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Overall survival of patients with hepatocellular carcinoma receiving sorafenib versus selective internal radiation therapy with predicted osimetry in the SARAH trial
abstracts 734P
Selection of patients with hepatocellular carcinoma for selective internal radiation therapy based on tumour burden and liver function: A post-hoc analysis of the SARAH trial
D.H. Palmer1, N.S. Hawkins2, V. Vilgrain3, H. Pereira4, G. Chatellier4, P.J. Ross5 Molecular and Cancer Medicine, University of Liverpool, Liverpool, UK, 2Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK, 3Radiology, Hoˆpital Beaujon (AP-HP), Clichy, France, 4CIC-EC4 URC HEGP, Hoˆpitaux Universitaires Paris Ouest (APHP), Paris, France, 5Medical Oncology, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK
1
Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Sirtex. N.S. Hawkins: Research grant / Funding (institution), Travel / Accommodation / Expenses: Sirtex. V. Vilgrain: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sirtex. P.J. Ross: Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Shire; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sirtex; Honoraria (self), Travel / Accommodation / Expenses: Servier; Research grant / Funding (institution): Sanofi. All other authors have declared no conflicts of interest.
735P
Second-line chemotherapy (SLC) in patients with advanced biliary tract and gallbladder cancers (ABGC) prolongs survival: A retrospective population-based cohort study
A. Zaidi1, N. Chandna2, G. Narasimhan3, M. Moser4, K. Haider5, H.I. Chalchal6, J. Shaw7, S. Ahmed5 1 Oncology, Saskatoon Cancer Centre University of Saskatchewan, Saskatoon, SK, Canada, 2Pathology, McMaster University, Hamilton, ON, Canada, 3Epidemiology, Saskatoon Cancer Centre University of Saskatchewan, Saskatoon, SK, Canada, 4Surgery, University of Saskatchewan, Saskatoon, SK, Canada, 5Oncology, Saskatoon Cancer Centre University of Saskatchewan, Saskatoon, SK, Canada, 6Oncology, Saskatchewan Cancer Agency-Allan Blair Cancer Centre at Pasqua Hosp, Regina, SK, Canada, 7 Surgery, University of Saskatchewan, Saskatoon, SK, Canada Background: Limited evidence is available regarding survival benefit of SLC in patients with ABGC. After failure of first-line treatment, currently no "standard" second-line therapy is available. There is a lack of randomized clinical trials and well-designed population-based study to address this important question in the management of ABGC. In this population-based cohort study we evaluated if SLC prolongs survival in patients with ABGC. Methods: Patients with biopsy proven ABGC who were diagnosed in the province of Saskatchewan during the period of 2006 to 2015 and received first-line chemotherapy were assessed. Based on the use of SLC, patients were divided into ‘Treatment’ group or ‘Control’. Cox proportional multivariate analyses were performed to determine survival benefit of SLC.
v282 | Gastrointestinal Tumours, Non-Colorectal
Results: 136 eligible patients with median age of 66 (IQR, 55-73) and M:F of 1:1.34 were identified. Primary tumor sites were as followed: gallbladder 31%, intrahepatic cholangiocarcinoma 36%, bile duct 23%, and ampullary 10%. 68% patients had metastatic disease.37% patients received SLC and of those 42% received combination therapy. There were significant differences between the two groups with respect to age and baseline liver function. The median overall survival (mOS) of treatment group was 17 months (95%CI, 12.5-21.5) vs. 7 months (5.3-8.7) of control (p < 0.0001). Patients who received combination SLC had mOS of 20 months (14.0-26.1) vs. 17 (13.5-20.5) with single agent chemotherapy (p ¼ 0.73). On progression 36% received 3rd or subsequent line treatment. On univariate analysis SLC HR 0.51 (0.35-0.73), bilirubin 0.52 (0.34-0.79), and neutrophil to lymphocyte ratio (NLR) 1.11 (1.07-1.16) significantly correlated with survival. Test for interaction between SLC and all the other variables were not significant. On multivariate analysis SLC HR 0.55 (0.36-0.83) and NLR 1.10 (1.05-1.15) were significantly correlated with survival. Conclusions: This well-designed population based cohort study suggests a substantial survival benefit associated with SLC. Patients with ABGC who are potential candidate for chemotherapy should be offered active treatment or participation in the clinical trial. Legal entity responsible for the study: The authors. Funding: Saskatchewan Cancer Agency Research Grant. Disclosure: All authors have declared no conflicts of interest.
