SIRT DELIVERY

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2. The partition model or voxel-based dosimetry (when available) are preferred over other methodologies, such as BSA, but it might not be applicable in patients with poorly defined, multiple and/or small tumors in which actual tumor volume cannot be determined.

References: SIRT with resin microspheres in Asian regions

Article

Grade

Key Points

Chow et al. SIRveNIB: Selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol. 2018;36(19):1913-1921. doi: 10.1200/JCO.2017.76.0892

B-R

  • Multi-center open-label RTC of SIRT (resin) vs sorafenib for Asian patients with locally advanced HCC
  • Liver function parameters for inclusion: total bilirubin < 2.0mg/dL; INR ≤ 2.0; ALP ≤ 5 x institutional ULN; AST and ALT ≤ 5 x institutional ULN; albumin ≥ 2.5g/dL
  • No difference in OS between SIRT and sorafenib, but better safety profile for SIRT than sorafenib
  • Patient characteristics included ECOG 0/1 (SIRT, n=135/47; sorafenib, n=141/37) BCLC A/B/C (SIRT, n=0/93/88; sorafenib, n=1/97/80); Child Pugh A/B (SIRT, n=165/14; sorafenib, n=160/16); hepatitis B/C/B+C (SIRT, n=93/26/4; sorafenib, n=104/19/5) 
  • Activity administered was calculated by BSA or partition model and mean activity was 1.8 GBq
  • Response was evaluated with RECIST 1.1
  • Median daily dose was 644.5 mg sorafenib for patients who were planned to receive 400 mg twice daily
  • ITT Median OS was 8.8 months for SIRT and 10.0 months for sorafenib; PP median OS was 11.3 month and 10.4 months; median PFS at any site was 5.8 and 5.1 respectively  
  • BCLC C treated population had median OS of 9.2 months for SIRT and 5.8 months for sorafenib (P=0.0475)
  • Reported AEs were 437 events for SIRT and 1031 events for sorafenib
  • Fewer SIRT patients than sorafenib patients experienced one or more AEs: 78 (60.0%) of 130 patients and 137 (84.6%) of 162 patients; AEs of grade ≥ 3: 36 (27.7%) and 82 (50.6%); or serious AEs (SAEs): 27 (20.8%) and 57 (35.2%)
Kim et al. Usefulness of Bremsstrahlung images after intra-arterial Y-90 resin microphere radioembolization for hepatic tumors. Nucl Med Mol Imaging. 2011;45(1):59-67. doi: 10.1007/s13139-010-0066-4

C-LD

  • Single-center (Korea) case series of patients with unresectable HCC (n=18) or liver metastasis (n=2) treated with SIRT (resin)
  • Partition model was used to calculate the activity, which ranged from 0.28-2.86 GBq
  • Injected 90Y dose and liver count on bremsstrahlung images were significantly correlated, demonstrating this method of post-treatment imaging was able to confirm achievement of adequate dose delivery
Song et al. PET/CT-based dosimetry in 90Y-microsphere selective internal radiation therapy: Single cohort comparison with pretreatment planning on 99mTc-MAA imaging and correlation with treatment efficacy. Medicine (Baltimore). 2015;94(23):e945. doi: 10.1097/MD.0000000000000945

C-LD

  • Retrospective single-center (Korea) case series of patients with HCC (and other malignancies) treated with SIRT (resin microspheres)
  • Partition model (n=21) was used to calculate the injected activity (absorbed dose 2.1 BGq) except when the lung shunt fraction was high (>0.1), which used the BSA method (n=2) and reduced up to 40% according to manufacturer’s package insert (absorbed dose 1.7 BGq)
  • 99mTc SPECT/CT can be used as a conservative activity planning method
  • Stasis prevented full planned injected activity in 4 patients
  • PFS was 207 days, PFS was 286 days for patients with high absorbed dose (>200 Gy) and 92 days for patients with low absorbed dose (≤200Gy, P=0.046)
  • 90Y-PET-CT was effective method for post-SIRT dosimetry and prediction of treatment efficacy
Ng et al. Patient dosimetry for 90Y selective internal radiation treatment based on 90Y PET imaging. J Appl Clin Med Phys. 2013;14(5):212-21. doi: 10.1120/jacmp.v14i5.4371

C-LD

  • Retrospective single-center (Hong Kong) case series of patients with HCC (n=3) or colorectal liver metastases (n=2) treated with SIRT (resin)
  • Partition model was used to calculate the absorbed dose and injected activity ranges from 1-1.3 GBq with a mean target dose range of 51.7-163 Gy
  • A method computing 3D dose distributions was proposed using 90Y PET was performed 6 h after SIRT
Lim et al. Alpha-fetoprotein, des-gamma-carboxy prothrombin (DCP), and modified RECIST response as predictors of survival after transarterial radioembolization for hepatocellular carcinoma. J Vasc Interv Radiol. 2019 Aug;30(8):1194-1200.e1. doi: 10.1016/j.jvir.2019.03.016

C-LD

  • Retrospective single-center (Korea) case series of patients with HCC and elevated AFP and DCP treated with SIRT (resin or glass)
  • MIRD was used to calculate prescribed activity for glass and partition model was used for resin
  • Average activity was 2.1 GBq; average lung dose was 11.3 Gy; average liver dose was 48 Gy and tumor resin dose was 149.9 Gy; average target dose for glass was 134.5 Gy
  • AFP, DCP and mRECIST response at 3 months occurred in 68.5%, 66.0% and 45.4% and were predictive of OS 
  • Median OS was longer for responders than non-responders

References: SIRT with resin microspheres in non-Asian regions

Article

Grade

Key Points

Ricke et al. Safety and toxicity of radioembolization plus Sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC. Liver Int. 2015;35(2):620-6. doi: 10.1111/liv.12622

B-R

  • Multi-center open-label RCT conducted in Europe on HCC patients with or without PVT treated with resin microspheres
  • Both arms received sorafenib 200 mg twice daily for 1 week before increasing the dose to sorafenib 400 mg twice daily
  • Sorafenib initiated 3 days after SIRT 
  • Patient characteristics included ECOG 0/1 (n=27/13); Child Pugh 5/6-7/unknown (n=30/7/3), BCLC B/C (n=14/26); treatment naïve (n=30) 
  • BSA method was used to calculate activity; median activity 1.87 BGq administered only to the SIRT+sorafenib arm either sequentially (n=10) or to right (n=7) or left lobe (n=3)
  • Median daily sorafenib dose was 614 mg over median of 8.5 months for the SIRT+sorafenib arm and 557 mg over 9.6 months in the sorafenib arm
  • Percentage of AEs were similar between groups or in grade 3/4 toxicities

Pitton et al. Randomized comparison of selective internal radiotherapy (SIRT) versus drug-eluting bead transarterial chemoembolization (DEB-TACE) for the treatment of hepatocellular carcinoma. Cardiovasc Intervent Radiol. 2015;38(2):352-60. doi: 10.1007/s00270-014-1012-0

B-R

  • Single-center (Germany) pilot RCT of patients with unresectable HCC treated with SIRT (resin) or DEB-TACE
  • Patient characteristics included hepatitis B/C (SIRT, n=0/5; TACE, n=1/4) Child Pugh A/B/C (SIRT, n=10/2/0; TACE, n=9/3/0); BCLC A/B (SIRT, n=0/12; TACE, n=1/11)
  • Body surface model used to calculate activity to treat lobes, either singly (n=4) sequential treatments (n=8) were 4 weeks apart
  • DEB-TACE performed with maximal 150 mg doxorubicin per session for a median of 3.8 session within an interval of 48.2 days between session
  • Administer activity for SIRT was 1.847 GBq
  • No differences in TTP, PFS and OS between groups
Vilgrain et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2017;18(12):1624-1636. doi: 10.1016/S1470-2045(17)30683-6

B-R

  • Multi-center open-label RCT conducted in France on SIRT (with resin microspheres) vs sorafenib on locally advanced and unresectable HCC after unsuccessful TACE 
  • No significant difference in OS between SIRT and sorafenib
  • Compared sorafenib 400 mg twice daily with SIRT to lobe, sector or segment
  • Activity was calculated using BSA method
  • Patient characteristics included hepatitis C/B (SIRT, n=55/13; sorafenib, n=49/15); ECOG 0/1 (SIRT, n=145/92; sorafenib, n=139/83); BCLC A/B/C (SIRT, n=9/66/162; sorafenib n=12/61/149); Child Pugh A(5-6)/B7/unknown (SIRT, n=196/39/2; sorafenib, n=187/35/0); bilobar (SIRT, n=50; sorafenib, n=35); macrovascular invasion (SIRT, n=149; sorafenib, n=128); AFP (SIRT, median 87 ng/mL, sorafenib, median 80.0 ng/mL)
  • Calculation of the hepatopulmonary shunt fraction and tracer distribution was evaluated with 99Tc MAA SPECT imaging
  • Activity delivered per patient was 1.394 GBq
  • Median follow-up was 27.9 months in the SIRT group, 28.1 months in sorafenib group
  • Response was evaluated with RECIST 1.1
  • Median OS and PFS was 8.0 and 4.1 months for SIRT and 9.9 and 3.7 months for sorafenib
  • Best overall response include CR (SIRT, n=5; sorafenib, n=2), PR (SIRT, n=31; sorafenib, n=21), SD (SIRT, n=93; sorafenib, n=131), PD (SIRT, n=60; sorafenib, n=44)
  • 1088 serious adverse events were reported (SIRT, n=518 events; sorafenib, n=570 events)
Hermann et al. Relationship of tumor radiation-absorbed dose to survival and response in hepatocellular carcinoma treated with transarterial radioembolization with 90Y in the SARAH study. Radiology. 2020 Jun 30:191606. doi: 10.1148/radiol.2020191606

