2, 3, 4, 5, 6, 7, 8
The post treatment survival duration of 11 months was in general agreement with other studies:
Technical success after the procedure was noted in all patients (n = 115; 100%).
New or increased laboratory toxicity was observed in 43 patients (42%), 4 of whom experienced grade 3 toxicity (4%).
Dr Jon Bell, coordinator for SUN and an author of the study commented:
"The retrospective analysis is an important study of SIRT in ICC patients and it showed that the survival estimates, regardless of delivery type, were superior to best supportive care.
In terms of what matters for patients, the findings from this study also show that liver-directed procedure with SIRT in ICC is well tolerated in ICC patients with good performance status.
I believe this consideration should be a critical factor in treatment options for this patient population in the future."
The full study can be accessed here
1Stefan Buettner, Arthur J.A.T.Braat, Georgios Antonios, et al, “Yttrium-90 Radioembolization in Intrahepatic Cholangiocarcinoma: A Multicenter Retrospective Analysis”, JVIR, Vol 31, issue 7, July 2020, https://doi.org/10.1016/j.jvir.2020.02.008
2A. Saxena, L. Bester, T.C. Chua, F.C. Chu, D.L. Morris Yttrium-90 radiotherapy for unresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this novel treatment option. Ann Surg Oncol, 17 (2010), pp. 484-491
3J. Valle, H. Wasan, D.H. Palmer, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer N Engl J Med, 362 (2010), pp. 1273-1281
4J.C. Camacho, N. Kokabi, M. Xing, H.J. Prajapati, B. El-Rayes, H.S. Kim. Modified response evaluation criteria in solid tumors and European Association for The Study of the Liver criteria using delayed-phase imaging at an early time point predict survival in patients with unresectable intrahepatic cholangiocarcinoma following yttrium-90 radioembolization. J Vasc Interv Radiol, 25 (2014), pp. 256-265
5S. Mouli, K. Memon, T. Baker, et al. Yttrium-90 radioembolization for intrahepatic cholangiocarcinoma: safety, response, and survival analysis. J Vasc Interv Radiol, 24 (2013), pp. 1227-1234
6S. Rafi, S.M. Piduru, B. El-Rayes, et al. Yttrium-90 radioembolization for unresectable standard-chemorefractory intrahepatic cholangiocarcinoma: survival, efficacy, and safety study. Cardiovasc Intervent Radiol, 36 (2013), pp. 440-448R.T. Hoffmann, P.M. Paprottka, A. Schon, et al.
7Transarterial hepatic yttrium-90 radioembolization in patients with unresectable intrahepatic cholangiocarcinoma: factors associated with prolonged survival. Cardiovasc Intervent Radiol, 35 (2012), pp. 105-116
8S.M. Ibrahim, M.F. Mulcahy, R.J. Lewandowski, et al. Treatment of unresectable cholangiocarcinoma using yttrium-90 microspheres: results from a pilot study. Cancer, 113 (2008), pp. 2119-2128
9A. Saxena, L. Bester, T.C. Chua, F.C. Chu, D.L. Morris. Yttrium-90 radiotherapy for unresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this novel treatment option. Ann Surg Oncol, 17 (2010), pp. 484-491
10J. White, G. Carolan-Rees, M. Dale, et al. Yttrium-90 transarterial radioembolization for chemotherapy-refractory intrahepatic cholangiocarcinoma: a prospective, observational study. J Vasc Interv Radiol, 30 (2019), pp. 1185-1192
11R.T. Hoffmann, P.M. Paprottka, A. Schon, et al. Transarterial hepatic yttrium-90 radioembolization in patients with unresectable intrahepatic cholangiocarcinoma: factors associated with prolonged survival. Cardiovasc Intervent Radiol, 35 (2012), pp. 105-116
SIRFLOX and FOXFIRE-Global Trial findings suggest that adding liver-directed Selective Internal Radiation Therapy (SIRT) to standard first-line chemotherapy may improve overall survival in metastatic colorectal cancer (mCRC) patients with right-sided primary tumours, compared to those receiving chemotherapy alone.
