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Prognostic factors for effectiveness outcomes after transarterial radioembolization in metastatic colorectal cancer: results from the multicentre observational study CIRT

Open AccessPublished:September 19, 2022DOI:https://doi.org/10.1016/j.clcc.2022.09.002

      Abstract

      Background

      Transarterial radioembolisation (TARE) with Yttrium-90 resin microspheres is a treatment option for patients with metastatic colorectal cancer in the liver (mCRC). A better understanding of the prognostic factors and treatment application can improve survival outcomes.

      Methods

      We analysed the safety and effectiveness of 237 mCRC patients included in the prospective observational study CIRSE Registry for SIR-Spheres Therapy (CIRT) for independent prognostic factors for overall survival (OS), progression-free survival (PFS) and hepatic progression-free survival (hPFS) using the Cox proportional-hazard model.

      Results

      The median OS was 9.8 months, median PFS was 3.4 months and median hPFS was 4.2 months. Independent prognostic factors for an improved overall survival were the absence of extra-hepatic disease (p=0.0391), prior locoregional procedures (p=0.0037), an Aspartate transaminase to Platelet Ratio Index (APRI) value of ≤0.40 (p<0.0001) and International Normalised Ratio (INR) ≤1 (p=0.0078). Partition model dosimetry resulted in improved OS outcomes compared to the body surface area model (p=0.0120). Independent predictors for PFS were APRI >0.40 (p=0.0416) and prior ablation (p=0.0323), and for hPFS these were 2-5 tumour nodules (p=0.0148), Albumin-bilirubin (ALBI) grade 3 (p=0.0075) and APRI >0.40 (p=0.0207). During the study, 95/237 (40.1%) patients experienced 197 adverse events, with 28/237 (11.8%) patients having a grade 3 or higher adverse events.

      Conclusions

      Including easy-to-acquire laboratory markers INR, APRI, ALBI and using partition model dosimetry can identify mCRC patients that may benefit from TARE.
      Micro abstract
      This study explored factors that can predict effectiveness outcomes after transarterial radioembolization in colorectal liver metastases in the liver. In a cohort of 237 patients, among other factors, we found that an Aspartate transaminase to Platelet Ratio Index (APRI) value of >0.40 was a particularly strong independent predictor of worse overall survival, progression-free survival and hepatic progression-free survival outcomes.

      Graphical abstract

      Keywords

      List of abbreviations:

      ALBI (albumin-bilirubin), ALT (alanine transaminase), APRI (aspartate transaminase to platelet ratio index), AST (aspartate transaminase), BSA (body surface area), CI (confidence interval), CIRSE (Cardiovascular and Interventional Radiological Society of Europe), CIRT (CIRSE Registry for SIR-Spheres Therapy), CIRT-FR (CIRSE Registry for SIR-Spheres Therapy in France), ECOG (Eastern Cooperative Oncology Group), GBq (giga-becquerel), HCC (hepatocellular carcinoma), hPFS (hepatic progression-free survival), HR (hazard ratio), mCRC (metastatic colorectal cancer), INR (international normalized ratio), IQR (interquartile range), KM (Kaplan Meier), mBSA (modified body surface area), OS (overall survival), PFS (progression-free survival), REILD (radioembolization-induced liver disease), SD (standard deviation), SIRT (selective internal radiation therapy), SAE (serious adverse event), SPECT/CT (single-photon emission computer tomography combined with computer tomography), TACE (transcatheter arterial chemoembolization), TARE (trans-arterial radioembolization), Tc99m MAA (technetium 99mTc macroaggregated albumin), Y90 (yttrium-90)

      Introduction

      Colorectal cancer is the third most common form of cancer worldwide and the second in mortality
      • Sung H
      • Ferlay J
      • Siegel RL
      • Laversanne M
      • Soerjomataram I
      • Jemal A
      • et al.
      Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.
      . The most frequent site of colorectal cancer-associated metastasis is the liver: while about 25% present liver metastases at initial diagnosis, 30% develop liver metastases later during the course of the disease
      • Donadon M
      • Ribero D
      • Morris-Stiff G
      • Abdalla EK
      • Vauthey JN.
      New paradigm in the management of liver-only metastases from colorectal cancer.
      . Potential treatments with curative intent for liver-only metastatic colorectal cancer (mCRC) are complete resection, with a five-year survival of up to 70% in small, solitary tumours
      • Akgul O
      • Cetinkaya E
      • Ersoz S
      • Tez M.
      Role of surgery in colorectal cancer liver metastases.
      and thermal ablation for tumours of less than three centimetres and clear tumour margins
      • Benson AB
      • Venook AP
      • Al-Hawary MM
      • Arain MA
      • Chen YJ
      • Ciombor KK
      • et al.
      Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.
      .
      Beyond resection or thermal ablation, a plethora of treatment options have been introduced for mCRC. Chemotherapy, usually a combination of irinotecan and/or oxaliplatin with 5-FU/LV used together with biologicals such as cetuximab or panitumumab, and bevacizumab or aflibercept in more advanced disease is well established in earlier therapy lines
      • Benson AB
      • Venook AP
      • Al-Hawary MM
      • Arain MA
      • Chen YJ
      • Ciombor KK
      • et al.
      Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.
      ,
      • Van Cutsem E
      • Cervantes A
      • Adam R
      • Sobrero A
      • Van Krieken JH
      • Aderka D
      • et al.
      ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.
      . Liver-directed approaches such as transcatheter arterial chemoembolization (TACE), hepatic artery infusion of chemotherapy, stereotactic radiation, or ablative therapies such as radiofrequency ablation, microwave ablation or cryoablation are treatment options for this patient population
      • Benson AB
      • Venook AP
      • Al-Hawary MM
      • Arain MA
      • Chen YJ
      • Ciombor KK
      • et al.
      Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.
      • Van Cutsem E
      • Cervantes A
      • Adam R
      • Sobrero A
      • Van Krieken JH
      • Aderka D
      • et al.
      ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.
      • Tan HL
      • Lee M
      • Vellayappan BA
      • Neo WT
      • Yong WP.
      The Role of Liver-Directed Therapy in Metastatic Colorectal Cancer.
      . However, a comparison of outcomes among techniques remains a challenge and hence, no standardised approach to palliative treatment of liver dominant mCRC has been developed
      • Tan HL
      • Lee M
      • Vellayappan BA
      • Neo WT
      • Yong WP.
      The Role of Liver-Directed Therapy in Metastatic Colorectal Cancer.
      .
      In recent years, the body of evidence on the application of trans-arterial radioembolization (TARE, also known as Selective Internal Radiation Therapy (SIRT)) with Yttrium-90 (Y90) has grown
      • d'Andrea E
      • Russi M
      • Pacilio M
      • Bilotta F
      Yttrium-90 Radioembolization of Colorectal Cancer Liver Metastases: A Systematic Review of Clinical Evidence.
      . In brief, TARE is an interventional therapeutic procedure with targeted delivery of high doses of radiation to liver tumours via the hepatic artery by means of glass or resin microspheres
      • Kennedy A
      • Coldwell D
      • Sangro B
      • Wasan H
      • Salem R.
      Radioembolization for the treatment of liver tumors general principles.
      . Most of the data supporting the use of TARE has been published for hepatocellular carcinoma (HCC) patients and the procedure has been included in the standard “tool-box” of unresectable HCC
      • Benson AB
      • D'Angelica MI
      • Abbott DE
      • Abrams TA
      • Alberts SR
      • Anaya DA
      • et al.
      Guidelines Insights: Hepatobiliary Cancers, Version 2.2019.
      European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma.
      • Valle JW
      • Borbath I
      • Khan SA
      • Huguet F
      • Gruenberger T
      • Arnold D
      • et al.
      Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      . In mCRC, the current clinical landscape in systemic treatments, locoregional approaches and surgery remains complex and further evidence on how to implement TARE is warranted
      • Kwan J
      • Pua U.
      Review of Intra-Arterial Therapies for Colorectal Cancer Liver Metastasis.
      .
      An early randomised phase 2 trial of TARE in mCRC comparing TARE with Y90 resin microspheres with hepatic arterial chemotherapy showed improved local tumour control in the TARE arm (44% vs 17%)
      • Gray B
      • Van Hazel G
      • Hope M
      • Burton M
      • Moroz P
      • Anderson J
      • et al.
      Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer.
      . Further trials and case series, evaluating patients undergoing salvage treatment with TARE in combination with 5-FU/LV were confirming TAREs ability for local disease control with a good toxicity profile
      • Hendlisz A
      • Van den Eynde M
      • Peeters M
      • Maleux G
      • Lambert B
      • Vannoote J
      • et al.
      Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy.
      • Van Hazel G
      • Blackwell A
      • Anderson J
      • Price D
      • Moroz P
      • Bower G
      • et al.
      Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer.
      • Golfieri R.
      SIR-Spheres yttrium-90 radioembolization for the treatment of unresectable liver cancers.
      • Mulcahy MF
      • Lewandowski RJ
      • Ibrahim SM
      • Sato KT
      • Ryu RK
      • Atassi B
      • et al.
      Radioembolization of colorectal hepatic metastases using yttrium-90 microspheres.
      . Despite these promising early results, large randomised controlled trials comparing systemic treatments in a first line setting (FOLFOX6m ± bevacizumab) with or without the addition Y90 resin microspheres were unable to show benefits to overall survival and progression-free survival in the Y90 arm
      • van Hazel GA
      • Heinemann V
      • Sharma NK
      • Findlay MP
      • Ricke J
      • Peeters M
      • 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.
      ,
      • Wasan HS
      • Gibbs P
      • Sharma NK
      • Taieb J
      • Heinemann V
      • Ricke J
      • et al.
      First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials.
      . In the second line setting, the randomised, multicentre open-label EPOCH trial showed that the addition of TARE with Y90 glass microspheres to FOLFOX or FOLFIRI resulted in a prolonged progression free survival with equal safety compared to second-line chemotherapy alone, the trial's primary end point, but no improvement in overall survival (OS)
      • Mulcahy MF
      • Mahvash A
      • Pracht M
      • Montazeri AH
      • Bandula S
      • Martin 2nd, RCG
      • et al.
      Radioembolization With Chemotherapy for Colorectal Liver Metastases: A Randomized, Open-Label, International, Multicenter, Phase III Trial.
      . Even though TARE has consistently shown promising results in local tumour control, identifying the patient group that benefits the most of TARE might be the way to improve OS.
      The objective of the current subgroup analysis was to report on safety and to investigate effectiveness in terms of potential prognostic factors for OS, progression-free survival (PFS) and hepatic-progression-free survival (hPFS) in patients with liver-dominant mCRC treated with TARE with Y90 resin microspheres, using the data from the European-wide prospective, multicentre observational study CIRSE Registry for SIR-Spheres Therapy (CIRT, NCT 02305459). This study, conducted by the Cardiovascular and Interventional Radiological Society of Europe (CIRSE), investigated the clinical application and outcomes of TARE with Y90 resin microspheres (SIR-Spheres® Y-90 resin microspheres, Sirtex Medical Pty Limited; St. Leonards, NSW, Australia)
      • Helmberger T
      • Arnold D
      • Bilbao JI
      • de Jong N
      • Maleux G
      • Nordlund A
      • et al.
      Clinical Application of Radioembolization in Hepatic Malignancies: Protocol for a Prospective Multicenter Observational Study.
      . This study prospectively included patients with a clinical indication for TARE with Y90 resin microspheres and was open for all cancer types.