B-NR

  • Secondary analysis of SIRT patients from the multi-center (France) RCT of SIRT (resin) vs sorafenib
  • Liver function parameters for inclusion: bilirubin under or equals 50 µmol/L, AST or ALT under or equals 5 x ULN, INR under or equals 1.5
  • Dose activity was calculated using the BSA method
  • For the dose-survival group, median OS was 9.3 months, median tumor radiation-absorbed dose was 112 Gy, median tumor volume as 152 cm3, median injected 90Y activity was 1342 mBq 
  • Median OS was 14.1 months for patients who had ≥ 100 Gy tumor radiation-absorbed dose, and 6.1 months for patients who had <100 Gy
  • Strong predictors of survival were ≥ 100 Gy tumor radiation-absorbed dose, ALBI grade of A1 and tumor burden ≤25%
  • No difference existed between tumor radiation-absorbed dose and objective response at 6 months, but participants who achieved disease control had median tumor radiation-absorbed dose of 121 Gy while participants with progressive disease this dose was 85 Gy (P=0.02)
  • Grade 1 and 2 fatigue occurred more often in participants who received ≥100 Gy tumor radiation-absorbed dose (P=0.05)
  • Longest survival and highest disease control rate were achieved when participants received ≥100 Gy with optimal agreement between 99mTc-MAA SPECT/CT and 90Y SPECT/CT or PET/CT
Van der Gucht et al. Resin versus glass microspheres for 90Y transarterial radioembolization: Comparing survival in unresectable hepatocellular carcinoma using pretreatment partition model dosimetry. J Nucl Med. 2017 Aug;58(8):1334-1340. doi: 10.2967/jnumed.116.184713

B-NR

  • Retrospective cohort study (prospectively collected data) (Switzerland) of patients with unresectable HCC treated with SIRT (resin or glass)
  • HBV: 12.2% in resin group, 8.3% in glass group. HCV: 29.3% in resin group, 19.4% in glass group
  • Median administered activity was calculated using the partition model for resin (1.8 GBq) and using 2-compartment model for glass (1.8 GBq)
  • In the resin group, 90Y tumor-absorbed dose was 160 Gy, normal liver-absorbed dose was 36 Gy
  • PFS and OS for resin were higher than for glass but not statistically significant
  • No survival differences were detected when BCLC stages early/intermediate and advanced were compared
  • BCLC staging and serum AFP were associated with PFS for glass only

 

 

Strigari et al. Efficacy and toxicity related to treatment of hepatocellular carcinoma with 90Y-SIR spheres: radiobiologic considerations. J Nucl Med. 2010;51(9):1377-85. doi: 10.2967/jnumed.110.075861

C-LD

  • Retrospective single-center (Italy) case series analysis of 73 HCC patients treated with SIRT (resin)
  • BSA empiric method used to calculate activity to treat whole liver (n=35) or lobes (right, n=35; left, n=3), but also developed a tumor to normal tissue ratio using activity counts
  • Administered activity was 1.00 GBq to 2.26 GBq, median 1,73 GBq; median liver dose was 36 Gy, with liver toxicity reported (≥grade 2, 31%; ≥grade 3, 21%; ≥grade 4, 11%)
  • Median absorbed doses per unit activity were 18 Gy/BGq to non-tumor liver and 60 Gy/BGq to tumor
  • LSF calculated and activity decreased by 20% or 40% as needed for high LSF
  • Tumor response was measured using RECIST and EASL and responses varied depending on criteria used
  • Mean dose needed to achieve CR was 150 Gy using EASL and 122 Gy for RECIST
Gallio et al. Calculation of tumour and normal tissue biological effective dose in 90Y liver radioembolization with different dosimetric methods. Phys Med. 2016;32(12):1738-1744. doi: 10.1016/j.ejmp.2016.10.023

C-LD

  • Multi-center cross-sectional study (Italy) on patients with HCC using SIRT with resin or glass microspheres
  • Dose was calculated using the mono-compartimental method for glass microspheres (mean injected dose 2.6 GBq) and partition model for resin microspheres (mean injected dose 1.5 GBq) 
  • Predicted tumor and healthy liver average doses were calculated for all patients using 3 methods: AAPM recommendations, multicompartimental MIRD, and convolution-based Voxel method
  • The AAPM method is less accurate than the other 2 for accurate dosimetry in SIR
Gnesin 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(11):1672-1678. doi: 10.2967/jnumed.116.173104

C-LD

  • Prospective case series analysis (Switzerland) of patients with HCC using SIRT with resin or galss microspheres
  • Activity was determined based on 3-compartment partition model (resin) and 2-compartment model (glass)
  • Data show that no relevant quantitative differences in the predictive and post-SIRT dosimetry between glass and resin for tumors volumes of 150 mL or less.
  • Post-SIRT dosimetry should be performed based on 90Y time of flight PET/CT, especially if fractionated treatment or dose-response/toxicity studies are needed, and can be informative for extrahepatic shunting
Kafrouni et al. Retrospective voxel-based dosimetry for assessing the ability of the body-surface-area model to predict delivered dose and radioembolization outcome. J Nucl Med. 2018;59(8):1289-1295. doi: 10.2967/jnumed.117.202937

C-LD

  • Retrospective single-center (France) case series analysis of patients with HCC treated with SIRT (resin)
  • Activity was planned using the BSA method
  • Only 16 patients had treatment response data due to death of participant prior to the 6-month follow-up imaging
  • Using EASL criteria, 26 treatments resulted in 14 responding and 12 non-responding 
  • Median value of the average dose was 60 Gy, and only 6 case had tumor average dose >120 Gy; the dose to nontumor liver (NTL) was <50 Gy 
  • 62% of treatments had 120 Gy delivered to the tumor while keeping NTL and lung doses < 50Gy and 30 Gy respectively
  • Underdosing was related to the use of the BSA method
Lam et al. Safety of 90Y radioembolization in patients who have undergone previous external beam radiation therapy. Int J Radiat Oncol Biol Phys. 2013 Oct 1;87(2):323-9. doi: 10.1016/j.ijrobp.2013.05.041

C-LD

  • Retrospective case series analysis of 31 patients with HCC treated with SIRT (n=29 resin, n=2 glass) at a mean time interval of 22.5 months after receiving EBRT
  • EBRT liver dose was calculated using 3D planning with dose-volume histogram analysis
  • Patients who experienced hepatotoxicity had higher EBRT mean liver doses
  • Fatal REILD (n=2) occurred at the 2 highest EBRT mean liver doses and also at the highest cumulative liver doses
  • V30 (fraction of the liver exposed to >30 Gy) was the strongest predictor of toxicity

3. SIRT treatment should be discussed in terms of dose (Gy) not activity (GBq).

References: SIRT with resin microspheres in Asian regions

Article

Grade

Key Points

Chow et al. SIRveNIB: Selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol. 2018;36(19):1913-1921. doi: 10.1200/JCO.2017.76.0892

B-R

  • Multi-center open-label RTC of SIRT (resin) vs sorafenib for Asian patients with locally advanced HCC
  • Liver function parameters for inclusion: total bilirubin < 2.0mg/dL; INR ≤ 2.0; ALP ≤ 5 x institutional ULN; AST and ALT ≤ 5 x institutional ULN; albumin ≥ 2.5g/dL
  • No difference in OS between SIRT and sorafenib, but better safety profile for SIRT than sorafenib
  • Patient characteristics included ECOG 0/1 (SIRT, n=135/47; sorafenib, n=141/37) BCLC A/B/C (SIRT, n=0/93/88; sorafenib, n=1/97/80); Child Pugh A/B (SIRT, n=165/14; sorafenib, n=160/16); hepatitis B/C/B+C (SIRT, n=93/26/4; sorafenib, n=104/19/5) 
  • Activity administered was calculated by BSA or partition model and mean activity was 1.8 GBq
  • Response was evaluated with RECIST 1.1
  • Median daily dose was 644.5 mg sorafenib for patients who were planned to receive 400 mg twice daily
  • ITT Median OS was 8.8 months for SIRT and 10.0 months for sorafenib; PP median OS was 11.3 month and 10.4 months; median PFS at any site was 5.8 and 5.1 respectively  
  • BCLC C treated population had median OS of 9.2 months for SIRT and 5.8 months for sorafenib (P=0.0475)
  • Reported AEs were 437 events for SIRT and 1031 events for sorafenib
  • Fewer SIRT patients than sorafenib patients experienced one or more AEs: 78 (60.0%) of 130 patients and 137 (84.6%) of 162 patients; AEs of grade ≥ 3: 36 (27.7%) and 82 (50.6%); or serious AEs (SAEs): 27 (20.8%) and 57 (35.2%)