A post-hoc analysis of data from the 739-patient SIRFLOX and FOXFIRE-Global studies indicates that adding SIRT with liver-directed SIR-Spheres® Y-90 resin microspheres to standard first-line mFOLFOX6 chemotherapy for liver-only or liver-dominant metastatic colorectal cancer (mCRC) in patients with right-sided primary (RSP) tumours led to a statistically significant and clinically meaningful 4.9-month median overall survival benefit (Hazard Ratio [HR]: 0.64 [95% CI: 0.46-0.89]; p=0.007). This translates into a 36% reduction in the risk of death at any given time compared to patients who received chemotherapy alone.1
"This striking and essentially unexpected finding may bring new hope to mCRC patients with liver-only or liver-dominant tumours that have spread from the right side of the bowel or colon. These cancers are genetically and structurally different from tumours that start on the left side of the colon. Patients with RSP tumours have a worse prognosis for survival and fewer treatment options. They do not respond well to biological therapies such as cetuximab or panitumumab" said Professor Guy van Hazel, Clinical Professor of Medicine at the University of Western Australia, Perth, who presented the new data at the European Society of Medical Oncology's 19th World Congress on Gastrointestinal Cancer (WCGC) in Barcelona.1
The new data are consistent with a 2016 meta-analysis of 66 studies involving more than 1.4 million CRC patients, which found a significant prognostic impact of primary tumour site on overall survival.2 In particular, patients with mCRC from a left-sided primary (LSP) tumour had a 27% reduced risk of death at any given time compared to RSP patients (HR: 0.73; p<0.001).2 Patients with RSP represented more than a third (35-38%) of mCRC cases in this analysis.2
"We had not defined primary tumour 'sidedness' as a formal endpoint in the SIRFLOX and FOXFIRE Global studies, which we originally designed in 2005. At that time, scientific understanding of tumour site as a potentially significant variable in the management of CRC was only beginning to emerge," Prof. van Hazel explained. "However, we had a strong academic interest in the subject and were prescient enough to record primary tumour location for every patient we enrolled and to look at these data as an independent secondary variable in our statistical plan."
"We were not alone in our initial conservatism about the effect of tumour site in colorectal cancer," he noted. "It was only at the 2016 ASCO Annual Meeting, for example, that Prof. Alan Venook of the University of California, San Francisco, stated that, although earlier studies had introduced the idea that tumour location could affect colorectal cancer treatment outcomes, 'the effect we observed in our retrospective analysis of the Phase III CALGB/SWOG 80405 clinical trial appears to be far greater than we expected,' and could change the course of disease management," Prof. van Hazel added.3,4
"Scientific debate must and will continue on this subject," he said, "but if primary tumour sidedness effectively splits colorectal cancer and its metastases into two very different diseases, then treatment paradigms must be carefully reassessed to assure the best possible treatment outcomes for each patient. Our findings do require further validation and, subject to this, may support considering earlier use of SIRT for mCRC patients with liver-only or liver-dominant metastases from right-sided primary tumours."
"It is also important to remember," Prof. van Hazel stated, "that the data we are reporting now are from first-line studies that combined SIRT with chemotherapy for patients with mCRC, and this does not alter previously established evidence supporting the role of SIRT using SIR-Spheres Y-90 resin microspheres in treating mCRC patients who have failed or are intolerant to initial chemotherapy that led to the recommendations in the ESMO and NCCN clinical guidelines."5,6
Professor Ricky Sharma, Chair of Radiation Oncology at University College London and a Scientific Group Leader at the UCL Cancer Institute and Coordinator for SUN commented:
"We have learnt over the last decade that left-sided and right-sided colorectal cancers are both biologically and anatomically different. Right-sided tumour primaries are currently difficult to treat and patients with mCRC (metastatic colorectal cancer) from right-sided primary tumours can have a worse prognosis and a poorer response to anticancer drug treatments.
This post-hoc subgroup analysis suggests that adding Selective Internal Radiation Therapy (SIRT) to first-line mCRC treatment may improve overall survival for patients with liver cancer arising from right-sided colon tumours. The effect of sidedness in response to SIRT merits further evaluation in other clinical studies to validate this unexpected finding."
The analysis of outcomes by primary tumour location that Prof. van Hazel presented at WCGC was based on new data from SIRFLOX, a 530-patient study first reported at ASCO in 2015 and published subsequently in the Journal of Clinical Oncology,7 and FOXFIRE Global, a 209-patient study whose findings were first reported at the 2017 ASCO meeting along with the findings of FOXFIRE, a 364-patient UK study.8
The data from these three studies were pooled prospectively in the 1,103-patient FOXFIRE Combined Analysis, which was presented at ASCO in June 2017 by Professor Ricky Sharma, Chair of Radiation Oncology at University College London, UK. This analysis showed no difference in the primary endpoint of overall survival from adding SIRT to first-line FOLFOX-based chemotherapy in liver-only or liver-dominant mCRC independent of the site of the patient's primary CRC tumour.8
However, Prof. Sharma's ASCO presentation did call attention to the finding of a possible survival benefit for RSP patients treated with SIRT using SIR-Spheres Y-90 resin microspheres, and noted that further analyses were merited.