      Material and methods

      Study design

      The mCRC cohort (n=237) collected in the CIRT study was used in this analysis. CIRT is a prospective, single device, multicentre observational study of patients with primary and metastatic hepatic malignancies treated with TARE with Y90 resin microspheres as the standard of care. The CIRT methodology was published by Helmberger et al.
      • Helmberger T
      • Arnold D
      • Bilbao JI
      • de Jong N
      • Maleux G
      • Nordlund A
      • et al.
      Clinical Application of Radioembolization in Hepatic Malignancies: Protocol for a Prospective Multicenter Observational Study.
      . Sites were invited to participate if they had reported to have at least 40 TARE cases overall and ten cases in the twelve months prior to invitation. The 27 participating sites were identified and enrolled from April 2014 until April 2017, of which 24 sites enrolled mCRC patients
      • Helmberger T
      • Golfieri R
      • Pech M
      • Pfammatter T
      • Arnold D
      • Cianni R
      • et al.
      Clinical Application of Trans-Arterial Radioembolization in Hepatic Malignancies in Europe: First Results from the Prospective Multicentre Observational Study CIRSE Registry for SIR-Spheres Therapy (CIRT).
      .
      Data was collected using a customised electronic data capturing system and electronic case report form that was developed by ConexSys Inc (Lincoln, RI, United States) and hosted on a local secure server in Vienna, Austria maintained by ITEA (Vienna, Austria). Statistical analyses were performed in SAS (Cary, NC, United States) and RStudio (R Foundation, Vienna, Austria).

      Patient selection

      Patients eligible for analysis were adults diagnosed with mCRC and scheduled to receive TARE with Y90 resin microspheres. There were no specific exclusion criteria. All included patients signed an informed consent form. This research project was performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
      Patient recruitment took place between 1 January 2015 and 31 December 2017. Follow-up data was collected until 31 December 2019. Sites were requested to follow-up with the patient every 3 months for 24 months after the first TARE treatment. In addition, sites were encouraged to obtain follow-up information from referring physicians if follow-up evaluations were not performed at the site of the TARE treatment.

      Assessments

      Detailed information concerning the timing of assessments can be found in Helmberger et al, 2020 [21].
      At the time of first treatment, baseline data, demographics and treatment-related data were collected. The number of tumours were considered for the whole liver, whereby the category “uncountable” was included in cases where the number of tumours exceeded reliable counting of lesions. Tumour burden was presented as percentage of tumour volume (ml) per liver volume (ml). Treatment intention was defined before the procedure, whereby “ablation” was defined as an attempt to create an ablative effect with the Y90 resin microspheres, and “palliative” as any intention not part of a curative approach. Information concerning post-TARE treatments, safety data and time to event data were collected at every follow-up. Sites were requested to include available imaging data, but the observational nature of the study prevent any mandates on the type of imaging (CT, MRI, PET). Imaging data was evaluated by the local investigator or physician performing the follow-up imaging. Time-to-event was defined from the date of the first TARE treatment until the date of the event. Safety outcomes are described as occurrences of any adverse events according to the Common Terminology Criteria for Adverse Events, version 4.03. A priori expected serious adverse events (SAEs, grade 3 and 4) were abdominal pain, fatigue, fever, nausea, vomiting, gastrointestinal ulceration, gastritis, radiation cholecystitis, radiation pancreatitis and radioembolization-induced liver disease (REILD) and were included as answer options in the electronic case report form. An open text field allowed for collecting details on other serious adverse events. Clinical parameters were tumour burden, prior procedures, dose methodology, prescribed radiation activity as well as relevant blood markers including albumin, bilirubin, liver transaminases, International Normalised Ratio (INR) and the resulting indicators of liver function: Aspartate Aminotransferase to Platelet Ratio Index (APRI), Albumin-Bilirubin (ALBI) Grade (see Supplement 1 for APRI and ALBI formulas) and the Aspartate Aminotransferase/Alanine Aminotransferase (AST/ALT) ratio
      • Pereyra D
      • Rumpf B
      • Ammann M
      • Perrodin SF
      • Tamandl D
      • Haselmann C
      • et al.
      The Combination of APRI and ALBI Facilitates Preoperative Risk Stratification for Patients Undergoing Liver Surgery After Neoadjuvant Chemotherapy.
      ,
      • Starlinger P
      • Ubl DS
      • Hackl H
      • Starlinger J
      • Nagorney DM
      • Smoot RL
      • et al.
      Combined APRI/ALBI score to predict mortality after hepatic resection.
      . Based on published literature, we categorized APRI as ≤0.40 or >0.40; and grade ALBI as 1, 2 or 3
      • Hu K
      • Yuan J
      • Tang B
      • Zhang F
      • Lu S
      • Chen R
      • et al.
      Albumin-bilirubin index and platelet-albumin-bilirubin index contribute to identifying survival benefit candidates in patients with hepatocellular carcinoma and Child-Pugh grade A undergoing transcatheter arterial chemoembolization with sorafenib treatment.
      ,
      • Tang T
      • Qiu JL
      • Li GW
      • Huang MP
      • Li Y
      • Li YJ
      • et al.
      Aspartate aminotransferase-to-platelet ratio predicts response to transarterial chemoembolisation and prognosis in hepatocellular carcinoma patients.
      .

      Statistical analysis

      Data is presented as mean ± standard deviation or median (interquartile range [IQR]) for continuous variables and number (%) for categorical variables. Percentages are based on the whole cohort (n=237) unless otherwise indicated. Patients who died during the study are defined to have progression for the purpose of PFS and hPFS. Patients that were alive and progression-free were censored on the day of the last follow-up. The simultaneous occurrence of hepatic progression and extra-hepatic progression was considered as hepatic progression. The median OS, PFS and hPFS times were calculated with the associated 95% confidence interval (CI).
      Multivariable survival analysis for OS, PFS and hPFS was performed using a Cox proportional-hazards model, whereby the selection of variables was determined following a univariable analysis and a subsequent stepwise variable selection procedure with a significance level of 0.2 when deciding to enter a predictor into the stepwise model. The model with the lowest Akaike information criterion value was considered as the final model. Data was presented using hazard ratio (HR) and 95% confidence interval (CI). All available data are used, and no imputations of missing data are made. Where data was missing, it was indicated in the tables.
      An additional propensity score analysis was performed to further analyse the role of the two main methods to calculate the prescribed Y90 activity, [modified] Body Surface Area ([m]BSA) and partition model, in the survival outcomes of TARE treatments (see Supplement 1 for the propensity score analysis methods).