References: SIRT with resin microspheres in non-Asian regions

Article

Grade

Key Points

Vilgrain et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2017;18(12):1624-1636. doi: 10.1016/S1470-2045(17)30683-6

B-R

  • Multi-center open-label RCT conducted in France on SIRT (with resin microspheres) vs sorafenib on locally advanced and unresectable HCC after unsuccessful TACE 
  • No significant difference in OS between SIRT and sorafenib
  • Compared sorafenib 400 mg twice daily with SIRT to lobe, sector or segment
  • Activity was calculated using BSA method
  • Patient characteristics included hepatitis C/B (SIRT, n=55/13; sorafenib, n=49/15); ECOG 0/1 (SIRT, n=145/92; sorafenib, n=139/83); BCLC A/B/C (SIRT, n=9/66/162; sorafenib n=12/61/149); Child Pugh A(5-6)/B7/unknown (SIRT, n=196/39/2; sorafenib, n=187/35/0); bilobar (SIRT, n=50; sorafenib, n=35); macrovascular invasion (SIRT, n=149; sorafenib, n=128); AFP (SIRT, median 87 ng/mL, sorafenib, median 80.0 ng/mL)
  • Activity delivered per patient was 1.394 GBq
  • Median follow-up was 27.9 months in the SIRT group, 28.1 months in sorafenib group
  • Response was evaluated with RECIST 1.1
  • Median OS and PFS was 8.0 and 4.1 months for SIRT and 9.9 and 3.7 months for sorafenib
  • Best overall response include CR (SIRT, n=5; sorafenib, n=2), PR (SIRT, n=31; sorafenib, n=21 ), SD (SIRT, n=93; sorafenib, n=131), PD (SIRT, n=60; sorafenib, n=44)
  • 1088 serious adverse events were reported (SIRT, n=518 events; sorafenib, n=570 events)
Ricke et al. Safety and toxicity of radioembolization plus Sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC. Liver Int. 2015;35(2):620-6. doi: 10.1111/liv.12622

B-R

  • Multi-center open-label RCT conducted in Europe on HCC patients with or without PVT treated with resin microspheres
  • Both arms received sorafenib 200 mg twice daily for 1 week before increasing the dose to sorafenib 400 mg twice daily
  • Sorafenib initiated 3 days after SIRT 
  • Patient characteristics included ECOG 0/1 (n=27/13); Child Pugh 5/6-7/unknown (n=30/7/3), BCLC B/C (n=14/26); treatment naïve (n=30) 
  • BSA method was used to calculate activity; median activity 1.87 BGq administered only to the SIRT+sorafenib arm either sequentially (n=10) or to right (n=7) or left lobe (n=3)
  • Median daily sorafenib dose was 614 mg over median of 8.5 months for the SIRT+sorafenib arm and 557 mg over 9.6 months in the sorafenib arm
  • Percentage of AEs were similar between groups or in grade 3/4 toxicities
Hermann et al. Relationship of tumor radiation-absorbed dose to survival and response in hepatocellular carcinoma treated with transarterial radioembolization with 90Y in the SARAH study. Radiology. 2020 Jun 30:191606. doi: 10.1148/radiol.2020191606

B-NR

  • Secondary analysis of SIRT patients from the multi-center (France) RCT of SIRT (resin) vs sorafenib
  • Liver function parameters for inclusion: bilirubin under or equals 50 µmol/L, AST or ALT under or equals 5 x ULN, INR under or equals 1.5
  • Tumor etiology: HBV (4% in dose-survival group, 5% in dose-tumor response group), HCV (23% in dose-survival group, 26% in dose-tumor response group)
  • For the dose-survival group, median OS was 9.3 months, median tumor radiation-absorbed dose was 112 Gy, median tumor volume as 152 cm3, median injected 90Y activity was 1342 mBq 
  • Median OS was 14.1 months for patients who had ≥ 100 Gy tumor radiation-absorbed dose, and 6.1 months for patients who had <100 Gy
  • Strong predictors of survival were ≥ 100 Gy tumor radiation-absorbed dose, ALBI grade of A1 and tumor burden ≤25%
  • No difference existed between tumor radiation-absorbed dose and objectiveresponse at 6 months, but participants who achieved disease control had median tumor radiation-absorbed dose of 121 Gy while participants with progressive disease this dose was 85 Gy (P=0.02)
  • Grade 1 and 2 fatigue occurred more often in participants who received ≥100 Gy tumor radiation-absorbed dose (P=0.05)
  • Longest survival and highest disease control rate were achieved when participants received ≥100 Gy with optimal agreement between 99mTc-MAA SPECT/CT and 90Y SPECT/CT or PET/CT

 

 

James et al. Differences in radiation activity between glass and resin 90Y microspheres in treating unresectable hepatic cancer. Health Phys. 2017;112(3):300-304. doi: 10.1097/HP.0000000000000631

C-LD

  • Retrospective case series analysis (USA) of HCC patients (and other malignancies) treated with SIRT (glass or resin)
  • For HCC, 40 patients received glass and 11 received resin microspheres
  • Actual and projected activity were calculated according to manufacturer’s formula
  • Average prescribed activity was 2.73 GBq for glass and 1.06 GBq for resin across all cancer types
  • In HCC patients, administered mean glass activity was 2.73 GBq, and projected resin activity, 1.12 Gbq. Administered resin activity was 1.12 Gbq and projected glass activity, 3.38 Gbq
Strigari et al. Efficacy and toxicity related to treatment of hepatocellular carcinoma with 90Y-SIR spheres: radiobiologic considerations. J Nucl Med. 2010;51(9):1377-85. doi: 10.2967/jnumed.110.075861

C-LD

  • Retrospective single-center (Italy) case series analysis of 73 HCC patients treated with SIRT (resin)
  • BSA empiric method used to calculate activity to treat whole liver (n=35) or lobes (right, n=35; left, n=3), but also developed a tumor to normal tissue ratio using activity counts
  • Administered activity was 1.00 GBq to 2.26 GBq, median 1,73 GBq; median liver dose was 36 Gy, with liver toxicity reported (≥grade 2, 31%; ≥grade 3, 21%; ≥grade 4, 11%)
  • Median absorbed doses per unit activity were 18 Gy/BGq to non-tumor liver and 60 Gy/BGq to tumor
  • LSF calculated and activity decreased by 20% or 40% as needed for high LSF
  • Tumor response was measured using RECIST and EASL and responses varied depending on criteria used
  • Mean dose needed to achieve CR was 150 Gy using EASL and 122 Gy for RECIST

4. The therapeutic index should be optimized and, for conventional SIRT, adhering to ALARA principles, the dose should be as low as possible and the maximum dose to normal liver tissue should not exceed 70 Gy (40 Gy for single-dose SIRT to compromised liver).

References: SIRT with resin microspheres in Asian regions

Article

Grade

Key Points

Chow et al. SIRveNIB: Selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol. 2018;36(19):1913-1921. doi: 10.1200/JCO.2017.76.0892

B-R

  • Multi-center open-label RTC of SIRT (resin) vs sorafenib for Asian patients with locally advanced HCC
  • Liver function parameters for inclusion: total bilirubin < 2.0mg/dL; INR ≤ 2.0; ALP ≤ 5 x institutional ULN; AST and ALT ≤ 5 x institutional ULN; albumin ≥ 2.5g/dL
  • No difference in OS between SIRT and sorafenib, but better safety profile for SIRT than sorafenib
  • Patient characteristics included ECOG 0/1 (SIRT, n=135/47; sorafenib, n=141/37) BCLC A/B/C (SIRT, n=0/93/88; sorafenib, n=1/97/80); Child Pugh A/B (SIRT, n=165/14; sorafenib, n=160/16); hepatitis B/C/B+C (SIRT, n=93/26/4; sorafenib, n=104/19/5) 
  • Activity administered was calculated by BSA or partition model and mean activity was 1.8 GBq
  • Response was evaluated with RECIST 1.1
  • Median daily dose was 644.5 mg sorafenib for patients who were planned to receive 400 mg twice daily
  • ITT Median OS was 8.8 months for SIRT and 10.0 months for sorafenib; PP median OS was 11.3 month and 10.4 months; median PFS at any site was 5.8 and 5.1 respectively
  • BCLC C treated population had median OS of 9.2 months for SIRT and 5.8 months for sorafenib (P=0.0475)
  • Reported AEs were 437 events for SIRT and 1031 events for sorafenib
  • Fewer SIRT patients than sorafenib patients experienced one or more AEs: 78 (60.0%) of 130 patients and 137 (84.6%) of 162 patients; AEs of grade ≥ 3: 36 (27.7%) and 82 (50.6%); or serious AEs (SAEs): 27 (20.8%) and 57 (35.2%)
Ho et al. Partition model for estimating radiation doses from yttrium-90 microspheres in treating hepatic tumours. Eur J Nucl Med. 1996;23:947–52. doi: 10.1007/BF01084369