736P
Overall survival of patients with hepatocellular carcinoma receiving sorafenib versus selective internal radiation therapy with predicted osimetry in the SARAH trial
N.S. Hawkins1, P.J. Ross2, D.H. Palmer3, G. Chatellier4, H. Pereira4, V. Vilgrain5 Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK, 2Medical Oncology, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK, 3Molecular and Cancer Medicine, University of Liverpool, Liverpool, UK, 4CIC-EC4 URC HEGP, Hoˆpitaux Universitaires Paris Ouest (AP-HP), Paris, France, 5Radiology, Hoˆpital Beaujon (AP-HP), Clichy, France
1
Background: Selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres was compared to sorafenib 400mg bid in a phase 3 randomised trial (SARAH) in the treatment of intermediate or advanced hepatocellular carcinoma (HCC) not amenable to curative treatment. The trial did not show a survival benefit of SIRT over sorafenib in the intention to treat (ITT) population. The effectiveness of SIRT may depend on the tumour-absorbed dose, which can be predicted with the analysis of SPECT/CT imaging during each patient work-up, before the administration of SIRT. In this post hoc analysis we explored the comparative effectiveness of SIRT and sorafenib in a subgroup of patients defined by their predicted tumour-absorbed dose. Methods: Cox proportional hazards regressions were conducted in the ITT population of the SARAH trial. Since predicted tumour-absorbed dose was only available for SIRT, the comparisons between SIRT at a given dose and sorafenib were not randomised. Inverse probability of treatment weighting (IPTW) using propensity scores was used to account for potential confounding by differences in prognostic factors between the treatment arms, with the sorafenib sample reweighted to match the SIRT patients. A cut-off value of 100 Gy was used for tumour absorbed dose, approximating the median dose, with 120 Gy used in a sensitivity analysis. Results: For patients with a predicted dose 100 Gy, the hazard ratio (HR) for overall survival (OS) from the unweighted sample was 0.70 (95% CI: 0.50-0.98, p ¼ 0.04). After reweighting, the HR was 0.74 (95% CI: 0.51-1.04, p ¼ 0.09). Predicted mean OS was 22.5 months (mos) for SIRT vs 17.9 mos for sorafenib. Results were similar with a 120 Gy cut-off: the HR for OS was 0.76 (95% CI 0.52-1.10, p ¼ 0.14). Among patients who received subsequent curative therapy post-SIRT, 11/12 were alive at the end of follow-up (median 26.6 mos, range 16.0-34.8) and only one had a predicted dose <100 Gy. Conclusions: The analysis suggests that HCC patients may derive a meaningful benefit from treatment using SIRT with a predicted dose 100 Gy compared to sorafenib. This may inform personalised treatment selection and clinical trial design. Clinical trial identification: NCT01482442. Legal entity responsible for the study: Sirtex Medical UK Ltd. Funding: Sirtex Medical UK Ltd. Disclosure: N.S. Hawkins: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Sirtex. P.J. Ross: Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self): Roche; Honoraria (self), Travel / Accommodation / Expenses: Servier; Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy: Shire; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sirtex. D.H. Palmer: Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. V. Vilgrain: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sirtex. All other authors have declared no conflicts of interest.