      Results

      Patient demographics

      The mCRC cohort is represented by 237 patients (23.1% of the total CIRT cohort, 237/1027) from 24 European centres. The median follow-up time was 7.8 months; 42/237 (17.7%) of the patients were lost to follow-up at any point during data collection. The median age is 63 years (IQR 55 – 71) and 62.0% (147/237) are male patients (Table 1). Median time from diagnosis of liver metastases until TARE treatment was 14.4 months (IQR 7.6-25.8). At baseline, most patients had Eastern Cooperative Oncology Group (ECOG) status 0 (143/237, 60.3%) or 1 (72/237, 30.4%) and no extra-hepatic disease prior to treatment (140/237, 59.1%). Nine patients (9/237, 3.8%) presented with radiological evidence of ascites.
      Table 1Baseline patient characteristics
      CategorySubcategorymCRC (n=237)
      Gendern233 (98.3%)
      Male147 (62.0%)
      Female86 (36.3%)
      Age (years)n237 (100%)
      Median, IQR63.0, 55.0-71.0
      Time since primary diagnosis (months)n233 (98.3%)
      Median, IQR19.5, 11.0-34.1
      Time since metastatic diagnosis (months)n198 (83.5%)
      Median, IQR14.4, 7.6-25.8
      ECOG performance statusn233 (98.3%)
      0143 (60.3%)
      172 (30.4%)
      2 or higher18 (7.6%)
      Ascitesn237 (100%)
      Yes9 (3.8%)
      No228 (96.2%)
      Cirrhosisn237 (100%)
      Yes2 (0.8%)
      No235 (99.2%)
      Number of tumour nodulesn237 (100%)
      127 (11.4%)
      2-550 (21.1%)
      >579 (33.3%)
      Uncountable81 (34.2%)
      Location of tumorn236 (99.6%)
      Bilobar152 (64.1%)
      Left only23 (9.7%)
      Right only61 (25.7%)
      Extrahepatic metastasesn237 (100%)
      Yes97 (40.9%)
      No140 (59.1%)
      Bilirubin (µmol/L)n236 (99.6%)
      Mean ± SD10.8 ± 8.7
      Albumin (g/dl)n181 (76.4%)
      Mean ± SD3.9 ± 0.6
      ALBI graden180 (75.9%)
      A1102 (43.0%)
      A275 (31.6%)
      A33 (1.3%)
      APRIn204 (86.1%)
      Mean ± SD0.5 ± 0.4
      ≤0.4099 (41.8%)
      >0.40105 (44.3%)
      AST/ALTn204 (86.1%)
      Mean ± SD1.4 ± 0.7
      ≤0.9644 (18.6%)
      >0.96160 (67.5%)
      INRn176 (74.3%)
      Mean ± SD1.1 ± 0.1
      ≤178 (32.9%)
      >198 (41.4%)
      ALBI: Albumin-Bilirubin; ALT: Alanine Aminotransferase; APRI: Aspartate Aminotransferase to Platelet Ratio Index; AST: Aspartate Aminotransferase; BCLC Barcelona Clinic Liver Cancer; ECOG: Eastern Cooperative Oncology Group; INR: International Normalized Ratio; IQR: Interquartile Range; mCRC: metastatic colorectal cancer; SD: Standard Deviation.

      Treatment context and application

      One hundred fifty-two (152/237, 64.1%) patients had bilobar disease. Unilobar disease was mostly right sided (61/237, 25.7%) compared to left sided (23/237, 9.7%). In terms of number of liver tumours, the largest groups had an “uncountable” number (81/237, 34.2%) or five or more liver tumours (79/237, 33.3%), 50/237 (21.1%) had two to five liver tumours, while 27/237 (11.4%) had only one liver tumour. Median total liver tumour burden was 8.9% (IQR 3.8% – 18.3%, Table 2). Body Surface Area (BSA, 123/237, 51.9%) or modified BSA (mBSA, 71/237, 30.0%) were the preferred methods for determining the dose. Partition model was used in 42/237 (17.7%) patients. Whole liver treatment was prescribed in 114/237 (48.1%) patients, compared to right (90/237, 38.0%) and left (26/237, 11.0%) separately. Median prescribed activity was 1.50 GBq for whole-liver treatments (IQR 1.20 – 1.80), 1.20 GBq for right lobe treatments (IQR 0.90 – 1.40) and 0.50 (IQR 0.00 – 0.80) for left lobe treatments. Technical success, defined as delivered activity within 90% of the prescribed activity, was achieved in 222/237 (93.7%) patients.
      Table 2Treatment-associated parameters
      CategorySubcategorymCRC (n=237)
      Activity prescribed (GBq)n
      Whole liver (median; IQR)1.50 (1.20;1.80)
      Right lobe (median; IQR)1.20 (0.90;1.40)
      Left lobe (median; IQR)0.50 (0.0;0.80)
      Target treatmentn237 (100%)
      Whole liver114 (48.1%)
      Right lobe90 (38.0%)
      Left lobe26 (11.0%)
      Segmental7 (3.0%)
      Were all liver tumours targetedn198 (83.5%)
      Yes137 (57.8%)
      No45 (19.0%)
      Unknown16 (6.8%)
      Technical success: delivered activity within 90% of the prescribed activityn237 (100%)
      Yes222 (93.7%)
      No15 (6.3%)
      Target tumor volume (ml)n199 (84.0%)
      median; IQR131 (55-287)
      Target liver volume (ml)n199 (84.0%)
      median; IQR1480 (1287-1791)
      Total tumour burden (%)n199 (84.0%)
      median; IQR8.9% (3.8%-18.3%)
      Right-lobe tumour burden (%)n80 (33.8%)
      median; IQR10.3% (5.0%-21.3%)
      Left-lobe tumour burden (%)n61 (25.7%)
      median; IQR10.4% (3.3%-19.7%)
      Number of treatmentsn237 (100%)
      1210 (88.6%)
      227 (11.4%)
      Method to calculate the dosen236 (99.6%)
      BSA123 (51.9%)
      Modified BSA71 (30.0%)
      Compartment model42 (17.7%)
      BSA: Body Surface Area; GBQ: Giga-becquerel; IQR: Interquartile Range; mCRC: metastatic colorectal cancer.
      At patient enrolment, 226/237 (95.4%) patients had received prior systemic therapy (previously: 1 line, 68/237 (30.1%); 2-3 lines 78/237 (32.9%); >3 lines 77/237 (32.5%), primarily FOLFOX (129/237, 54.4%) and FOLFIRI (90/237, 38.0%) regimens (Table 3 and Supplement 2) and 86/237 (36.3%) had received prior locoregional treatments, of which 66/86 (76.7%) were surgical and 27/86 (31.4%) ablative procedures (Table 3). The investigator-assessed treatment intent was predominantly palliative (176/237, 74.3%) or tumour downsizing (41/237, 17.3%). Following TARE, 87/237 (36.7%) of the patients received further systemic treatment and 35/237 (14.8%) received locoregional treatments, the majority of which were provided >4 weeks after TARE in patients without progression (29/35, 82.9% for locoregional treatments, and 54/87, 62.1% for systemic treatments, see Supplement 3).
      Table 3treatment context of TARE
      CategorySubcategorymCRC (n=237)
      Intention of TAREn237 (100%)
      Ablation18 (7.6%)
      Bridge to surgery or transplant2 (0.8%)
      Down-sizing/down-staging41 (17.3%)
      Palliative176 (74.3%)
      Before TARE
      Locoregional proceduresn
      Patients can have multiple locoregional procedures before or after TARE. mCRC: metastatic colorectal cancer; TACE: Transcatheter Arterial Chemoembolization; TARE: Trans-arterial Radioembolization.
      86 (36.3%)
      Surgery66 (27.8%)
      Ablation27 (11.4%)
      TACE3 (1.3%)
      Abdominal radiotherapy6 (2.5%)
      Other embolotherapies3 (1.3%)
      Systemic therapiesn237 (100%)
      Yes226 (95.4%)
      No11 (4.6%)
      Number of systemic therapy linesn223 (94.1%)
      168 (30.1%)
      2-378 (32.9%)
      >377 (32.5%)
      Missing3 (1.3%)
      After TARE
      Locoregional proceduresn
      Patients can have multiple locoregional procedures before or after TARE. mCRC: metastatic colorectal cancer; TACE: Transcatheter Arterial Chemoembolization; TARE: Trans-arterial Radioembolization.
      35 (14.8%)
      Surgery10 (4.2%)
      Ablation11 (4.6%)
      TACE6 (2.5%)
      Abdominal radiotherapy10 (4.2%)
      Other embolotherapies2 (0.8%)
      Systemic therapiesn193 (81.4%)
      Yes87 (36.7%)
      No106 (44.7%)
      Number of systemic therapy linesn87 (36.7%)
      125 (10.5%)
      2-325 (10.5%)
      >334 (14.3%)
      a Patients can have multiple locoregional procedures before or after TARE.mCRC: metastatic colorectal cancer; TACE: Transcatheter Arterial Chemoembolization; TARE: Trans-arterial Radioembolization.