C-LD

  • Single-center (Hong Kong) case series of 14 patients with HCC treated with SIRT (resin)
  • 99mTc MAA scintigraphy is used to estimate percentage of activity shunted to the lung and the T/N ratio
  • MIRD was used to compute radiation doses
  • The partition model was used for estimating the radiation doses to the tumor and normal liver
  • Total activity of Y90 administered ranged from 2 to 7 GBq with a median of 3 GBq. Estimated activity shunted into the pulmonary system ranged 0.044–0.798 GBq, with a median of 0.219 GBq
Ng et al. Patient dosimetry for 90Y selective internal radiation treatment based on 90Y PET imaging. J Appl Clin Med Phys. 2013;14(5):212-21. doi: 10.1120/jacmp.v14i5.4371

C-LD

  • Retrospective single-center (Hong Kong) case series of patients with HCC (n=3) or colorectal liver metastases (n=2) treated with SIRT (resin)
  • Partition model was used to calculate the absorbed dose and injected activity ranges from 1-1.3 GBq with a mean target dose range of 51.7-163 Gy
  • A method computing 3D dose distributions was proposed using 90Y PET was performed 6 h after SIRT
Lim et al. Alpha-fetoprotein, des-gamma-carboxy prothrombin (DCP), and modified RECIST response as predictors of survival after transarterial radioembolization for hepatocellular carcinoma. J Vasc Interv Radiol. 2019 Aug;30(8):1194-1200.e1. doi: 10.1016/j.jvir.2019.03.016

C-LD

  • Retrospective single-center (Korea) case series of patients with HCC and elevated AFP and DCP treated with SIRT (resin or glass)
  • MIRD was used to calculate prescribed activity for glass and partition model was used for resin
  • Average activity was 2.1 GBq; average lung dose was 11.3 Gy; average liver dose was 48 Gy and tumor resin dose was 149.9 Gy; average target dose for glass was 134.5 Gy
  • AFP, DCP and mRECIST response at 3 months occurred in 68.5%, 66.0% and 45.4% and were predictive of OS 
  • Median OS was longer for responders than non-responders
Lau et al. Patient selection and activity planning guide for selective internal radiotherapy with yttrium-90 resin microspheres. Int J Radiat Oncol Biol Phys 2012 Jan 1;82(1):401-7, doi: 10.1016/j.ijrobp.2010.08.015

C-EO

  • Clinical consensus statement on use of resin microspheres for HCC patients
  • Most common activity calculation method is the empiric planning adjusted for body surface area
  • Delivered dose must be calculated for uninvolved, normal parenchyma (preferably <50 Gy). Some institutions in Asia have lower thresholds (40–43 Gy). If the uninvolved parenchyma is functionally impaired before SIRT, the maximal dose should remain <50 Gy and even <40 Gy
  • 99mTc MAA scanning should be carried out for every patient
  • Planning SIRT delivery must consider: safety thresholds for T/N ratio (lowest threshold of 2.0), lung shunt fraction, and parenchymal radiation exposure
  • BSA calculation should be used for all patients, regardless of application of partition model
  • Microsphere activity must be calculated for every administration. A very high initial dose may preclude further radioembolization

References: SIRT with resin microspheres in non-Asian regions

Article

Grade

Key Points

Vilgrain et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2017;18(12):1624-1636. doi: 10.1016/S1470-2045(17)30683-6

B-R

  • Multi-center open-label RCT conducted in France on SIRT (with resin microspheres) vs sorafenib on locally advanced and unresectable HCC after unsuccessful TACE 
  • No significant difference in OS between SIRT and sorafenib
  • Compared sorafenib 400 mg twice daily with SIRT to lobe, sector or segment
  • Activity was calculated using BSA method
  • Patient characteristics included hepatitis C/B (SIRT, n=55/13; sorafenib, n=49/15); ECOG 0/1 (SIRT, n=145/92; sorafenib, n=139/83); BCLC A/B/C (SIRT, n=9/66/162; sorafenib n=12/61/149); Child Pugh A(5-6)/B7/unknown (SIRT, n=196/39/2; sorafenib, n=187/35/0); bilobar (SIRT, n=50; sorafenib, n=35); macrovascular invasion (SIRT, n=149; sorafenib, n=128); AFP (SIRT, median 87 ng/mL, sorafenib, median 80.0 ng/mL)
  • Activity delivered per patient was 1.394 GBq
  • Median follow-up was 27.9 months in the SIRT group, 28.1 months in sorafenib group
  • Response was evaluated with RECIST 1.1
  • Median OS and PFS was 8.0 and 4.1 months for SIRT and 9.9 and 3.7 months for sorafenib
  • Best overall response include CR (SIRT, n=5; sorafenib, n=2), PR (SIRT, n=31; sorafenib, n=21), SD (SIRT, n=93; sorafenib, n=131), PD (SIRT, n=60; sorafenib, n=44)
  • 1088 serious adverse events were reported (SIRT, n=518 events; sorafenib, n=570 events)
Ricke et al. Safety and toxicity of radioembolization plus Sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC. Liver Int. 2015;35(2):620-6. doi: 10.1111/liv.12622

B-R

  • Multi-center open-label RCT conducted in Europe on HCC patients with or without PVT treated with resin microspheres
  • Both arms received sorafenib 200 mg twice daily for 1 week before increasing the dose to sorafenib 400 mg twice daily
  • Sorafenib initiated 3 days after SIRT 
  • Patient characteristics included ECOG 0/1 (n=27/13); Child Pugh 5/6-7/unknown (n=30/7/3), BCLC B/C (n=14/26); treatment naïve (n=30) 
  • BSA method was used to calculate activity; median activity 1.87 BGq administered only to the SIRT+sorafenib arm either sequentially (n=10) or to right (n=7) or left lobe (n=3)
  • Median daily sorafenib dose was 614 mg over median of 8.5 months for the SIRT+sorafenib arm and 557 mg over 9.6 months in the sorafenib arm
  • Percentage of AEs were similar between groups or in grade 3/4 toxicities
Birgin et al. Contralateral liver hypertrophy and oncological outcome following radioembolization with 90Y-microspheres: A systematic review. Cancers (Basel). 2020 Feb; 12(2): 294. doi: 10.3390/cancers12020294

B-NR

  • Systematic review of 16 papers comprising 602 patients treated with SIRT (resin or glass): 81% had primary liver cancer and 22% secondary malignancies
  • The ratio of the future liver remnant to the total liver volume ranged between 23.4% and 49.6% at baseline and between 27% and 68.6% after SIRT
  • Evidence of SIRT-induced liver hypertrophy was based mainly on retrospective studies, which had low Methodological Index for Non-Randomized Studies scores
  • Only 1 prospective study of 24 patients treated with SIRT for palliative care of advanced HCC was identified; however, it was too small to report on subgroup analyses of patients at high risk for poor hypertrophy 
  • Mean degree of relative hypertrophy in the studies ranged from 7% to 43.4%
  • Mean SIRT delivered dose ranged from 112 Gy to 154 Gy
  • Mean follow-up ranged from 4 weeks to 12 months
Ahmadzadehfar et al. Evaluation of the delivered activity of yttrium-90 resin microspheres using sterile water and 5% glucose during administration. EJNMMI Res. 2015;5(1):54. doi: 10.1186/s13550-015-0133-z

B-NR

  • Retrospective single-center (Germany) comparative study of unresectable HCC (and other malignancies) treated with SIRT (resin)
  • The prescribed activity was calculated using the BSA method based on target volumes of tumor and liver for each patient
  • Median planned activity was 1.5 GBq and 1.4 GBq for patients treated using sterile water and isotonic 5% glucose, respectively
  • Median activity delivered was 1.0 GBq and 1.4 GBq for patients treated using sterile water and isotonic 5% glucose, respectively, (P<0.005)
  • Prior TACE treatment did not affect early flow reduction or stasis
  • Incidence stasis during SIRT was reduced using isotonic glucose 5% water and non-ionic contract media
Gramenzi et al. Yttrium-90 radioembolization vs sorafenib for intermediate-locally advanced hepatocellular carcinoma: a cohort study with propensity score analysis. Liver Int. 2015;35(3):1036-47. doi: 10.1111/liv.12574