Of the 739 patients recruited in the SIRFLOX and FOXFIRE-Global studies and reported by Prof van Hazel at WCGC, 179 (24.2%) had an RSP tumour and 540 (73.1%) had an LSP tumour; 16 (2.2%) patients had a primary in both sides and the primary tumour location was unknown in 4 patients (0.5%).1 As expected, patients with a RSP were older (mean: 64.4 vs. 61.6 years) and a higher proportion were female (42.5% vs. 32.0%), compared to those with a LSP, however there were no significant differences between the treatment arms by primary tumour location.
Overall Survival was significantly improved by the addition of SIRT with SIR-Spheres Y-90 resin microspheres to first-line mFOLFOX6 chemotherapy (± bevacizumab) in mCRC patients with a right-sided primary tumour (median 22.0 vs. 17.1 months, with or without SIRT, respectively; HR: 0.64 [95% CI: 0.46-0.89]; p=0.007). No improvement in survival was seen from the addition of SIRT to first-line mFOLFOX6 chemotherapy for patients with LSP tumours (median 24.6 vs. 26.6 months, with or without SIRT, respectively; HR: 1.12 [95% CI: 0.92-1.36]; p=0.279).
A standard statistical test of treatment interaction by location for overall survival also proved highly significant (Chi-square: 9.49; p=0.002; HR: 0.548 [95% CI: 0.37-0.80]), providing further evidence that the observed benefit of adding SIRT to mFOLFOX6 chemotherapy in RSP mCRC patients was not a chance finding.
Patients with RSP tumours treated with SIRT plus mFOLFOX6 also showed a trend towards improved Progression-Free Survival (PFS) compared with those who received mFOLFOX6 alone (median 10.8 vs. 8.7 months, respectively; HR: 0.73 [95% CI: 0.53-1.01]; p=0.053).
There were no significant differences in the incidence of adverse events (AEs) between patients with RSP tumours and those with LSP tumours. "Although AEs were more common in the chemotherapy plus SIRT group of the Combined Analysis, these were generally predictable and manageable," noted Prof. van Hazel.
Prof. van Hazel concluded that, "The location of the primary tumour in mCRC is emerging as a major prognostic factor and predictor of response to treatment. Patients with mCRC from right-sided primary tumours clearly have a worse prognosis and an inferior response to treatment compared to patients with left-sided primaries. Our analysis of the impact of primary tumour location on outcomes in the SIRFLOX and FOXFIRE Global studies cohorts shows that the addition of SIR-Spheres Y-90 resin microspheres to first-line FOLFOX-based chemotherapy was associated with a statistically significant and clinically relevant gain in Overall Survival for patients with a right-sided primary tumour."
"We believe that our data add to the growing literature on the impact of primary tumour location on mCRC outcomes, which has been observed with various treatments and may, if validated, support a side-based approach to patient selection for SIRT in first-line treatment of liver-only or liver-dominant mCRC."
1van Hazel G, Heinemann V, Sharma N et al. Impact of primary tumour location on survival in patients with metastatic colorectal cancer receiving selective internal radiation therapy and chemotherapy as first-line therapy. ESMO 19th World Congress on Gastrointestinal Cancer, Ann Oncol 2017; Abs. LBA-006.
2Petrelli F, Tomasello G, Borgonovo K et al. Prognostic survival associated with left-sided vs right-sided colon cancer: A systematic review and meta-analysis. JAMA Oncol 2017; 3: 211-9.
3Venook AP, Niedzwiecki D, Innocenti F et al. Impact of primary (1°) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance). 2016 ASCO Annual Meeting; J Clin Oncol 2016; 34 (Suppl): Abs 3504.
4Medscape. Big Difference in Colorectal Cancer on Right vs Left Side. 2016 May 19; http://www.medscape.com/viewarticle/863537. Last accessed June 2017.
5Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016; 27: 1386-1422.
6National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Colon Cancer. Version 2.2017 www.nccn.org/professionals/physician_gls/PDF/colon.pdf. Last accessed June 2017.
7van Hazel GA, Heinemann V, Sharma NK et al. SIRFLOX: Randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol 2016; 34: 1723-1731.