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz247.063/5576666 by guest on 24 October 2019
Background: The most recent ESMO (2018) and EASL Clinical Practice Guidelines (2018) for the treatment of hepatocellular carcinoma (HCC) recommend considering liver function and tumour burden when selecting patients for intra-arterial therapy, such as selective internal radiation therapy (SIRT). The SARAH randomised trial did not show a statistically significant benefit of SIRT using yttrium-90 (Y-90) resin microspheres over sorafenib 400mg bid in terms of overall survival (OS) in the overall trial population of European patients with HCC. In this post-hoc analsis we explored the comparative effectivenes of these treatments in a subgroup of patients with low tumour burden (25% of total liver volume) and good liver function (ALBI grade 1). Methods: A Cox proportional hazards survival regression was conducted in the intention to treat (ITT) population of the SARAH trial to explore treatment effect modification including low tumour burden/good liver function as an interaction effect with treatment. Results: Among the ITT population, 37 (16%) patients in the SIRT arm and 48 (22%) patients in the sorafenib arm had a tumour burden 25% and an ALBI grade of 1. The interaction effect estimate from the Cox regression was 0.609 (95% CI: 0.344 to 1.079, p ¼ 0.089) indicating that SIRT was relatively more effective in this subgroup. In the low tumour burden/good liver function subgroup the HR for SIRT vs sorafenib was 0.73 (95% CI: 0.44 to 1.21). Median OS was 21.9 months (95% CI: 15.2 to 32.5) for SIRT vs 17.0 months (95% CI: 11.6 to 20.8) for sorafenib. Subsequent curative therapy was more frequent after SIRT than sorafenib (14% vs 2%). The drop-out rate from randomisation to SIRT treatment was lower in the subgroup than in the overall ITT population (8% vs 22%). Conclusions: The analysis suggests that it may be possible to select patients with HCC and a low tumour burden/good liver function, who would derive a meaningful benefit from treatment with SIRT compared to sorafenib. Further prospective validation is required. Clinical trial identification: NCT01482442. Legal entity responsible for the study: Sirtex Medical UK Ltd. Funding: Sirtex Medical UK Ltd. Disclosure: D.H. Palmer: Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer;
Annals of Oncology
Selection of patients with hepatocellular carcinoma for selective internal radiation therapy based on tumour burden and liver function: A post-hoc analysis of the SARAH trial
D.H. Palmer1, N.S. Hawkins2, V. Vilgrain3, H. Pereira4, G. Chatellier4, P.J. Ross5 Molecular and Cancer Medicine, University of Liverpool, Liverpool, UK, 2Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK, 3Radiology, Hoˆpital Beaujon (AP-HP), Clichy, France, 4CIC-EC4 URC HEGP, Hoˆpitaux Universitaires Paris Ouest (APHP), Paris, France, 5Medical Oncology, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK
1
Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Sirtex. N.S. Hawkins: Research grant / Funding (institution), Travel / Accommodation / Expenses: Sirtex. V. Vilgrain: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sirtex. P.J. Ross: Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Shire; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sirtex; Honoraria (self), Travel / Accommodation / Expenses: Servier; Research grant / Funding (institution): Sanofi. All other authors have declared no conflicts of interest.
735P
Second-line chemotherapy (SLC) in patients with advanced biliary tract and gallbladder cancers (ABGC) prolongs survival: A retrospective population-based cohort study
A. Zaidi1, N. Chandna2, G. Narasimhan3, M. Moser4, K. Haider5, H.I. Chalchal6, J. Shaw7, S. Ahmed5 1 Oncology, Saskatoon Cancer Centre University of Saskatchewan, Saskatoon, SK, Canada, 2Pathology, McMaster University, Hamilton, ON, Canada, 3Epidemiology, Saskatoon Cancer Centre University of Saskatchewan, Saskatoon, SK, Canada, 4Surgery, University of Saskatchewan, Saskatoon, SK, Canada, 5Oncology, Saskatoon Cancer Centre University of Saskatchewan, Saskatoon, SK, Canada, 6Oncology, Saskatchewan Cancer Agency-Allan Blair Cancer Centre at Pasqua Hosp, Regina, SK, Canada, 7 Surgery, University of Saskatchewan, Saskatoon, SK, Canada Background: Limited evidence is available regarding survival benefit of SLC in patients with ABGC. After failure of first-line treatment, currently no "standard" second-line therapy is available. There is a lack of randomized clinical trials and well-designed population-based study to address this important question in the management of ABGC. In this population-based cohort study we evaluated if SLC prolongs survival in patients with ABGC. Methods: Patients with biopsy proven ABGC who were diagnosed in the province of Saskatchewan during the period of 2006 to 2015 and received first-line chemotherapy were assessed. Based on the use of SLC, patients were divided into ‘Treatment’ group or ‘Control’. Cox proportional multivariate analyses were performed to determine survival benefit of SLC.