      Effectiveness

      The median OS was 9.8 months (95% CI 8.3-12.9). Univariable analysis (Supplement 4) showed favourable OS for ECOG 0, absence of extra-hepatic disease, low tumour burden, right-sided tumours, partition model and APRI ≤0.40 (Figure 1). Multivariable analysis (Table 4) identified independent prognostic factors for a worse overall survival as the presence of extra-hepatic disease (HR 1.48, 95% CI 1.02 – 2.14, p=0.0412), an APRI value of >0.40 (HR 2.25, 95% CI 1.54 – 3.30, p<0.0001) and INR <1 (HR 1.66, 95% CI 1.13 – 2.43, p=0.0091). Prior locoregional procedures predicted an improved OS (HR 0.34, 95% CI 0.17 – 0.71, p = 0.0038). Furthermore, patients whose prescribed dose was determined with partition model had an increased chance of surviving longer compared to patients treated with the BSA or mBSA model (HR 0.45, 95% CI 0.24 – 0.84, p=0.0120, Figure 2). To further challenge this result, a propensity score analysis considering the population used for the multivariable model was performed. The matching showed a large degree of variability among cases and patient matching could only be performed in a smaller group. Considering 159 patients for the propensity score analysis using Inverse Probability Treatment Weighting, we obtained for OS a HR 0.59 (0.32-1.06; p=0.0792, data not shown).
      Figure 1
      Figure 1Kaplan-Meier graph comparing Aspartate aminotransferase to Platelets Ratio Index (APRI) <0.40 with >0.40 in terms of overall survival (A), progression-free survival (B), and hepatic-progression-free survival (C)
      Table 4Multivariable analysis for overall survival, progression-free survival and hepatic progression-free survival
      VariableThresholdHR (95% CI)p value
      Overall survival
      Extra-hepatic disease prior to treatment (vs no)Yes1.48 (1.02-2.15)0.0391
      Prior locoregional procedures (vs no)Yes0.34 (0.17-0.71)0.0037
      Prior surgery (vs no)Yes1.99 (0.91-4.34)0.0830
      Dose methodology (vs BSA/mBSA)Compartment Model0.45 (0.24-0.84)0.0120
      APRI (vs ≤0.40)>0.402.28 (1.56-3.33)<0.0001
      INR (vs ≤1)>11.67 (1.15-2.45)0.0078
      Progression-free survival
      APRI (vs ≤0.40)>0.401.42 (1.01-1.98)0.0416
      Ablation (vs no)Yes0.59 (0.36-0.96)0.0323
      ALBI (vs A1)A21.36 (0.97-1.90)0.0720
      A33.24 (1.00-10.55)0.0506
      Hepatic progression-free survival
      Number of tumour nodules (vs 1)2-50.42 (0.21-0.85)0.0148
      >50.56 (0.30-1.06)0.0772
      Uncountable1.00 (0.54-1.85)0.9877
      Prior locoregional procedures (vs no)Yes0.87 (0.50-1.51)0.6303
      Prior surgery (vs no)Yes1.18 (0.64-2.19)0.5918
      ALBI grade (vs A1)A21.43 (0.98-2.09)0.0653
      A35.29 (1.56-17.97)0.0075
      APRI (vs ≤0.40)>0.401.50 (1.06-2.11)0.0207
      P values are from the Cox model. The proportional hazard function of the Cox model was verified.
      ALBI: Albumin-Bilirubin; ALT: Alanine Aminotransferase; APRI: Aspartate Aminotransferase to Platelet Ratio Index; AST: Aspartate Aminotransferase; BSA: Body Surface Area; HR: Hazard Ratio; INR: International Normalised Ratio.
      Figure 2
      Figure 2Kaplan-Meier graph comparing overall survival outcomes for patients whose prescribed activity was calculated with partition model dosimetry compared to (modified) Body Surface Area.
      Median PFS was 3.4 months (95% CI 3.1-4.1) and median hPFS was 4.2 months (95% CI 3.4-4.7). Univariable analysis found a significantly worse PFS (Supplement 5) for ECOG >0, presence of extra-hepatic disease, >5 tumour nodules and uncountable tumour nodules, ALBI grade A3, AST/ALT >0.96, and APRI >0.40. Intention to downsize the tumour predicted a better PFS. ECOG 1, uncountable tumour nodules, ALBI grade A3, AST/ALT >0.96, and APRI >0.40 predicted worse hPFS (Supplement 6). In multivariable analysis (Table 4), independent predictors for PFS were APRI >0.40 (HR 1.42, 95% CI 1.01 – 1.98, p=0.0416) and prior ablation (HR 0.59, 95% CI 0.36 – 0.96, p=0.0323), and for hPFS these were 2-5 tumour nodules (HR 0.42 (0.21 – 0.85, p=0.0148), ALBI grade 3 (HR 5.29, 95% CI 1.56 – 17.97, p=0.0075) and APRI >0.40 (HR 1.50, 95% CI 1.06 – 2.11, p=0.0207). Dose methodology predicted neither hepatic PFS nor overall progression free survival.

      Safety

      During the study, 95/237 (40.1%) patients experienced 197 adverse events, with 28/237 (11.8%) patients having a grade 3 or higher adverse events: abdominal pain 4/237 (1.7%), nausea 1/237 (0.4%), gastrointestinal ulceration 2/237 (0.8%), gastritis 2/237 (0.8%), radiation cholecystitis 1/237 (0.4%); 18/237 (7.6%) patients experienced 29 all-cause “other” grade 3-4 adverse events. (Supplement 7).

      Discussion

      The current dataset from the prospective multicentre observational CIRT study represents the real-world patient population treated with Y90 resin microspheres for liver dominant mCRC in Europe. Our results underline the importance of blood value-based markers for predicting the outcomes of TARE: APRI is a strong predictor for OS, PFS and hPFS in patients receiving TARE, while INR predicted OS and ALBI predicted hPFS outcomes. Furthermore, partition model should be considered to optimise treatment outcomes.
      In the mCRC patient population of CIRT, we have found an OS of 9.8 months (95% CI 8.3-12.9), a PFS of 3.4 months (95% CI 3.1-4-1) and a hepatic PFS of 4.2 months (95% CI 3.4-4.7). Kennedy et al. published a retrospective series of 208 mCRC patients and described a median OS of 10.5 months in responding patients and 4.5 months in non-responders
      • Kennedy AS
      • Coldwell D
      • Nutting C
      • Murthy R
      • Wertman Jr., DE
      • Loehr SP
      • et al.
      Resin 90Y-microsphere brachytherapy for unresectable colorectal liver metastases: modern USA experience.
      while Cianni et al. found an OS of 11.5 months and a PFS of 9.1 months in 41 patients
      • Cianni R
      • Urigo C
      • Notarianni E
      • Saltarelli A
      • Salvatori R
      • Pasqualini V
      • et al.
      Selective internal radiation therapy with SIR-spheres for the treatment of unresectable colorectal hepatic metastases.
      . Despite the similarities in OS, our low median PFS may be due to our heterogeneous patient population, which includes patients at various stages of the disease and treatment pathway. Both cohorts reported that TARE was well-tolerated by patients with an acceptable toxicity (7% and 3% SAEs, respectively) similar to our findings (11.8%). Other studies evaluating safety data observed that the occurrence of SAEs can range from 3% to 15%
      • Hickey R
      • Lewandowski RJ
      • Prudhomme T
      • Ehrenwald E
      • Baigorri B
      • Critchfield J
      • et al.
      90Y Radioembolization of Colorectal Hepatic Metastases Using Glass Microspheres: Safety and Survival Outcomes from a 531-Patient Multicenter Study.
      • Loffroy R
      • Ronot M
      • Greget M
      • Bouvier A
      • Mastier C
      • Sengel C
      • et al.
      Short-term Safety and Quality of Life Outcomes Following Radioembolization in Primary and Secondary Liver Tumours: a Multi-centre Analysis of 200 Patients in France.
      • Maleux G
      • Deroose C
      • Laenen A
      • Verslype C
      • Heye S
      • Haustermans K
      • et al.
      Yttrium-90 radioembolization for the treatment of chemorefractory colorectal liver metastases: Technical results, clinical outcome and factors potentially influencing survival.
      • Brown D
      • Krebs H
      • Brower J
      • O'Hara R
      • Wang E
      • Vaheesan K
      • et al.
      Incidence and risk factors for sustained hepatic function toxicity 6 months after radioembolization: analysis of the radiation-emitting sir-spheres in non-resectable liver tumor (RESIN) registry.
      • White J
      • Carolan-Rees G
      • Dale M
      • Morgan HE
      • Patrick HE
      • See TC
      • et al.
      Analysis of a National Programme for Selective Internal Radiation Therapy for Colorectal Cancer Liver Metastases.
      . The dataset from the French prospective multicentre observational study CIRSE Registry for SIR-Spheres in France (CIRT-FR) reported 27% SAE occurrence in 63 mCRC patients treated with TARE (data forthcoming).
      Despite many promising efficacy signals from above studies, the SIRFLOX and FOXFIRE randomised controlled trials remained without any significant survival benefit for first line mCRC patients compared to chemotherapy
      • van Hazel GA
      • Heinemann V
      • Sharma NK
      • Findlay MP
      • Ricke J
      • Peeters M
      • 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.
      ,
      • Wasan HS
      • Gibbs P
      • Sharma NK
      • Taieb J
      • Heinemann V
      • Ricke J
      • et al.
      First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials.
      . With TARE as second line treatment combined with systemic therapy, the recent randomised controlled EPOCH trial reported a significant improvement in PFS and hPFS compared to systemic therapy alone (HR 0.69; 95% CI 0.54-0.88; 1-sided p=0.0013 for PFS and HR 0.59; 95% CI 0.46 -0.77; 1-sided p=0.0001 for hPFS)), but no improvement in OS (HR 1.07; 95% CI 0.86-1.32; 1-sided p=0.7229 for the TARE and chemotherapy group)
      • Mulcahy MF
      • Mahvash A
      • Pracht M
      • Montazeri AH
      • Bandula S
      • Martin 2nd, RCG
      • et al.
      Radioembolization With Chemotherapy for Colorectal Liver Metastases: A Randomized, Open-Label, International, Multicenter, Phase III Trial.
      . At the same time, patients enrolled in the EPOCH trial experienced poorer results in right-sided tumours, while patients from the SIRFLOX and FOXFIRE Global trials had better efficacy results in right-sided tumours. It was proposed that this discrepancy may indicate different optimal time points of TARE in the continuum of care of left- and right-sided tumours
      • Mulcahy MF
      • Mahvash A
      • Pracht M
      • Montazeri AH
      • Bandula S
      • Martin 2nd, RCG
      • et al.
      Radioembolization With Chemotherapy for Colorectal Liver Metastases: A Randomized, Open-Label, International, Multicenter, Phase III Trial.
      . In a broader sense, it is testimony to the fact that, despite the experience in clinical use of TARE in mCRC patients, there is a demand to optimise the treatment application and a need to identify better prognostic markers.