8Sharma RA, Wasan H, van Hazel G et al. Overall survival analysis of the FOXFIRE prospective randomized studies of first-line selective internal radiotherapy (SIRT) in patients with liver metastases from colorectal cancer. 2017 ASCO Annual Meeting; J Clin Oncol 2017; 35 (Suppl): Abs 3507.
9GLOBOCAN 2012. Estimated cancer mortality, incidence and prevalence worldwide, Available at http://globocan.iarc.fr/Default.aspx. Last accessed June 2017.
1Adam R, De Gramont A, Figueras J et al. The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus. Oncologist 2012; 17: 1225-39.
2Van de Eynde M, Hendlisz A. Treatment of colorectal liver metastases: A review. Rev Rec Clin Trials 2009; 4: 56-62.
The REsect study - surgeons' blinded assessment of pre- and post-treatment CT scans of patients with previously unresectable colorectal cancer liver metastases treated in the SIRFLOX study - was presented at the 12th Annual European-African HPB meeting at the end of May in Mainz, Germany.
Compared to chemotherapy alone, adding selective internal radiation therapy (SIRT) with SIR-Spheres Y-90 resin microspheres to first-line FOLFOX-based chemotherapy was associated with a statistically significant gain in potentially curative liver resectability, an independent, international panel of expert liver surgeons has reported.1
"We performed a blinded evaluation of the extensive radiological database of the recently-reported SIRFLOX study to compare potential liver resectability at baseline and follow-up," said Dr. Benjamin Garlipp, the principal author of the REsect study and a liver surgeon at Otto-von-GuerickeUniversität, Magdeburg, Germany.
"We found that while resectability increased from baseline to follow-up in both the chemotherapy only arm and the chemotherapy + SIRT arm of the SIRFLOX study, the increase was significantly more pronounced in patients receiving the combination treatment - 38.1% of these were resectable on the basis of their liver CT scan at follow-up, compared to 28.9% of the patients receiving chemotherapy only (p< 0.0001). This is an important finding because surgical resection is the mainstay of potentially curative treatments for these patients, and there is an increasing body of evidence suggesting that it can prolong their lives even though most of them eventually recur."
The REsect study was conducted by a panel of 14 Hepato-Pancreato-Biliary surgeons from leading medical centres in Belgium, France, Germany, Italy, The Netherlands, Spain, the UK and the USA.1
Five surgeons performed independent, blinded analyses of 100 baseline and follow-up scans chosen at random from the 472 cases to be reviewed. Blinded analysis of the remaining scans was conducted of 22-25 cases at a time by three surgeons working independently and chosen at random from the nine other members of the REsect panel. The reviewers were blinded to patient identifiers, visit (baseline or follow-up), treatment and clinical information, as well as being blinded to the other reviewers' assessments. A patient was deemed to be resectable or unresectable by majority agreement (≥3 of 5 surgeons or ≥2 of 3 surgeons).
Of the 472 SIRFLOX study patients whose pre- and post-treatment liver CT scans were evaluable by the REsect surgeons, 228 had received first-line mFOLFOX6 chemotherapy ( ± bevacizumab), while 244 were treated with the combination of chemotherapy and SIR-Spheres Y-90 resin microspheres.1,2
There was no significant difference in the resectability of the patients' liver metastases at baseline (11.0% vs. 11.9%; p=0.775). In a second analysis, of patients who were not resectable at baseline, a second analysis of scans post-treatment showed significantly more patients in the Y-90 resin microspheres group had resectable liver metastases compared to those who received chemotherapy alone (31.2% vs. 22.7%; p< 0.0001).1
"As a surgeon, it is always my aim to offer the option of a potentially curative liver resection to patients with mCRC. We know that in many patients with metastatic colorectal cancer the liver is the only organ with cancer deposits, and converting patients from a stage where resection of the disease is not possible into one where potential curative resection becomes an option again has an enormous impact for patients. This retrospective analysis suggests that SIRT with Y-90 resin microspheres could be a means to achieving resection for more of these patients," Dr Garlipp emphasized..
Professor Ricky Sharma, coordinator of SUN, commented:
"Resection is the gold standard treatment across tumour types but it is particularly difficult to assess and execute in mCRC. Many CRC patients will have inoperable liver metastases at presentation and treatment options can be very limited. This is also true for patients who have previously undergone chemotherapy.