B-NR

  • Retrospective single-center (Italy) review of patients with locally advanced HCC/very large intermediate HCC/recurrent HCC treated with either SIRT (resin) (n=63) or sorafenib (n=74) who were SIRT eligible
  • OS similar for SIRT and sorafenib
  • Patient characteristic included hepatitis C/B (SIRT, n=29/9; sorafenib, n=32/11); AFP>200ng/mL (SIRT, n=22; sorafenib, n=20); prior HCC treatments (SIRT, n=32; sorafenib, n=42); no PVT (SIRT, n=32; sorafenib, n=47); Child Pugh A/B (SIRT, n=58/5; sorafenib, n=64/10); MELD (SIRT, 9; sorafenib, 9); BCLC B/C (SIRT, n=26/37; sorafenib, n=39/35)
  • Sorafenib was reduced for 56 patients and interrupted for 66 patients (cancer progression, n=31; SAEs, n=27; liver failure, n=8); 33 patients received a half dose for >70% of treatment period of median 4 months.
  • Activity administered was 1.71 BGq for whole liver (n=1), right/left lobe (n=26/7) or segment (n=29)
  • Tumor dose was 263.2 Gy for 27 patients with complete dosimetry
  • Median OS was 13.5 months, no difference was found between SIRT and sorafenib groups
  • More AEs occurred in patients taking sorafenib had grade 1/2 AE (63 events) than who received SIRT (16 events), but events for grade 3/4 AE were similar (n=21 and 22)
Cardarelli-Leite et al. Ablative Transarterial Radioembolization Improves Survival in Patients with HCC and Portal Vein Tumor Thrombus. Cardiovasc Intervent Radiol. 2020 Mar;43(3):411-422. doi: 10.1007/s00270-019-02404-5

B-NR

  • Retrospective single-center (Canada) study of patients with advanced HCC with PVTT treated with SIRT (resin or glass)
  • Cohorts treated with ablative intent transarterial radioembolization (A-TARE, n=21), or conventional technique (cTARE, n=36)
  • Dosimetry resin (partition model): >70 Gy to liver parenchyma with A-TARE, >100 Gy to tumor with cTARE
  • Dosimetry glass (MIRD model): >190 Gy to total volume with A-TARE, >120 Gy to total volume with cTARE
  • A-TARE was associated with longer median OS (45.3 vs 18.2 months; P = 0.003), longer post-treatment survival
  • (19.1 vs 4.9 months; P = 0.005), a 70% lower risk of death (hazard ratio 0.30; 95% CI, 0.13–0.70; P = 0.005), and improved 4-year survival (53.9% vs 11.2%) than cTARE.
  • Overall survival did not differ between resin and glass microspheres (27.5 vs 22.2 months; P = 0.62).
Van der Gucht et al. Resin versus glass microspheres for 90Y transarterial radioembolization: Comparing survival in unresectable hepatocellular carcinoma using pretreatment partition model dosimetry. J Nucl Med. 2017 Aug;58(8):1334-1340. doi: 10.2967/jnumed.116.184713

B-NR

  • Retrospective cohort study (prospectively collected data) (Switzerland) of patients with unresectable HCC treated with SIRT (resin or glass)
  • HBV: 12.2% in resin group, 8.3% in glass group. HCV: 29.3% in resin group, 19.4% in glass group
  • Median administered activity was calculated using the partition model for resin (1.8 GBq) and using 2-compartment model for glass (1.8 GBq)
  • In the resin group, 90Y tumor-absorbed dose was 160 Gy, normal liver-absorbed dose was 36 Gy
  • PFS and OS for resin were higher than for glass but not statistically significant
  • No survival differences were detected when BCLC stages early/intermediate and advanced were compared
  • BCLC staging and serum AFP were associated with PFS for glass only

 

 

Hermann et al. Relationship of tumor radiation-absorbed dose to survival and response in hepatocellular carcinoma treated with transarterial radioembolization with 90Y in the SARAH study. Radiology. 2020 Jun 30:191606. doi: 10.1148/radiol.2020191606

B-NR

  • Secondary analysis of SIRT patients from the multi-center (France) RCT of SIRT (resin) vs sorafenib
  • Liver function parameters for inclusion: bilirubin under or equals 50 µmol/L, AST or ALT under or equals 5 x ULN, INR under or equals 1.5
  • For the dose-survival group, median OS was 9.3 months, median tumor radiation-absorbed dose was 112 Gy, median tumor volume as 152 cm3, median injected 90Y activity was 1342 mBq 
  • Median OS was 14.1 months for patients who had ≥ 100 Gy tumor 
  • radiation-absorbed dose, and 6.1 months for patients who had <100 Gy
  • Strong predictors of survival were ≥ 100 Gy tumor radiation-absorbed dose, ALBI grade of A1 and tumor burden ≤25%
  • No difference existed between tumor radiation-absorbed dose and objective response at 6 months, but participants who achieved disease control had median tumor radiation-absorbed dose of 121 Gy while participants with progressive disease this dose was 85 Gy (P=0.02)
  • Grade 1 and 2 fatigue occurred more often in participants who received ≥100 Gy tumor radiation-absorbed dose (P=0.05)
  • Longest survival and highest disease control rate were achieved when participants received ≥100 Gy with optimal agreement between 99TmTc-MAA SPECT/CT and 90Y SPECT/CT or PET/CT agreement
Richetta et al. PET-CT post therapy dosimetry in radioembolization with resin 90Y microspheres: Comparison with pre-treatment SPECT-CT 99mTc-MAA results. Phys Med. 2019;64:16-23. doi: 10.1016/j.ejmp.2019.05.025

C-LD

  • Single-center (Italy) case series of HCC patients treated with SIRT (resin)
  • With the MIRD method, mean doses to tumor were 201.2 Gy and 216.11 Gy and mean normal liver doses were 48.1 Gy and 46.6 Gy for SPECT-CT and PET-CT
  • Using the Voxel method, mean doses to tumor were 203.3 Gy and 209.1 Gy and mean normal liver doses were 50.4 Gy and 46.3 Gy for SPECT-CT and PET-CT
  • Correlation between SPECT-CT and PET-CT dose was good
  • 90% of patients received mean tumor dose higher than 150 Gy
James et al. Differences in radiation activity between glass and resin 90Y microspheres in treating unresectable hepatic cancer. Health Phys. 2017;112(3):300-304. doi: 10.1097/HP.0000000000000631

C-LD

  • Retrospective case series analysis (USA) of HCC patients (and other malignancies) treated with SIRT (glass or resin)
  • For HCC, 40 patients received glass and 11 received resin microspheres
  • Actual and projected activity were calculated according to manufacturer’s formula
  • Average prescribed activity was 2.73 GBq for glass and 1.06 GBq for resin across all cancer types
  • In HCC patients, administered mean glass activity was 2.73 GBq, and projected resin activity, 1.12 Gbq. Administered resin activity was 1.12 Gbq and projected glass activity, 3.38 Gbq
Rodriguez et al. A descriptive analysis of remnant activity during 90Y resin microspheres radioembolization of hepatic tumors: Technical factors and dosimetric implications. Ann Nucl Med. 2016;30(3):255-61. doi: 10.1007/s12149-015-1052-9

C-LD

  • Single-center retrospective case series of patients with unresectable HCC (n=70) or liver metastases (n=7) treated with SIRT (resin)
  • Administered activity was calculated using the partition model (n=73) or BSA method (n=4), and calculated absorbed dose loss to implanted tumor was 12.2 Gy
  • Median IQR total activity was 1.3 GBq and total median loss was 0.1 GBq and increased 0.244 GBq when given in 3 split doses (<0.0001)
  • Split activity numbers were 1 (n=34) , 2 (n=33) or 3 (n=10)
  • No patient had visible stasis
Strigari et al. Efficacy and toxicity related to treatment of hepatocellular carcinoma with 90Y-SIR spheres: radiobiologic considerations. J Nucl Med. 2010;51(9):1377-85. doi: 10.2967/jnumed.110.075861

C-LD

  • Retrospective single-center (Italy) analysis of patients with HCC treated with SIRT (resin)
  • BSA empiric method used to calculate activity to treat whole liver (n=35) or lobes (right, n=35; left, n=3), but also developed a tumor to normal tissue ratio using activity counts
  • Administered activity was 1.00 GBq to 2.26 GBq, median 1,73 GBq; median liver dose was 36 Gy, with liver toxicity reported (≥grade 2, 31%; ≥grade 3, 21%; ≥grade 4, 11%)
  • Median absorbed doses per unit activity were 18 Gy/BGq to non-tumor liver and 60 Gy/BGq to tumor
  • LSF calculated and activity decreased by 20% or 40% as needed for high LSF
  • Tumor response was measured using RECIST and EASL and responses varied depending on criteria used
  • Mean dose needed to achieve CR was 150 Gy using EASL and 122 Gy for RECIST
Kafrouni et al. Retrospective voxel-based dosimetry for assessing the ability of the body-surface-area model to predict delivered dose and radioembolization outcome. J Nucl Med. 2018;59(8):1289-1295. doi: 10.2967/jnumed.117.202937