      Prognostic factors

      Our mCRC cohort suggests that laboratory values indicative of liver status and potential liver damage are strong predictors of reduced survival after TARE. Our multivariable analysis found INR >1 (p=0.0078) and APRI >0.40 (p<0.0001) to be independent prognostic factors for reduced overall survival. APRI >0.40 predicted reduced PFS and hPFS (p=0.0416 and p=0.0207) and ALBI grade 3 was significantly associated with shorter hPFS (p=0.0075). A prognostic scoring system for TARE in mCRC, developed by Damm et al., identified tumour load, CEA levels, CA 19-9 levels and Karnofsky index as predictive variables
      • Damm R
      • Seidensticker R
      • Ulrich G
      • Breier L
      • Steffen IG
      • Seidensticker M
      • et al.
      Y90 Radioembolization in chemo-refractory metastastic, liver dominant colorectal cancer patients: outcome assessment applying a predictive scoring system.
      , while Kurilova et al. used CEA level, baseline ALT and albumin levels, tumour size and differentiation level and number of extrahepatic sites to estimate outcomes after TARE
      • Kurilova I
      • Beets-Tan RGH
      • Flynn J
      • Gonen M
      • Ulaner G
      • Petre EN
      • et al.
      Factors Affecting Oncologic Outcomes of 90Y Radioembolization of Heavily Pre-Treated Patients With Colon Cancer Liver Metastases.
      . Our cohort is the first to show the importance of APRI, ALBI and INR as possible predictive markers for survival outcomes after TARE in mCRC and it is recommended that future predictive models further evaluate and validate these variables.
      ALBI and APRI are already well-established prognostic parameters in HCC prior to interventional procedures
      • Pereyra D
      • Rumpf B
      • Ammann M
      • Perrodin SF
      • Tamandl D
      • Haselmann C
      • et al.
      The Combination of APRI and ALBI Facilitates Preoperative Risk Stratification for Patients Undergoing Liver Surgery After Neoadjuvant Chemotherapy.
      • Starlinger P
      • Ubl DS
      • Hackl H
      • Starlinger J
      • Nagorney DM
      • Smoot RL
      • et al.
      Combined APRI/ALBI score to predict mortality after hepatic resection.
      • Hu K
      • Yuan J
      • Tang B
      • Zhang F
      • Lu S
      • Chen R
      • et al.
      Albumin-bilirubin index and platelet-albumin-bilirubin index contribute to identifying survival benefit candidates in patients with hepatocellular carcinoma and Child-Pugh grade A undergoing transcatheter arterial chemoembolization with sorafenib treatment.
      • Tang T
      • Qiu JL
      • Li GW
      • Huang MP
      • Li Y
      • Li YJ
      • et al.
      Aspartate aminotransferase-to-platelet ratio predicts response to transarterial chemoembolisation and prognosis in hepatocellular carcinoma patients.
      ,
      • Peng Y
      • Wei Q
      • He Y
      • Xie Q
      • Liang Y
      • Zhang L
      • et al.
      ALBI versus child-pugh in predicting outcome of patients with HCC: A systematic review.
      . APRI specifically has been utilised as a non-invasive score to predict liver fibrosis
      • Loaeza-del-Castillo A
      • Paz-Pineda F
      • Oviedo-Cardenas E
      • Sanchez-Avila F
      • Vargas-Vorackova F.
      AST to platelet ratio index (APRI) for the noninvasive evaluation of liver fibrosis.
      . However, an understanding of the underlying mechanisms shows that APRI can also be a signifier of general liver injury, whereby elevated AST correlates with injury of hepatocytes and reduced platelet counts mainly correlate with a reduction in thrombopoietin production in damaged liver tissue
      • Tomimaru Y
      • Eguchi H
      • Gotoh K
      • Kawamoto K
      • Wada H
      • Asaoka T
      • et al.
      Platelet count is more useful for predicting posthepatectomy liver failure at surgery for hepatocellular carcinoma than indocyanine green clearance test.
      ,
      • Peck-Radosavljevic M.
      Thrombocytopenia in chronic liver disease.
      . Such liver injury can be caused by oxaliplatin or irinotecan, common chemotherapeutic agents in first line mCRC, and Pereyra et al. have demonstrated that the combination of APRI and ALBI score can predict the presence of this chemotherapy-associated liver injury in this patient group
      • Pereyra D
      • Rumpf B
      • Ammann M
      • Perrodin SF
      • Tamandl D
      • Haselmann C
      • et al.
      The Combination of APRI and ALBI Facilitates Preoperative Risk Stratification for Patients Undergoing Liver Surgery After Neoadjuvant Chemotherapy.
      . Similarly, the ALBI score was developed by Johnson et al. to evaluate liver function in patients with virus induced HCC
      • Johnson PJ
      • Berhane S
      • Kagebayashi C
      • Satomura S
      • Teng M
      • Reeves HL
      • et al.
      Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade.
      and is considered superior to Child-Pugh in its predictive value in HCC
      • Peng Y
      • Wei Q
      • He Y
      • Xie Q
      • Liang Y
      • Zhang L
      • et al.
      ALBI versus child-pugh in predicting outcome of patients with HCC: A systematic review.
      . Although ALBI has been shown to predict outcomes in HCC patients undergoing TARE
      • Mohammadi H
      • Abuodeh Y
      • Jin W
      • Frakes J
      • Friedman M
      • Biebel B
      • et al.
      Using the Albumin-Bilirubin (ALBI) grade as a prognostic marker for radioembolization of hepatocellular carcinoma.
      , to our knowledge our study is the first to identify ALBI as an independent marker for hPFS in mCRC, albeit only in grade 3 patients. INR, a marker of liver synthesis capacity, has shown prognostic value in a univariable analysis in mCRC patients undergoing TARE
      • Magnetta MJ
      • Ghodadra A
      • Lahti SJ
      • Xing M
      • Zhang D
      • Kim HS.
      Connecting cancer biology and clinical outcomes to imaging in KRAS mutant and wild-type colorectal cancer liver tumors following selective internal radiation therapy with yttrium-90.
      and has here been shown for the first time as an independent predictor for OS. Our results therefore suggest that adding the easy-to-collect laboratory markers APRI, ALBI and INR to routine practice can be valuable in identifying the mCRC patients that may benefit the most from TARE and should be considered in future predictive models.