It has proved difficult to produce consensus criteria that all surgeons agree on to represent when liver metastases are resectable or not operable. The strength of this study is the blinded and objective way in which the scans were assessed by a panel of experts. It is not currently clear whether all patients with mCRC have access to appropriate liver surgery after their disease has responded to SIRT treatment."
1 Garlipp B et al. REsect: Blinded assessment of resectability of previously unresectable colorectal cancer liver metastases following chemotherapy ± Y90-RadioEmbolization. 12th Biennial European-African Hepato-Pancreato-Biliary Association (E-AHPBA Congress) 2017; Abs. FP 15.08.
2 van Hazel GA et al. SIRFLOX: Randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol 2016; 34: 1723-1731.
The results of the FOXFIRE Combined Analysis, a study of 1,103 patients randomised to receive either standard first-line chemotherapy for colorectal cancer that has spread to the liver, or the same chemotherapy plus a treatment procedure called selective internal radiotherapy using radioactive yttrium-90 resin microspheres is to be presented at the American Society of Clinical Oncology ASCO on 5th June. The abstract was published by ASCO on 17th May.
The primary analysis combines data from the SIRFLOX study, first presented in 2015, with data from two new studies - FOXFIRE and FOXFIRE-Global.
Although it demonstrates no difference in overall survival between patients treated with microspheres plus chemotherapy compared to patients treated with chemotherapy alone, there were clinical benefits shown by the study.
More detailed analysis of different patient groups within has suggested that the survival of patients with bowel cancer that originates within the right side of the bowel may benefit significantly more from the addition of SIRT using Y-90 resin microspheres to chemotherapy, compared to other patients. The validity of this new finding is currently being analysed using data from other clinical studies.
The FOXFIRE Combined Analysis also confirmed that progression-free survival in the liver was significantly longer and that the tumour response was increased in SIRT-treated patients, which correlate with the results of the SIRFLOX study presented in 2015.
Commenting on the findings, Professor Ricky Sharma, Coordinator for SUN said:
"Although overall survival is the gold standard for randomised phase III clinical trials, it is often difficult to see statistically significant results since patients have multiple lines of therapy after they receive the new treatment and there is no way of controlling cross-over to the new treatment after the patient has completed protocol therapy. Even in a very large phase III study, it is difficult to control for all biological factors since researchers are still discovering previously unknown factors that drive cancer, for example recent studies that show that right-sided colorectal cancer is a different disease from left-sided colorectal cancer whereas we classified them as a single disease when the FOXFIRE and SIRFLOX studies were planned over a decade ago.
The FOXFIRE Combined Analysis was addressed to ask a specific question about the use of SIRT in combination with one type of chemotherapy used as first-line treatment for metastatic colorectal cancer. The study was the largest phase III undertaking ever performed in the history of Inverventional Oncology. It included patients with poor prognosis metastatic colorectal cancer, often with the primary tumour remaining, and patients with some metastases that were outside the liver, for example the lungs.
The combined analysis has confirmed that SIRT improves control of disease in the liver, but we were disappointed to see that the improved control of the liver disease did not impact on overall survival of these patients much later in the patient journey, which was after patients had received other lines of therapy.
One very interesting finding from this large dataset is a possible survival benefit in patients with a primary tumour that originated in the right side of the colon, particularly since we now know that these patients are not well served by current chemotherapy and biological therapies and there are currently few effective treatment options that are available.
Within the next few months, we will be exploring this important finding in more detail to confirm its relevance to patients with colorectal cancer."
The primary endpoint from the combination study should have little or no impact on current treatment practice as patients currently offered SIRT in most countries are those who have already failed all standard chemotherapy treatments.
Colorectal cancer is the fourth most frequently diagnosed cancer worldwide, and the third leading cause of cancer deaths, taking almost 700,000 lives annually. More than half of all patients with colorectal cancer will be diagnosed with metastases, most commonly in the liver.
The FOXFIRE Combined Analysis was a study of 1,103 patients randomised to receive either standard first-line chemotherapy for colorectal cancer that has spread to the liver, or the same chemotherapy plus a treatment procedure called selective internal radiotherapy using radioactive yttrium-90 resin microspheres.
The primary analysis of this study combines data from the SIRFLOX study first presented in 2015 with data from two new studies - FOXFIRE and FOXFIRE-Global.
In the FOXFIRE Combined Analysis, patients in one arm of the study received oxaliplatin-based chemotherapy (mFOLFOX6 or OxMdG), either with or without a biologically targeted agent. In the other arm of the study, patients received the same systemic therapy (with a dose modification of oxaliplatin), plus a single treatment with radioactive yttrium-90 resin microspheres.