v282 | Gastrointestinal Tumours, Non-Colorectal
Results: 136 eligible patients with median age of 66 (IQR, 55-73) and M:F of 1:1.34 were identified. Primary tumor sites were as followed: gallbladder 31%, intrahepatic cholangiocarcinoma 36%, bile duct 23%, and ampullary 10%. 68% patients had metastatic disease.37% patients received SLC and of those 42% received combination therapy. There were significant differences between the two groups with respect to age and baseline liver function. The median overall survival (mOS) of treatment group was 17 months (95%CI, 12.5-21.5) vs. 7 months (5.3-8.7) of control (p < 0.0001). Patients who received combination SLC had mOS of 20 months (14.0-26.1) vs. 17 (13.5-20.5) with single agent chemotherapy (p ¼ 0.73). On progression 36% received 3rd or subsequent line treatment. On univariate analysis SLC HR 0.51 (0.35-0.73), bilirubin 0.52 (0.34-0.79), and neutrophil to lymphocyte ratio (NLR) 1.11 (1.07-1.16) significantly correlated with survival. Test for interaction between SLC and all the other variables were not significant. On multivariate analysis SLC HR 0.55 (0.36-0.83) and NLR 1.10 (1.05-1.15) were significantly correlated with survival. Conclusions: This well-designed population based cohort study suggests a substantial survival benefit associated with SLC. Patients with ABGC who are potential candidate for chemotherapy should be offered active treatment or participation in the clinical trial. Legal entity responsible for the study: The authors. Funding: Saskatchewan Cancer Agency Research Grant. Disclosure: All authors have declared no conflicts of interest.
736P
Overall survival of patients with hepatocellular carcinoma receiving sorafenib versus selective internal radiation therapy with predicted osimetry in the SARAH trial
N.S. Hawkins1, P.J. Ross2, D.H. Palmer3, G. Chatellier4, H. Pereira4, V. Vilgrain5 Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK, 2Medical Oncology, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK, 3Molecular and Cancer Medicine, University of Liverpool, Liverpool, UK, 4CIC-EC4 URC HEGP, Hoˆpitaux Universitaires Paris Ouest (AP-HP), Paris, France, 5Radiology, Hoˆpital Beaujon (AP-HP), Clichy, France
1
Background: Selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres was compared to sorafenib 400mg bid in a phase 3 randomised trial (SARAH) in the treatment of intermediate or advanced hepatocellular carcinoma (HCC) not amenable to curative treatment. The trial did not show a survival benefit of SIRT over sorafenib in the intention to treat (ITT) population. The effectiveness of SIRT may depend on the tumour-absorbed dose, which can be predicted with the analysis of SPECT/CT imaging during each patient work-up, before the administration of SIRT. In this post hoc analysis we explored the comparative effectiveness of SIRT and sorafenib in a subgroup of patients defined by their predicted tumour-absorbed dose. Methods: Cox proportional hazards regressions were conducted in the ITT population of the SARAH trial. Since predicted tumour-absorbed dose was only available for SIRT, the comparisons between SIRT at a given dose and sorafenib were not randomised. Inverse probability of treatment weighting (IPTW) using propensity scores was used to account for potential confounding by differences in prognostic factors between the treatment arms, with the sorafenib sample reweighted to match the SIRT patients. A cut-off value of 100 Gy was used for tumour absorbed dose, approximating the median dose, with 120 Gy used in a sensitivity analysis. Results: For patients with a predicted dose 100 Gy, the hazard ratio (HR) for overall survival (OS) from the unweighted sample was 0.70 (95% CI: 0.50-0.98, p ¼ 