C-LD

  • Retrospective single-center (France) case series analysis of patients with HCC treated with SIRT (resin)
  • Activity was planned using the BSA method
  • Only 16 patients had treatment response data due to death of participant prior to the 6-month follow-up imaging
  • Using EASL criteria, 26 treatments resulted in 14 responding and 12 non-responding 
  • Median value of the average dose was 60 Gy, and only 6 case had tumor average dose >120 Gy; the dose to nontumor liver (NTL) was <50 Gy 
  • 62% of treatments had 120 Gy delivered to the tumor while keeping NTL and lung doses < 50Gy and 30 Gy respectively
  • Underdosing was related to the use of the BSA method

5. Ablative strategy should target a parenchymal exposure >70 Gy to the intended hepatic regions.

References: SIRT with resin microspheres in non-Asian regions

Article

Grade

Key Points

Cardarelli-Leite et al. Ablative Transarterial Radioembolization Improves Survival in Patients with HCC and Portal Vein Tumor Thrombus. Cardiovasc Intervent Radiol. 2020 Mar;43(3):411-422. doi: 10.1007/s00270-019-02404-5

B-NR

  • Retrospective single-center (Canada) study of patients with advanced HCC with PVTT treated with SIRT (resin or glass)
  • Cohorts treated with ablative intent transarterial radioembolization (A-TARE, n=21), or conventional technique (cTARE, n=36)
  • Dosimetry resin (partition model): >70 Gy to liver parenchyma with A-TARE, >100 Gy to tumor with cTARE
  • Dosimetry glass (MIRD model): >190 Gy to total volume with A-TARE, >120 Gy to total volume with cTARE
  • A-TARE was associated with longer median OS (45.3 vs 18.2 months; P = 0.003), longer post-treatment survival
  • (19.1 vs 4.9 months; P = 0.005), a 70% lower risk of death (hazard ratio 0.30; 95% CI, 0.13–0.70; P = 0.005), and improved 4-year survival (53.9% vs 11.2%) than cTARE.
  • Overall survival did not differ between resin and glass microspheres (27.5 vs 22.2 months; P = 0.62).

6. Post-treatment SPECT, PET-CT, or CT within 24 hours of SIRT may be used to confirm post-implantation dosimetry and predict radiographic response.

References: SIRT with resin microspheres in Asian regions

Article

Grade

Key Points

Kim et al. Usefulness of Bremsstrahlung images after intra-arterial Y-90 resin microphere radioembolization for hepatic tumors. Nucl Med Mol Imaging. 2011;45(1):59-67. doi: 10.1007/s13139-010-0066-4

C-LD

  • Single-center (Korea) case series of patients with unresectable HCC (n=18) or liver metastasis (n=2) treated with SIRT (resin)
  • Partition model was used to calculate the activity, which ranged from 0.28-2.86 GBq
  • Injected 90Y dose and liver count on bremsstrahlung images were significantly correlated, demonstrating this method of post-treatment imaging was able to confirm achievement of adequate dose delivery
Ng et al. Patient dosimetry for 90Y selective internal radiation treatment based on 90Y PET imaging. J Appl Clin Med Phys. 2013;14(5):212-21. doi: 10.1120/jacmp.v14i5.4371

C-LD

  • Retrospective single-center (Hong Kong) case series of patients with HCC (n=3) or colorectal liver metastases (n=2) treated with SIRT (resin)
  • Partition model was used to calculate the absorbed dose and injected activity ranges from 1-1.3 GBq with a mean target dose range of 51.7-163 Gy
  • A method computing 3D dose distributions was proposed using 90Y PET was performed 6 h after SIRT
Song et al. PET/CT-based dosimetry in 90Y-microsphere selective internal radiation therapy: Single cohort comparison with pretreatment planning on 99mTc-MAA imaging and correlation with treatment efficacy. Medicine (Baltimore). 2015;94(23):e945. doi: 10.1097/MD.0000000000000945

C-LD

  • Retrospective single-center (Korea) case series of patients with HCC (and other malignancies) treated with SIRT (resin microspheres)
  • Partition model (n=21) was used to calculate the injected activity (absorbed dose 2.1 BGq) except when the lung shunt fraction was high (>0.1), which used the BSA method (n=2) and reduced up to 40% according to manufacturer’s package insert (absorbed dose 1.7 BGq)
  • 99mTc SPECT/CT can be used as a conservative activity planning method
  • Stasis prevented full planned injected activity in 4 patients
  • PFS was 207 days, PFS was 286 days for patients with high absorbed dose (>200 Gy) and 92 days for patients with low absorbed dose (≤200Gy, P=0.046)
  • 90Y-PET-CT was effective method for post-SIRT dosimetry and prediction of treatment efficacy
Kim et al. Evaluation of early response to treatment of hepatocellular carcinoma with yttrium-90 radioembolization using quantitative computed tomography analysis. Korean J Radiol. 2019;20(3):449-458. doi: 10.3348/kjr.2018.0469

C-LD

  • Retrospective single-center (Korea) case series of patients with unresectable HCC treated with SIRT (resin)
  • Patient characteristics included hepatitis B (n=36), hepatitis C (n=4), B+C (n=1); Child Pugh A (n=43), B (n=1); ECOG 0 (n=26), ECOG 1 (n=18); BCLC A (n=5), B (n=22), C (n=17); unilobar (n=28), portal venous invasion (n=16), no previous HCC therapy (n=42)
  • 9 patients underwent hepatic resection and 1 had liver transplantation with curative intent
  • Estimated probabilities of PFS was 70.6% and 33.5% for 1-year and 2-year post-SIRT
  • CT completed 4 weeks after SIRT
  • RECIST identified SD in 41 patients and PR in 3; mRECIST identified SD in 34 and PR in 10

References: SIRT with resin microspheres in non-Asian regions

Article

Grade

Key Points

Debebe et al. 90Y SPECT/CT quantitative study and comparison of uptake with pretreatment 99mTc-MAA SPECT/CT in radiomicrosphere therapy. J Appl Clin Med Phys. 2019;20(2):30-42. doi: 10.1002/acm2.12512

C-LD

  • Retrospective case series (USA) using SIRT (resin)
  • A new technique was proposed for quantitative image improvement of post-treatment 90Y Bresmsstrahlung SPECT/CT with the goal of quantitative comparison between pre-treatment planning images and estimation of liver dosimetry
Gnesin 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(11):1672-1678. doi: 10.2967/jnumed.116.173104

C-LD

  • Retrospective single-center (USA) case series of patients with HCC (and other malignancies) treated with SIRT (glass or resin)
  • Glass microspheres used according to the manufacturer’s method and resin used BSA method to calculate activity to be administered
  • Delivered activity ranged from 0.7 GBq to 1.03 GBq with resin for HCC patients
  • Simultaneous PET/MR imaging was able to determine distribution within the liver, although this was not stratified by microsphere type
  • Average dose was useful in predicting response between responders and non-responders; and minimum dose to 70% of volume was useful in predicting response with vRECIST
  • Response was analyzed with RECIST and vRECIST
Fowler et al. PET/MRI of hepatic 90Y microsphere deposition determines individual tumor response. Cardiovasc Intervent Radiol. 2016;39(6):855-64. doi: 10.1007/s00270-015-1285-y

C-LD

  • Retrospective single-center (USA) case series of patients with HCC (and other malignancies) treated with SIRT (glass or resin)
  • Glass microspheres used according to the manufacturer’s method and resin used BSA method to calculate activity to be administered
  • Delivered activity ranged from 0.7 GBq to 1.03 GBq with resin for HCC patients
  • Simultaneous PET/MR imaging was able to determine distribution within the liver, although this was not stratified by microsphere type
  • Average dose was useful in predicting response between responders and non-responders; and minimum dose to 70% of volume was useful in predicting response with vRECIST
  • Response was analyzed with RECIST and vRECIST
Richetta et al. PET-CT post therapy dosimetry in radioembolization with resin 90Y microspheres: Comparison with pre-treatment SPECT-CT 99mTc-MAA results. Phys Med. 2019;64:16-23. doi: 10.1016/j.ejmp.2019.05.025

C-LD

  • Retrospective case series (USA) using SIRT (resin)
  • With the MIRD method, mean doses to tumor were 201.2 Gy and 216.11 Gy and mean normal liver doses were 48.1 Gy and 46.6 Gy for SPECT-CT and PET-CT
  • Using the Voxel method, mean doses to tumor were 203.3 Gy and 209.1 Gy and mean normal liver doses were 50.4 Gy and 46.3 Gy for SPECT-CT and PET-CT
  • Correlation between SPECT-CT and PET-CT dose was good
  • 90% of patients received mean tumor dose higher than 150 Gy

7. Safety and tolerability of combinatorial therapies (locoregional and systemic) has been shown, however further evidence is currently lacking and, as a result, the specific sequence of therapies as relating to SIRT is at the discretion of the multidisciplinary review.