In order to enter the study, patients were permitted to have a limited number of metastases outside the liver in addition to having metastases in the liver that could not be surgically removed.
Patients with advanced or inoperable Hepatocellular Carcinoma (HCC) who received one or two treatments with liver-directed SIRT (using SIR-Spheres Y-90 resin microspheres) in the 459 patient French SARAH study had similar survival compared to patients who received standard twice-daily systemic treatment with sorafenib. The SIRT patients had less than half the number and significantly fewer severe treatment-related adverse effects and significantly better Quality of Life, according to data presented at The International Liver Congress™ 2017 in Amsterdam.
The results, which could impact the treatment of liver cancer patients worldwide, were announced by the principal investigator of the SARAH study, Professor Valérie Vilgrain MD, PhD, Department of Radiology, Beaujon Hospital, Assistance Publique - Hôpitaux de Paris (AP-HP) and Université Paris Diderot, Sorbonne Paris Cité, France.
"Neither sorafenib nor SIR-Spheres Y-90 resin microspheres produced a statistically significant difference in Overall Survival (OS) of the patients we studied," said Professor Vilgrain. "Despite 26.6% of patients in the SIRT arm not receiving SIR-Spheres per protocol, the primary endpoint of Overall Survival by intention-to-treat [ITT] was not significantly different (median 8.0 vs. 9.9 months; p=0.18). Moreover, if we look at the patients who received SIR-Spheres or sorafenib according to the SARAH protocol, median OS was identical (9.9 vs. 9.9 months; p=0.92)."
"In terms of what matters for patients, the findings from this first large head-to-head comparison of liver-directed Selective Internal Radiation Therapy (SIRT) and systemic chemotherapy with sorafenib also show clearly that liver-directed procedures with SIR-Spheres result in a significantly better tolerance of treatment and quality of life," Professor Vilgrain stated. "I believe this consideration should be a critical factor in selecting first-line treatment for this patient population in the future."
About 10% of patients assigned to SIRT were treated with sorafenib because their condition worsened during the workup for SIRT, which took up to 3 weeks in this clinical trial, or because of technical issues with the mapping or administration of the beads. In clinical practice, that time could be shortened substantially, Professor Vilgrain stated.
Professor Ricky Sharma, coordinator for the SIRT Users' Network commented:
"The SARAH study is an important prospective randomised study of SIRT over the existing standard of care. Although SIRT did not demonstrate an advantage in overall survival, the study found no significant difference in overall survival. The value of this study is the superior quality of survival - safety, quality of life and superior response in the liver itself.
It is clear from these secondary endpoints that SIRT is an attractive option for some patients with locally advanced HCC and should be available in the oncological toolbox clinicians use to treat these patients.
This study effectively places SIRT as an important treatment option for locally advanced inoperable HCC."
The SARAH trial was a randomised, controlled, open-label, multicentre investigator initiated Phase 3 trial. Patients with locally advanced or inoperable HCC, who did not respond to 2 other treatments or had two failed rounds of transarterial chemoembolisation, were randomised to SIRT with Y-90 resin microspheres, or oral sorafenib 400 mg twice daily.
The primary endpoint of the study was OS and secondary endpoints included progression-free survival (PFS), time to radiological progression at any site and in the liver as the first event, tumour response, quality of life, and safety and toxicity.
There were 459 patients from 25 French clinical centres included in the study, 237 of whom received SIRT. Median PFS was 4.1 months and 3.7 months in the SIRT and sorafenib groups, respectively (p=0.765). Cumulative incidence of radiological progression at any site did not differ in either group (p=0.256). Overall, there were 1,297 and 2,837 treatment-related adverse events (AEs) including 230 and 411 grade ≥3, in the SIRT and sorafenib groups, respectively.
The number of patients with at least one treatment-related adverse event was 173 (76.5%) and 203 (94.0%), (p<0.001), including 92 (40.7%) and 136 (63.0%) grade ≥3 adverse events, (p<0.001), in the SIRT and sorafenib groups, respectively. Quality of life, assessed using the Global Health Status scale of the EORTC QLQ-C30 questionnaire, was significantly better in patients who received SIRT compared to the sorafenib group (p=0.005), an advantage that tended to increase with time (p=0.045).
Dr Andrew Kennedy presented a poster at the recent ASCO Gastrointestinal Cancers Symposium which provided an updated survival analysis of the MORE Study for patients with advanced liver-dominant metastatic colorectal cancer treated with selective internal radiotherapy (SIRT) using 90Y-labeled resin microspheres (SIR-Spheres®).