0.04). After reweighting, the HR was 0.74 (95% CI: 0.51-1.04, p ¼ 0.09). Predicted mean OS was 22.5 months (mos) for SIRT vs 17.9 mos for sorafenib. Results were similar with a 120 Gy cut-off: the HR for OS was 0.76 (95% CI 0.52-1.10, p ¼ 0.14). Among patients who received subsequent curative therapy post-SIRT, 11/12 were alive at the end of follow-up (median 26.6 mos, range 16.0-34.8) and only one had a predicted dose <100 Gy. Conclusions: The analysis suggests that HCC patients may derive a meaningful benefit from treatment using SIRT with a predicted dose 100 Gy compared to sorafenib. This may inform personalised treatment selection and clinical trial design. Clinical trial identification: NCT01482442. Legal entity responsible for the study: Sirtex Medical UK Ltd. Funding: Sirtex Medical UK Ltd. Disclosure: N.S. Hawkins: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Sirtex. P.J. Ross: Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self): Roche; Honoraria (self), Travel / Accommodation / Expenses: Servier; Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy: Shire; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sirtex. D.H. Palmer: Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. V. Vilgrain: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sirtex. All other authors have declared no conflicts of interest.
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz247.063/5576666 by guest on 24 October 2019
Background: The most recent ESMO (2018) and EASL Clinical Practice Guidelines (2018) for the treatment of hepatocellular carcinoma (HCC) recommend considering liver function and tumour burden when selecting patients for intra-arterial therapy, such as selective internal radiation therapy (SIRT). The SARAH randomised trial did not show a statistically significant benefit of SIRT using yttrium-90 (Y-90) resin microspheres over sorafenib 400mg bid in terms of overall survival (OS) in the overall trial population of European patients with HCC. In this post-hoc analsis we explored the comparative effectivenes of these treatments in a subgroup of patients with low tumour burden (25% of total liver volume) and good liver function (ALBI grade 1). Methods: A Cox proportional hazards survival regression was conducted in the intention to treat (ITT) population of the SARAH trial to explore treatment effect modification including low tumour burden/good liver function as an interaction effect with treatment. Results: Among the ITT population, 37 (16%) patients in the SIRT arm and 48 (22%) patients in the sorafenib arm had a tumour burden 25% and an ALBI grade of 1. The interaction effect estimate from the Cox regression was 0.609 (95% CI: 0.344 to 1.079, p ¼ 0.089) indicating that SIRT was relatively more effective in this subgroup. In the low tumour burden/good liver function subgroup the HR for SIRT vs sorafenib was 0.73 (95% CI: 0.44 to 1.21). Median OS was 21.9 months (95% CI: 15.2 to 32.5) for SIRT vs 17.0 months (95% CI: 11.6 to 20.8) for sorafenib. Subsequent curative therapy was more frequent after SIRT than sorafenib (14% vs 2%). The drop-out rate from randomisation to SIRT treatment was lower in the subgroup than in the overall ITT population (8% vs 22%). Conclusions: The analysis suggests that it may be possible to select patients with HCC and a low tumour burden/good liver function, who would derive a meaningful benefit from treatment with SIRT compared to sorafenib. Further prospective validation is required. Clinical trial identification: NCT01482442. Legal entity responsible for the study: Sirtex Medical UK Ltd. Funding: Sirtex Medical UK Ltd. Disclosure: D.H. Palmer: Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer;
Annals of Oncology