      Dose planning

      In addition to blood value-based markers we investigated whether dose planning methods had any predictive relevance in mCRC patients, by comparing standard BSA models with partition model. To our knowledge, there is no publication comparing dosimetry methods and outcomes for Y90 resin microspheres in mCRC. Following multivariable analysis and propensity score analysis, the data from our prospective cohort shows that patients undergoing partition model display a significantly longer OS. In brief, partition model dosimetry uses lung, tumoral and targeted non-tumoral liver volumes derived from pre-treatment Technetium 99mTc macroaggregated albumin (Tc-99m MAA) SPECT/CT leading to a tumoral-to-nontumoral ratio to predict tumoral volume and targeted nontumoral liver absorbed dose
      • Gnesin S
      • Canetti L
      • Adib S
      • Cherbuin N
      • Silva Monteiro M
      • Bize P
      • et al.
      Partition Model-Based 99mTc-MAA SPECT/CT Predictive Dosimetry Compared with 90Y TOF PET/CT Posttreatment Dosimetry in Radioembolization of Hepatocellular Carcinoma: A Quantitative Agreement Comparison.
      . It has been demonstrated that partition model dosimetry leads to a higher tumour-absorbed dose
      • Van Der Gucht A
      • Jreige M
      • Denys A
      • Blanc-Durand P
      • Boubaker A
      • Pomoni A
      • et al.
      Resin Versus Glass Microspheres for (90)Y Transarterial Radioembolization: Comparing Survival in Unresectable Hepatocellular Carcinoma Using Pretreatment Partition Model Dosimetry.
      which has been shown to have a positive efficacy outcome in patients with HCC
      • Hermann AL
      • Dieudonne A
      • Ronot M
      • Sanchez M
      • Pereira H
      • Chatellier G
      • et al.
      Relationship of Tumor Radiation-absorbed Dose to Survival and Response in Hepatocellular Carcinoma Treated with Transarterial Radioembolization with (90)Y in the SARAH Study.
      . The DOSISPHERE-01 trial investigating standard dosing (120 +/- 20Gy to the perfused lobe) against personalised dosimetry (≥205Gy to the index lesion) revealed a longer OS of patients receiving personalized dosing
      • Garin E
      • Tselikas L
      • Guiu B
      • Chalaye J
      • Edeline J
      • de Baere T
      • et al.
      Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial.
      . One analysis with glass microspheres, published as an abstract only, showed a significant dose-response relationship in patients receiving higher tumour-absorbed doses with an identical safety profile
      • Alsultan AA
      • van Roekel C
      • Barentsz MW
      • Smits MLJ
      • Kunnen B
      • Koopman M
      • et al.
      Dose-Response and Dose-Toxicity Relationships for Glass (90)Y Radioembolization in Patients with Liver Metastases from Colorectal Cancer.
      and a small prospective study on 24 patients with 57 mCRC lesions found a significant relationship between mean tumour-absorbed dose an OS (HR 2.6, 95% CI 0.98-7.00, p=0.012)
      • Levillain H
      • Duran Derijckere I
      • Marin G
      • Guiot T
      • Vouche M
      • Reynaert N
      • et al.
      (90)Y-PET/CT-based dosimetry after selective internal radiation therapy predicts outcome in patients with liver metastases from colorectal cancer.
      . Interestingly, dose methodology was not a predictor for PFS or hPFS in our cohort and is potentially not fully understood. Nevertheless, our data suggests that dose estimation based on body surface corrected with a total liver to tumour ratio (BSA model) might be insufficient, not only regarding efficacy but probably also toxicity, especially in our heavily pre-treated mCRC patient population.
      Overall, this prospective study further augments the body of evidence supporting TARE treatment in liver dominant mCRC. We identified several new independent prognostic markers in mCRC patients undergoing TARE: APRI, INR and dose methodology for overall survival, and APRI and ALBI for progression free survival and hepatic progression-free survival. To our knowledge, these independent predictive variables have not yet been described outside HCC in the context of TARE.

      Limitations

      A limitation of the study is the observational study design, whereby important confounding factors may not have been accounted for. The heterogeneity of the patient population and the single-device aspect of the study make a comparison to other treatment modalities difficult. However, it allowed us to evaluate real-life factors that independently influence effectiveness outcomes and thus inform future predictive models for mCRC patients, leading to optimal patient selection for TARE. Furthermore, the study was designed to explore the clinical outcome of TARE and, therefore, less focused on dosimetry-specific data. This meant, unfortunately, that retrospectively important data points such as precise injected dose and tumour-absorbed dose were not included in the evaluation at the time of study design. Additionally, no data on tumour markers relevant to mCRC, such as CEA and CA 19-9 levels, or molecular characteristics such as RAS, BRAF or MSI status were collected.
      Although selection bias cannot be ruled out, regular remote monitoring and contractual agreements were put in place to reduce selection bias. Sites were encouraged to follow-up with patients when follow-up visits happened with the patient's referring physician, instead of on site. Remote monitoring was done to improve data quality; however, no source data verification was performed. Investigators evaluating imaging data instead of a central image review could have introduced bias concerning PFS or hPFS and should be considered when interpreting this data. We attempted to collect quality-of-life data – on a voluntary basis for the patient – at the time of treatment and at every follow-up until the study exit. The relevance of the collected dataset is currently being evaluated. The relatively high number of censored patients of OS (62/237, 26.2%) and PFS (27/237, 11.4%) is comparable to other studies in oncology and reflects the clinical reality of patients being treated in larger institutions having access to multiple treatments and studies
      • Dudley WN
      • Wickham R
      • Coombs N.
      An Introduction to Survival Statistics: Kaplan-Meier Analysis.
      . Despite our promising results when comparing partition model with body surface driven dosing models, it must be noted that only 42/237 (17.7%) patients received TARE dosage calculated using partition model. This imbalance in dose calculation methods needs to be considered when interpreting the results. Nevertheless, it is encouraging that both the multivariable analysis and the propensity score analysis were consistent in pointing towards the survival benefits of partition model dosimetry. Finally, it cannot be ruled out that post-TARE treatments impacted the effectiveness results, although this subset of patients was too small to perform meaningful statistical analyses (Supplement 3).

      Conclusion

      This large prospective real-world study in patients with liver dominant mCRC demonstrates that TARE with Y90 resin microspheres can be applied safely and lead to encouraging effectiveness outcomes. Our results identified new predictive markers for this patient population (INR, APRI and ALBI), and highlight the need for advanced dose methodology techniques to optimise the outcome of TARE in mCRC patients. Partition model dosimetry has shown here a clear overall survival benefit in this patient population compared to body surface driven dosing models. These findings are of utmost importance as they can help optimise patient care by informing routine clinical practice as well as future trial designs.

      Clinical Practice Points

      • Transarterial radioembolizaton is a treatment option for patients with colorectal cancer liver metastases due to its tolerability by patients and local tumour control. However, selecting the optimal patients for this treatment is challenging. Several predictive models for effectiveness outcomes exist using a combination of blood values, tumour characteristics and spread of the disease.
      • Our study identified several predictive markers not included in previous models, especially APRI >0.40, which was a strong independent predictor of worse overall survival, progression-free survival and hepatic-progression free survival. Other independent predictive factors for overall survival were blood markers such as ALBI and INR, as well as previously identified factors such as the presence of extra-hepatic disease and the performance of locoregional treatments prior to transarterial radioembolizaton.
      • This study also showed for the first time in patients with colorectal cancer liver metastases that partition model dosimetry results in better overall survival than dose calculations using the standard body surface area model – previously only shown in hepatocellular carcinoma.
      • Blood values used to calculate APRI and ALBI are, together with INR, routinely taken in patients with colorectal cancer liver metastases and are here shown to be indispensable in determining the optimal treatment pathway for patients with colorectal cancer liver metastases. Furthermore, optimising the dosimetry methods of transarterial radioembolizaton can improve the effectiveness of the treatment.

      Authors’ contributions

      NS, DA, BP, BS, FK, GMa, Gmu, TH and NdJ contributed to the study concept, set up, and design. GG, MP, TP, CR, BS, Gma and TH acquired patient data. NS, HP, TH, BZ and NdJ analysed and interpreted the data. NS, HP, BZ, and NdJ drafted the manuscript. TH supervised the study. NS supervised the manuscript drafting and data interpretation. All authors contributed to critical revisions and approved the final version of the manuscript.