Patients were considered for 90Y RadioEmbolization (RE), an alternative name for SIRT, if they had advanced liver-dominant metastatic colorectal cancer which was not suitable for treatment by surgery, systemic therapy, or ablation, and which had progressed or become refractory to at least one line of systemic therapy.
Patients received a median of 2 prior lines of systemic chemotherapy (range 0-6) before treatment with 90Y RE alone.
All patients with a diagnosis of metastatic colorectal cancer who had received at least 1 RE treatment and 1 follow-up visit were included in this analysis.
Data on baseline characteristics, treatment histories, and adverse events were collected at baseline, at the first 90Y RE treatment, and at all subsequent visits or until death. Survival was calculated from the day of first 90Y RE treatment (day 0) to day of death or last follow-up. Patient medical charts and/or public records were accessed to obtain date of death.
Extended survival surveillance of patients from the MORE study was conducted to September 2016. During this analysis, Dr Kennedy and colleagues obtained dates of death for an additional 71 patients.
The Kaplan-Meier method was used to obtain updated estimates of overall survival for all patients. 45% of patients were still alive one year after 90Y RE treatment; however, less than 10% were alive 3 years after treatment.
The updated overall median survival was 10.0 months (95% CI: 9.2-11.8) at a median follow-up of 9.5 months versus 9.6 months (95% CI: 9.0-11.1) at a median follow-up of 8.6 months as reported in the first MORE study analysis.
Dr Kennedy commented:
"At the ASCO® Gastrointestinal Cancers Symposium, we presented data on the longest follow-up monitoring of mCRC patients after SIR-Spheres® Y-90 resin microspheres treatment. The data confirms our original findings that SIRT is safe and effective, providing significant clinical benefit in patients regardless of age."
Professor Ricky Sharma, chair of SUN said:
"Clinical trials including the elderly are particularly valuable since traditional clinical trials do not represent this important group of patients well. We know from our clinical experiences that SIRT can be used safely in the elderly, and these data confirm that and demonstrate its effectiveness.
The data from the MORE Study show how well SIRT is tolerated, regardless of age. It is also important to note that SIRT can be used as an effective stand-alone treatment after chemotherapy has stopped working. In that setting, the alternative is called "salvage" therapy and it can be poorly tolerated. SIRT appears to be a favourable alternative to be considered and discussed in detail with appropriate patients."
The MORE study was a retrospective analysis of 606 patients with advanced liver-dominant metastatic colorectal cancer treated with RE using 90Y-labeled resin microspheres (SIR-SpheresASCO®).
Patients were consecutively treated between July 2002 and December 2011 at one of 11 experienced RE centers in the U.S. An independent contract research organization collected data from each site. All centers received Institutional Review Board approval for this study.
A new analysis of the MORE dataset on 606 mCRC patients treated with SIR-Spheres Y-90 resin microspheres, published recently in the journal Clinical Colorectal Cancer, confirms that patient age is not a barrier to appropriate treatment with SIRT.
The report concluded that for patients with unresectable liver-dominant mCRC, who meet eligibility criteria for Radioembolisation (RE), SIR-Spheres Y-90 resin microspheres appear to be effective and well-tolerated, regardless of age.
The study concludes that the selection of patients for RE should not exclude the elderly.
Principal study author, Andrew S. Kennedy, MD, Director, Radiation Oncology Research, Sarah Cannon Research Institute said that "the analysis of the data from the MORE study confirmed that age alone should not exclude patients from being considered for, or receiving, SIR-Spheres® Y-90 resin microspheres treatment."
Overall, the study found that 90Y-RE was equally well tolerated in eligible elderly (≥ 70 years) and very elderly (≥ 75 years) and younger patients, without evidence of an increased risk of Radioembolization-induced liver disease or hepatic dysfunction in the elderly who were assessed up to 90 days after the procedure.
Overall, the incidence of grade 3+ events after 90Y-RE was low. Mild to moderate fatigue was slightly more prominent in the elderly than in the younger patients, although between-group differences were not statistically significant.