References: SIRT with resin microspheres in Asian regions

Article

Grade

Key Points

Chow et al. Multicenter phase II study of sequential radioembolization-sorafenib therapy for inoperable hepatocellular carcinoma. PLoS One. 2014;9(3):e90909. doi: 10.1371/journal.pone.0090909

B-NR

  • Multi-center open-label single-arm Phase II study conducted in Malaysia, Myanmar, Singapore and South Korea on patients with unresectable HCC (with or without macrovascular invasion) receiving resin microspheres
  • Patient characteristics included BCLC B/C (n=11/18); Child Pugh A/B (n=20/9); total bilirubin > 1.2 mg/dL (n=4), albumin <35 g/L (n=12)
  • Sorafenib initiated 14 days post-SIRT
  • Median activity delivered (IQR) was 3.0 GBq to whole liver (n=20) or right lobe (n=9)
  • Median sorafenib day dose per patients (IQR) was 600.0 mg taken for a median of 4.1 months; 11 patients received more than 80% of the planned dose of 400 mg twice daily
  • Best overall response was CR or PR in 7 of 28 patients, disease control rate was 79%
  • Median PFS and OS were 15.2 and 20.3 months for BCLC B and 6.5 and 8.6 months for BCLC C, respectively
  • 15 of 29 patients experienced ≥3 toxicities following treatment
  • Sequential radioembolization-sorafenib has potential efficacy and manageable toxicity
Irani et al. A phase II open-label, single centre, non-randomised trial of Y90-radioembolization in combination with nivolumab in Asian patients with advanced hepatocellular carcinoma: an interim analysis. CIRSE 2019; Abstract 2207.5.

B-NR

  • Single-arm, 2-stage, Phase II trial conducted in Singapore on patients with advanced HCC receiving SIRT combined with nivolumab
  • 11 patients: 7 (63.6%) BCLC B and 4 (36.4%) BCLC C.
  • After Y90 RE (Day1), Nivolumab 240mg IV infusion was given on Day 21 and continued every 2 weeks
  • 5 responders: median duration 29 weeks (longest 36 weeks)
  • 6 patients terminated study: TTP 9.1 to 36.6 weeks
  • Adverse events: Steven Johnson syndrome (n=1), Grade 3 fever (n=1) and Grade 3/4 ALT/AST rise (n=1). 
  • No treatment-related deaths
Wang et al. Combined Yttrium-90 microsphere selective internal radiation therapy and external beam radiotherapy in patients with hepatocellular carcinoma: From clinical aspects to dosimetry. PLoS One. 2018;13(1):e0190098. doi: 10.1371/journal.pone.0190098

C-LD

  • Retrospective single-center (Taiwan) case series 22 patients with unresectable HCC treated with EBRT after receiving SIRT (resin)
  • Patient characteristics include ECOG 0/1/2 (n=4/16/2) before EBRT, treatment naïve (n=4), prior treatment, including surgical resection, RFA, TACE and chemotherapy (n=18); chronic hepatitis B/C/B+C (n=17/2/2); Child Pugh A prior to SIRT (n=22)
  • SIRT was segmental (n=19) or whole liver (n=3)
  • Mean activity administered was 1.50 BGq; tumor absorbed dose was 115.8 Gy and dose to liver was 39.6 Gy
  • Mean days between SIRT and EBRT was 214 days
  • Mean prescribed dose of EBRT was 42.3 Gy in 14 fractions and targeted residual tumor (n=12), PVT (n=11, 6 should improvement after EBRT), and perihilar lymphadenopathies (n=4)
  • Actual delivered mean target and normal liver absorbed dose of EBRT was 42.3 Gy and 11.7 Gy; 3 patients did not complete RT
  • 1-, 2-, and 3-year overall survival at were 59.8%, 47.9%, and 47.9%
  • Median OS was 477 days
  • Median survival for Child Pugh A prior to EBRT was better than for Child Pugh B or C (P=0.01)
  • Tumor response 3 months after EBRT included PR (n=5), CR (n=4), PD (n=6) and new lesions were found in 7 patients
  • >Grade 2 liver toxicities developed in 8 patients; Grade 5 liver failure toxicity occurred in 5 patients
  • 7 patients had chronic hepatitis B infection and 1 had B+C; 6 were treated with antivirals, 1 had persistent low HBV titers
Kwon et al. Safety and Efficacy of Transarterial Radioembolization Combined with Chemoembolization for Bilobar Hepatocellular Carcinoma: A Single-Center Retrospective Study. Cardiovasc Intervent Radiol. 2018 Mar;41(3):459-465. doi: 10.1007/s00270-017-1826-7

C-LD

 

  • Retrospective single-center (Korea) case series analysis of 19 patients treated with combined SIRT (resin) and TACE for bilobar HCC (HCV 5.3%, HBV 89.5%)
  • For each patient, SIRT was used to treat a large, dominant HCC tumor in one lobe, while TACE was used for small nodules(s) in the other lobe
  • Median overall survival (OS) was 28.0 months (range 3–39 months) and median time-to-progression was 9.0 months (range 1–37 months) 
  • Procedure-related complications were mild and improved with conservative management
  • Combined SIRT and TACE appears to be safe and effective treatment for bilobar HCC
Cheng et al. Chinese Expert Consensus on Multidisciplinary Diagnosis and Treatment of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus (2018 Edition). Liver Cancer 2020;9:28–40, doi: 10.1159/000503685

C-EO

  • Clinical consensus statement from experts in China on HCC with PVTT
  • Doctors in China tend to use more curable treatments for PVTT patients 
  • PVTT should be diagnosed with Cheng’s classification
  • Different multidisciplinary treatments are recommended taking into account liver function (Child–Pugh), resectability, extrahepatic metastasis, and extent of PVTT
  • Surgery is the preferred option for patients with type I/II PVTT. Type III can undergo resection after downstaging with TACE and/or radiotherapy
  • SIRT is recommended for patients with unresectable primary tumors; PVTT types I–III; and Child–Pugh A liver function

References: SIRT with resin microspheres in non-Asian regions

Article

Grade

Key Points

Ricke et al. Safety and toxicity of radioembolization plus Sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC. Liver Int. 2015;35(2):620-6. doi: 10.1111/liv.12622

B-R

  • Multi-center open-label RCT conducted in Europe on HCC patients with or without PVT treated with resin microspheres
  • Both arms received sorafenib 200 mg twice daily for 1 week before increasing the dose to sorafenib 400 mg twice daily
  • Sorafenib initiated 3 days after SIRT 
  • Patient characteristics included ECOG 0/1 (n=27/13); Child Pugh 5/6-7/unknown (n=30/7/3), BCLC B/C (n=14/26); treatment naïve (n=30) 
  • BSA method was used to calculate activity; median activity 1.87 BGq administered only to the SIRT+sorafenib arm either sequentially (n=10) or to right (n=7) or left lobe (n=3)
  • Median daily sorafenib dose was 614 mg over median of 8.5 months for the SIRT+sorafenib arm and 557 mg over 9.6 months in the sorafenib arm
  • Percentage of AEs were similar between groups or in grade 3/4 toxicities
Ricke et al. Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma. J Hepatol. 2019;71(6):1164-1174. doi: 10.1016/j.jhep.2019.08.006

B-R

  • Multi-center open-label RCT conducted in Europe and Turkey on patients with advanced HCC treated with resin microspheres
  • The combination of SIRT and sorafenib was not associated with a significant improvement in OS compared with sorafenib alone 
  • Both arms received sorafenib 200 mg twice daily for 1 week before increasing the dose to sorafenib 400 mg twice daily
  • Sorafenib initiated 3 days after SIRT 
  • Patients were allocated to SIRT+sorafenib (SS, n=216) or sorafenib (S, n=208)
  • Patient characteristics include cirrhosis (SS, n=165; S, n=164); hepatitis B/C (SS, n=17/58; S, n=24/48), Child Pugh A/B (SS, n=190/21; S, n=190/17) BCLC A/B/C (SS, n=6/62/143; S, n=3/62/141, bilobar (SS, n=96; S, n=99), portal vein invasion (SS, n=91; Sn=90)
  • No differences were detected in the percentage of prior treatments for each treatment, including TACE, TAE, resection, RFA, Brachytherapy, others
  • Mean ALBI score of the safety population was -2.5 for SS and -2.4 for S
  • No differences were detected in the median daily doses of sorafenib between arm
  • Median OS was 12.1 months and 11.2 months, respectively
  • Per protocol subanalyses suggested survival benefit for patients in SIRT+sorafenib arm when they were ≤ 65 years old (P=0.046), non-cirrhotic (P=0.013) and had non-alcoholic etiology (P=0.009)
  • More Grade 3-4 AEs were reported by patients in the SIRT+sorafenib arm and in the sorafenib arm (64.8% vs 53.3%, P=0.036), 2 patients from each arm had Grade 5 AEs
  • SAEs: 63 patients in SIRT+sorafenib arm and 70 patients in sorafenib arm
Katsanos et al. Comparative Effectiveness of Different Transarterial Embolization Therapies Alone or in Combination With Local Ablative or Adjuvant Systemic Treatments for Unresectable Hepatocellular Carcinoma: A Network Meta-Analysis of Randomized Controlled Trials. PLoS One 2017 Sep 21;12(9):e0184597, doi: 10.1371/journal.pone.0184597