      Acknowledgements

      The authors want to thank the patients, the CIRT investigators and site staff involved in the study, in particular the local study nurses that contributed significantly to the quality of the collected data through feedback and comments during the data collection phase. The CIRT study was funded by an independent investigator-initiated research grant from SIRTEX Medical Europe GmbH (Bonn, Germany). The electronic data capturing system was developed and supported by ConexSys Inc (Lincoln, RI, United States) and a customised data management system was designed by Joaquin Padilla Montani (Vienna, Austria). Necessary server infrastructure was developed and maintained by ITEA GmbH (Vienna, Austria). The authors thank the CIRSE Central Office and the staff of the CIRSE Clinical Research department for their support during the design and setup of the study and drafting of the manuscript.
      On behalf of the CIRT Principal Investigators: Thomas Albrecht, Vivantes Klinikum Neukölln, Department for Radiology and Interventional Therapy, Rudower Str. 48, 12351, Berlin, Germany. Olivier D'Archambeau, University Hospital Antwerp, Department of Radiology, Wilrijkstraat 10, 2650, Antwerp, Belgium. Tugsan Balli, Cukurova University, Radiology Department, Balcalı Hospital, 01330, Adana, Turkey. Sadik Bilgic, Ankara University, Department of Radiology, Medical Faculty, Cebeci, 06590, Ankara, Turkey. Allan Bloom, Hadassah-Hebrew University Medical Center, Department of Radiology, Jerusalem, Israel. Roberto Cioni, University of Pisa, Diagnostic and Interventional Radiology, Department of Translational Research and New Technologies in Medicine, Via U. Foscolo 5, 50059, Vinci, Pisa, Italy. Roman Fischbach, Asklepios Klinik Altona, Department of Radiology and Neuroradiology, Paul-EhrlichStraße 1, 22763, Hamburg, Germany. Patrick Flamen, Institute Jules Bordet, Université Libre de Bruxelles, Nuclear Medicine Department, 121 Boulevard de Waterloo, 1000, Brussels, Belgium. Laurent Gerard, University Hospital of Liege, Division of Radiology, domaine du Sart-Tilman B35, 4000, Liège, Belgium. Rita Golfieri, Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy. Gerd Grözinger, Eberhard Karls University, Department of Diagnostic and Interventional Radiology, Hoppe-Seyler-Str. 3, D-72076, Tübingen, Germany. Marcus Katoh, Helios Hospital Krefeld, Department of Diagnostic and Interventional Radiology, Lutherplatz 40, 47805, Krefeld, Germany. Michael Koehler, University Hospital Muenster, Department of Clinical Radiology, Albert-Schweitzer-Strasse 33, 48129, Muenster, Germany. Jan Robert Kröger, Johannes Wesling Klinik Minden, Universitätsinstitut für Radiologie, Neuroradiologie und Nuklearmedizin der Mühlenkreiskliniken, Hans-Nolte-Straße 1, 32429 Minden, Germany. Christiane Kuhl, University Hospital Aachen, Department of Radiology, Pauwelsstr. 30, 52074, Aachen, Germany. Franco Orsi, European Institute of Oncology, Interventional Radiology Division, Via Ripamonti 435, 20100, Milan, Italy. Murat Özgün, St. Franziskus Hospital, Department of Radiology, Hohenzollernring 70, 48145, Muenster, Germany. Peter Reimer, Academic Teaching Hospital the University of Freiburg, Städtisches Klinikum Karlsruhe, Institute for Diagnostic and Interventional Radiology, Moltkestrasse 90, 76133, Karlsruhe, Germany. Maxime Ronot, APHP, University Hospitals Paris Nord Val de Seine, Department of Radiology, 100 bd general Leclerc, Beaujon, Clichy, Hauts-de-Seine, France. Axel Schmid, University Hospital Erlangen, Department of Radiology, Maximiliansplatz 1, 91054, Erlangen, Germany. Alessandro Vit, Azienda Ospedaliero Universitaria, SOC Diagnostica Angiografica e Radiologia Interventistica, via Grazzano 150/C, 33100, Udine, Italy.