Reference: Kennedy AS, Ball DS, Cohen SJ et al. Safety and efficacy of radioembolization in elderly (≥ 70 years) and younger patients with unresectable liver-dominant colorectal cancer. Clinical Colorectal Cancer 2015 Nov 2; ePub doi: 10.1016/j.clcc.2015.09.001
The study was a retrospective analysis of 160 elderly (≥ 70 years) and 446 younger (< 70 years) consecutive patients from 11 US centers who received RE using ytrrium-90 (90Y) resin microspheres (90Y radioembolization [90Y-RE]) between July 2002 and December 2011. A further analysis was conducted in 98 very elderly patients (≥ 75 years).
Mean ages (± standard deviation) in the younger (< 70 years), elderly (≥ 70 years), and very elderly (≥ 75 years) cohorts were 55.9 ± 9.4 years, 77.2 ± 4.8 years, and 80.2 ± 3.8 years, respectively. Overall survival was similar between elderly and younger patients: 9.3 months (95% confidence interval [CI], 8.0-12.1) and 9.7 months (95% CI, 9.0-11.4) (P = .335). There were no differences between cohorts for any grade adverse events (P = .433) or grade 3+ events (P = .482). Analysis of patients ≥ 75 years and < 75 years confirmed similar overall survival (median, 9.3 months vs. 9.6 months, respectively; P = .987) and grade 3+ events (P = .398) or any adverse event (P = .158) within 90 days of RE.
The American Society for Clinical Oncology (ASCO) has published the SIRFLOX Study Abstract as part of the 2015 Annual Meeting Abstracts which revealed a statistically significant improvement in median Progression-Free Survival (PFS) in the liver when combining FOLFOX chemotherapy (± bev) with SIRT using yttrium-90 (Y-90) resin microspheres as first-line treatment of patients with liver metastases from mCRC.
Key highlights of SIRFLOX study abstract:
It is anticipated by clinicians that important new information will arise from the Oral Abstract Session that facilitates a greater understanding of the implications and impact of the SIRFLOX study for SIR-Spheres® Y-90 resin microspheres in first-line mCRC, and how this may apply to clinical practice.
Overview of SIRFLOX Study Abstract
In first-line treatment of patients with non-resectable CRC liver metastases, the addition of SIRT to standard chemotherapy failed to improve overall PFS.
The SIRFLOX study results revealed a statistically significant improvement in median Progression-Free Survival (PFS) in the liver. Reported median PFS in the liver was 20.5 months in the SIR-Spheres microspheres + mFOLFOX6 chemotherapy+/- biologic agent bevacizumab arm versus 12.6 months in the mFOLFOX6 +/- bevacizumab arm, with a P value p=0.002 and a Hazard Ratio of HR=0.69.
This means that there was less than a 0.2% chance the result in the liver was due to chance alone and that there was a 31% reduction in the risk of tumour progression in the liver for patients whose treatment included SIR-Spheres microspheres while on study.
The Complete Response Rate in the liver was 6.0% in the SIR-Spheres microspheres + mFOLFOX6 +/- bevacizumab arm versus 1.9% in the mFOLFOX6 +/- bevacizumab arm, with a P value of p=0.02. This result indicates that patients who received SIR-Spheres microspheres as part of their treatment experienced approximately a threefold higher rate of complete disappearance of tumours in their liver, compared to patients who did not receive SIR-Spheres microspheres.
The Overall Survival (OS) data from the SIRFLOX study will be combined with the FOXFIRE and FOXFIRE Global studies to provide sufficient statistical power in over 1,000 patients globally to detect a clinical significant difference in OS between the SIR-Spheres microspheres and control arms. Analysis of OS from the SIRFLOX study cannot be progressed at this time for reasons of (a) bias and (b) statistical power for these studies. Overall OS data is anticipated in 2017.
The ASCO Annual Meeting in Chicago brings together 30,000 oncology professionals from around the world. Educational sessions feature world-renowned faculty discussing state-of-the-art treatment modalities, new therapies, and ongoing controversies in the field. Science sessions present the latest round-breaking research in oral and poster format.
The SIRFLOX data will be presented at ASCO by Dr Peter Gibbs in the oral presentation session starting at 3 pm on Saturday 30th May 2015.
The SIRFLOX study is an international, multi-centre, randomised controlled study that enrolled over 500 patients with mCRC whose disease was non-resectable and had spread to either the liver alone or the liver plus a limited number of sites outside the liver, including lymph nodes and the lungs.
The study was conducted in more than 100 hospitals across Australia, Europe, Israel, New Zealand and the United States. SIRFLOX is the first, large randomised controlled study that has examined the use of Selective Internal Radiation Therapy (SIRT, also known as radioembolisation) in the treatment of colorectal liver metastases. For more information, please visit www.sirflox.com
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