      Appendix. Supplementary materials

      References

        • Sung H
        • Ferlay J
        • Siegel RL
        • Laversanne M
        • Soerjomataram I
        • Jemal A
        • et al.
        Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.
        CA Cancer J Clin. 2021; 71: 209-249
        • Donadon M
        • Ribero D
        • Morris-Stiff G
        • Abdalla EK
        • Vauthey JN.
        New paradigm in the management of liver-only metastases from colorectal cancer.
        Gastrointest Cancer Res. 2007; 1: 20-27
        • Akgul O
        • Cetinkaya E
        • Ersoz S
        • Tez M.
        Role of surgery in colorectal cancer liver metastases.
        World J Gastroenterol. 2014; 20: 6113-6122
        • Benson AB
        • Venook AP
        • Al-Hawary MM
        • Arain MA
        • Chen YJ
        • Ciombor KK
        • et al.
        Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.
        J Natl Compr Canc Netw. 2021; 19: 329-359
        • Van Cutsem E
        • Cervantes A
        • Adam R
        • Sobrero A
        • Van Krieken JH
        • Aderka D
        • et al.
        ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.
        Ann Oncol. 2016; 27: 1386-1422
        • Tan HL
        • Lee M
        • Vellayappan BA
        • Neo WT
        • Yong WP.
        The Role of Liver-Directed Therapy in Metastatic Colorectal Cancer.
        Curr Colorectal Cancer Rep. 2018; 14: 129-137
        • d'Andrea E
        • Russi M
        • Pacilio M
        • Bilotta F
        Yttrium-90 Radioembolization of Colorectal Cancer Liver Metastases: A Systematic Review of Clinical Evidence.
        Am J Clin Oncol. 2022; 45: 175-181
        • Kennedy A
        • Coldwell D
        • Sangro B
        • Wasan H
        • Salem R.
        Radioembolization for the treatment of liver tumors general principles.
        Am J Clin Oncol. 2012; 35: 91-99
        • Benson AB
        • D'Angelica MI
        • Abbott DE
        • Abrams TA
        • Alberts SR
        • Anaya DA
        • et al.
        Guidelines Insights: Hepatobiliary Cancers, Version 2.2019.
        J Natl Compr Canc Netw. 2019; 17: 302-310
      1. European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma.
        J Hepatol. 2018; 69: 182-236
        • Valle JW
        • Borbath I
        • Khan SA
        • Huguet F
        • Gruenberger T
        • Arnold D
        • et al.
        Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2016; 27: v28-v37
        • Kwan J
        • Pua U.
        Review of Intra-Arterial Therapies for Colorectal Cancer Liver Metastasis.
        Cancers (Basel). 2021; 13
        • Gray B
        • Van Hazel G
        • Hope M
        • Burton M
        • Moroz P
        • Anderson J
        • et al.
        Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer.
        Ann Oncol. 2001; 12: 1711-1720
        • Hendlisz A
        • Van den Eynde M
        • Peeters M
        • Maleux G
        • Lambert B
        • Vannoote J
        • et al.
        Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy.
        J Clin Oncol. 2010; 28: 3687-3694
        • Van Hazel G
        • Blackwell A
        • Anderson J
        • Price D
        • Moroz P
        • Bower G
        • 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: 78-85
        • Golfieri R.
        SIR-Spheres yttrium-90 radioembolization for the treatment of unresectable liver cancers.
        Hepat Oncol. 2014; 1: 265-283
        • Mulcahy MF
        • Lewandowski RJ
        • Ibrahim SM
        • Sato KT
        • Ryu RK
        • Atassi B
        • et al.
        Radioembolization of colorectal hepatic metastases using yttrium-90 microspheres.
        Cancer. 2009; 115: 1849-1858
        • van Hazel GA
        • Heinemann V
        • Sharma NK
        • Findlay MP
        • Ricke J
        • Peeters M
        • 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
        • Wasan HS
        • Gibbs P
        • Sharma NK
        • Taieb J
        • Heinemann V
        • Ricke J
        • et al.
        First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials.
        Lancet Oncol. 2017; 18: 1159-1171
        • Mulcahy MF
        • Mahvash A
        • Pracht M
        • Montazeri AH
        • Bandula S
        • Martin 2nd, RCG
        • et al.
        Radioembolization With Chemotherapy for Colorectal Liver Metastases: A Randomized, Open-Label, International, Multicenter, Phase III Trial.
        J Clin Oncol. 2021; 39: 3897-3907
        • Helmberger T
        • Arnold D
        • Bilbao JI
        • de Jong N
        • Maleux G
        • Nordlund A
        • et al.
        Clinical Application of Radioembolization in Hepatic Malignancies: Protocol for a Prospective Multicenter Observational Study.
        JMIR Res Protoc. 2020; 9: e16296
        • Helmberger T
        • Golfieri R
        • Pech M
        • Pfammatter T
        • Arnold D
        • Cianni R
        • et al.
        Clinical Application of Trans-Arterial Radioembolization in Hepatic Malignancies in Europe: First Results from the Prospective Multicentre Observational Study CIRSE Registry for SIR-Spheres Therapy (CIRT).
        Cardiovasc Intervent Radiol. 2021; 44: 21-35
        • Pereyra D
        • Rumpf B
        • Ammann M
        • Perrodin SF
        • Tamandl D
        • Haselmann C
        • et al.
        The Combination of APRI and ALBI Facilitates Preoperative Risk Stratification for Patients Undergoing Liver Surgery After Neoadjuvant Chemotherapy.
        Ann Surg Oncol. 2019; 26: 791-799
        • Starlinger P
        • Ubl DS
        • Hackl H
        • Starlinger J
        • Nagorney DM
        • Smoot RL
        • et al.
        Combined APRI/ALBI score to predict mortality after hepatic resection.
        BJS Open. 2021; 5
        • Hu K
        • Yuan J
        • Tang B
        • Zhang F
        • Lu S
        • Chen R
        • et al.
        Albumin-bilirubin index and platelet-albumin-bilirubin index contribute to identifying survival benefit candidates in patients with hepatocellular carcinoma and Child-Pugh grade A undergoing transcatheter arterial chemoembolization with sorafenib treatment.
        Ann Transl Med. 2021; 9: 237
        • Tang T
        • Qiu JL
        • Li GW
        • Huang MP
        • Li Y
        • Li YJ
        • et al.
        Aspartate aminotransferase-to-platelet ratio predicts response to transarterial chemoembolisation and prognosis in hepatocellular carcinoma patients.
        Clin Radiol. 2018; 73: 259-265
        • Kennedy AS
        • Coldwell D
        • Nutting C
        • Murthy R
        • Wertman Jr., DE
        • Loehr SP
        • et al.
        Resin 90Y-microsphere brachytherapy for unresectable colorectal liver metastases: modern USA experience.
        Int J Radiat Oncol Biol Phys. 2006; 65: 412-425
        • Cianni R
        • Urigo C
        • Notarianni E
        • Saltarelli A
        • Salvatori R
        • Pasqualini V
        • et al.
        Selective internal radiation therapy with SIR-spheres for the treatment of unresectable colorectal hepatic metastases.
        Cardiovasc Intervent Radiol. 2009; 32: 1179-1186
        • Hickey R
        • Lewandowski RJ
        • Prudhomme T
        • Ehrenwald E
        • Baigorri B
        • Critchfield J
        • et al.
        90Y Radioembolization of Colorectal Hepatic Metastases Using Glass Microspheres: Safety and Survival Outcomes from a 531-Patient Multicenter Study.
        J Nucl Med. 2016; 57: 665-671
        • Loffroy R
        • Ronot M
        • Greget M
        • Bouvier A
        • Mastier C
        • Sengel C
        • et al.
        Short-term Safety and Quality of Life Outcomes Following Radioembolization in Primary and Secondary Liver Tumours: a Multi-centre Analysis of 200 Patients in France.
        Cardiovasc Intervent Radiol. 2021; 44: 36-49
        • Maleux G
        • Deroose C
        • Laenen A
        • Verslype C
        • Heye S
        • Haustermans K
        • et al.
        Yttrium-90 radioembolization for the treatment of chemorefractory colorectal liver metastases: Technical results, clinical outcome and factors potentially influencing survival.
        Acta Oncol. 2016; 55: 486-495
        • Brown D
        • Krebs H
        • Brower J
        • O'Hara R
        • Wang E
        • Vaheesan K
        • et al.
        Incidence and risk factors for sustained hepatic function toxicity 6 months after radioembolization: analysis of the radiation-emitting sir-spheres in non-resectable liver tumor (RESIN) registry.
        J Gastrointest Oncol. 2021; 12: 639-657
        • White J
        • Carolan-Rees G
        • Dale M
        • Morgan HE
        • Patrick HE
        • See TC
        • et al.
        Analysis of a National Programme for Selective Internal Radiation Therapy for Colorectal Cancer Liver Metastases.
        Clin Oncol (R Coll Radiol). 2019; 31: 58-66
        • Damm R
        • Seidensticker R
        • Ulrich G
        • Breier L
        • Steffen IG
        • Seidensticker M
        • et al.
        Y90 Radioembolization in chemo-refractory metastastic, liver dominant colorectal cancer patients: outcome assessment applying a predictive scoring system.
        BMC Cancer. 2016; 16: 509
        • Kurilova I
        • Beets-Tan RGH
        • Flynn J
        • Gonen M
        • Ulaner G
        • Petre EN
        • et al.
        Factors Affecting Oncologic Outcomes of 90Y Radioembolization of Heavily Pre-Treated Patients With Colon Cancer Liver Metastases.
        Clin Colorectal Cancer. 2019; 18: 8-18
        • Peng Y
        • Wei Q
        • He Y
        • Xie Q
        • Liang Y
        • Zhang L
        • et al.
        ALBI versus child-pugh in predicting outcome of patients with HCC: A systematic review.
        Expert Rev Gastroenterol Hepatol. 2020; 14: 383-400
        • Loaeza-del-Castillo A
        • Paz-Pineda F
        • Oviedo-Cardenas E
        • Sanchez-Avila F
        • Vargas-Vorackova F.
        AST to platelet ratio index (APRI) for the noninvasive evaluation of liver fibrosis.
        Ann Hepatol. 2008; 7: 350-357
        • Tomimaru Y
        • Eguchi H
        • Gotoh K
        • Kawamoto K
        • Wada H
        • Asaoka T
        • et al.
        Platelet count is more useful for predicting posthepatectomy liver failure at surgery for hepatocellular carcinoma than indocyanine green clearance test.
        J Surg Oncol. 2016; 113: 565-569
        • Peck-Radosavljevic M.
        Thrombocytopenia in chronic liver disease.
        Liver Int. 2017; 37: 778-793
        • Johnson PJ
        • Berhane S
        • Kagebayashi C
        • Satomura S
        • Teng M
        • Reeves HL
        • et al.
        Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade.
        J Clin Oncol. 2015; 33: 550-558
        • Mohammadi H
        • Abuodeh Y
        • Jin W
        • Frakes J
        • Friedman M
        • Biebel B
        • et al.
        Using the Albumin-Bilirubin (ALBI) grade as a prognostic marker for radioembolization of hepatocellular carcinoma.
        J Gastrointest Oncol. 2018; 9: 840-846
        • Magnetta MJ
        • Ghodadra A
        • Lahti SJ
        • Xing M
        • Zhang D
        • Kim HS.
        Connecting cancer biology and clinical outcomes to imaging in KRAS mutant and wild-type colorectal cancer liver tumors following selective internal radiation therapy with yttrium-90.
        Abdom Radiol (NY). 2017; 42: 451-459
        • Gnesin S
        • Canetti L
        • Adib S
        • Cherbuin N
        • Silva Monteiro M
        • Bize P
        • et al.
        Partition Model-Based 99mTc-MAA SPECT/CT Predictive Dosimetry Compared with 90Y TOF PET/CT Posttreatment Dosimetry in Radioembolization of Hepatocellular Carcinoma: A Quantitative Agreement Comparison.
        J Nucl Med. 2016; 57: 1672-1678
        • Van Der Gucht A
        • Jreige M
        • Denys A
        • Blanc-Durand P
        • Boubaker A
        • Pomoni A
        • et al.
        Resin Versus Glass Microspheres for (90)Y Transarterial Radioembolization: Comparing Survival in Unresectable Hepatocellular Carcinoma Using Pretreatment Partition Model Dosimetry.
        J Nucl Med. 2017; 58: 1334-1340
        • Hermann AL
        • Dieudonne A
        • Ronot M
        • Sanchez M
        • Pereira H
        • Chatellier G
        • et al.
        Relationship of Tumor Radiation-absorbed Dose to Survival and Response in Hepatocellular Carcinoma Treated with Transarterial Radioembolization with (90)Y in the SARAH Study.
        Radiology. 2020; 296: 673-684
        • Garin E
        • Tselikas L
        • Guiu B
        • Chalaye J
        • Edeline J
        • de Baere T
        • et al.
        Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial.
        Lancet Gastroenterol Hepatol. 2021; 6: 17-29
        • Alsultan AA
        • van Roekel C
        • Barentsz MW
        • Smits MLJ
        • Kunnen B
        • Koopman M
        • et al.
        Dose-Response and Dose-Toxicity Relationships for Glass (90)Y Radioembolization in Patients with Liver Metastases from Colorectal Cancer.
        J Nucl Med. 2021; 62: 1616-1623
        • Levillain H
        • Duran Derijckere I
        • Marin G
        • Guiot T
        • Vouche M
        • Reynaert N
        • et al.
        (90)Y-PET/CT-based dosimetry after selective internal radiation therapy predicts outcome in patients with liver metastases from colorectal cancer.
        EJNMMI Res. 2018; 8: 60
        • Dudley WN
        • Wickham R
        • Coombs N.
        An Introduction to Survival Statistics: Kaplan-Meier Analysis.
        J Adv Pract Oncol. 2016; 7: 91-100