B-NR

  • Systematic review of TACE alone or combined with ablative or adjuvant systemic therapies for treating patients with unresectable HCC
  • Survival benefit was similar between TACE and TAE, with providing a significant benefit over best supportive therapy.
  • TACE combined with either radiotherapy or ablation performed better than TACE alone
  • TACE and TAE resulted in a strong response rate compared to control treatment. TACE combined with chemotherapy or ablation was better than TACE alone
  • SIRT was the safest treatment; TACE combined with adjuvant systemic therapies had the highest risk
  • TACE, DEB-TACE, SIRT, and adjuvant systemic agents neither improved tumor objective response nor conferred patient survival compared to TAE
  • Quality of evidence is low to moderate regarding the combination of treatments
  • There is an absence of trials with direct comparative evidence of the various combinations of treatments
Golfieri et al. Efficacy of radioembolization according to tumor morphology and portal vein thrombosis in intermediate-advanced hepatocellular carcinoma. Future Oncol. 2015;11(23):3133-42. doi: 10.2217/fon.15.267

B-NR

  • Retrospective single-center cohort study (Italy) of unresectable HCC to evaluate the efficacy and safety of SIRT treatment (resin) with relation to tumor morphology and extent of portal vein thrombosis (PVT)
  • Retrospective analysis of 104 patients (80.8% HBV/HCV) with unresectable HCC treated with SIRT. ~60% had advanced BCLC stage C HCC, 50.0% had PVT, and 29.8% had infiltrative tumor morphology 
  • There was no significant difference in median overall survival (OS) between patients with segmental and patent portal vein PVT (17 months for both). However, OS did differ significantly between patients with patients with segmental PVT and lobar or main PVT (p = 0.031)
  • Survival was more dependent on disease stage and liver function than size, number, distribution or morphology of the tumors
  • There was no significant difference in median OS between patients with a nodular pattern of HCC and patients with an infiltrative pattern
  • Prior TACE treatment and a treatment response at 3 months were both significantly correlated with improved OS
Sangro et al. Radioembolisation in patients with hepatocellular carcinoma that have previously received liver-directed therapies. Eur J Nucl Med Mol Imaging. 2018;45(10):1721-1730. doi: 10.1007/s00259-018-3968-5

C-LD

  • Retrospective multi-center (Germany, Italy, Spain) cohort study of 325 patients with HCC treated with SIRT (resin)
  • Patient characteristics included cirrhosis (78.5%), Child Pugh A (82.5%), multinodular (75.9%), bilobar (53.1%) portal vein (23.3%); ECOG ≥1 (45.8%); BCLC C (56.3%)
  • SIRT was first-line (n=187), second line (n=111), or > second line (n=27)
  • Prior procedures included TACE or TAE (n=88) resection or LT (n=56) and ablation (n=28)
  • Cirrhosis at baseline incidence was lower in prior post surgical group than other subgroups of treatment (vascular, ablation or SIRT, P=0.002)
  • Treatment was more likely to be delivered as whole liver or whole remnant in ≥ second line (P=0.01)
  • High activity was delivered to treatment naïve (median 1.7 GBq vs 1.5 GBq, P=0.003) 
  • No survival advantage was found for number or type of prior treatments or BCLC stage
  • No difference in safety between prior treatment groups
Mahvash et al. Yttrium-90 resin microspheres as an adjunct to sorafenib in patients with unresectable hepatocellular carcinoma. J Hepatocell Carcinoma. 2016;3:1-7. doi: 10.2147/JHC.S62261

C-LD

  • Retrospective single-center case series of HCC patients (USA) receiving SIRT with resin microspheres during sorafenib treatment
  • Patient characteristics included hepatitis B/C (n=4/3); PVT (n=7), AFP> 400 ng/mL (n=6); ECOG 0/1 (n=6/13); Child Turcotte Pugh  A/B (n=16/3); prior to sorafenib prior treatments include systemic therapy (n=4) 
  • Patients received sorafenib for a median of 224 days, 10 received reduced dose due to toxic effect prior to SIRT
  • Post SIRT treatments included DEB-TACE, glass Y-90 SIRT, hepatic arterial infusion therapy or systemic therapy
  • Median activity delivered was 41.2 mCi to whole liver (n=12) or lobe (n=7)
  • No >grade 4 AEs were reported within 90 days of SIRT
  • Using RECIST, tumor responses were SD (n=17) and PR (n=4); EASL, SD (n=13) and PR (n=8)
  • Median OS was 19.52 months; median PFS was 6.63 months, median hepatic PFS was 7.82 months. OS and PFS were superior to those in studies with sorafenib alone in similar patients
Rana et al. Yttrium-90 radioembolization in patients with hepatocellular carcinoma who have previously received sorafenib. Front Oncol. 2013;3:323. doi: 10.3389/fonc.2013.00323

C-LD

  • Retrospective single-center case series of HCC patients (USA) receiving SIRT with resin microspheres after sorafenib
  • Patient characteristics included Child Pugh A/B (n=7/3); BCLC C (n=10), PVT (n=3)
  • Prior treatments included TACE (n=3), hepatectomy (n=1)
  • Sorafenib was given prior to SIRT (n=1) or continued use peri-SIRT (n=9)
  • Treatments were given to right lobe (n=8 procedures), left (n=7 procedures) mean activity administered 27.82 mCi, dose to liver lobe was 35.95 Gy
  • Using RECIST, tumor responses were PR (n=3), SD (n=6) and PD (n=1, who died 6 weeks after SIRT)
  • OS correlated with tumor and necrosis response (P=0.009); Median OS for SD was 30 weeks, not reach for PR. OS was lower than that reported in the literature on SIRT alone or sorafenib alone, possibly due to this study including more advanced patients
  • Median PFS was 10 weeks
  • AFP values for 3 who had >400 ng/mL before first SIRT had >20% response in AFP at first follow up
  • No patient reported grade≥4 acute clinical or biochemical toxicities
Zhan et al. Safety of combined yttrium-90 radioembolization and immune checkpoint inhibitor immunotherapy for hepatocellular carcinoma. J Vasc Interv Radiol. 2020;31(1):25-34. doi: 10.1016/j.jvir.2019.05.023

C-LD

  • Retrospective single-center case series of HCC patients (USA) receiving SIRT with resin or glass microspheres
  • Patient characteristics: HBV (31%), HCV (35%), HBV+HCV (0.04%); Child Pugh A/B7 (n=20/6); ALBI grade 1/2 (n=6/20); BCLC C (n=21) of which 14 had macrovascular invasion; prior locoregional therapy (n=11); prior sorafenib (n=4)
  • Lobar administration (n=32 procedures) with a median dose of 122 Gy
  • Segmental (n=12 procedures) with a median dose of 138 Gy
  • Median activity to treated site 1.8 GBq
  • Intravenous nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity; 6 patients receive dual treatment with ipilimumab 1 mg/kg every 6 weeks
  • Target tumor response was CR for 7 patients, PR for 13 patients 4 had stable disease, and 1 progressed
  • Median OS from first immunotherapy was 17.2 months and from first SIRT was 16.5 months, no patient characteristics were found to affect OS
  • Time to tumor progression was 5.7 months and PFS was 5.7 months, no patient characteristics were found to affect PFS or TTP
  • Use of immunotherapy in combination with SIRT appears safe
Fong and Tanabe. The Clinical Management of Hepatocellular Carcinoma in the United States, Europe, and Asia: A Comprehensive and Evidence-Based Comparison and Review. Cancer 2014 Sep 15;120(18):2824-38, doi: 10.1002/cncr.28730

Guidelines

  • Review of 3 clinical practice guidelines: NCCN, EASL–EORTC, and AOS
  • They are fairly similar, with variances in surveillance and treatment due to regional variations in disease
  • Diagnostic criteria remains controversial, especially for lesions <1 cm
  • EASL-EORTC uses BCLC staging; NCCN uses resectability; and AOS uses determinants of survival
  • Recommended treatment in all 3 is sorafenib for HCC that is not amenable to resection, ablation, or transplantation with well preserved liver function
  • A multidisciplinary team that includes surgeons, medical oncologists, hepatologists, radiologists, and pathologists is key in management of patients with HCC
Song et al. The management of hepatocellular carcinoma around the world: a comparison of guidelines from 2001 to 2011. Liver Int 2012 Aug;32(7):1053-63, doi: 10.1111/j.1478-3231.2012.02792.x

Guidelines

  • Systematic review of 17 clinical practice guidelines which used diagnostic algorithms that were either size-based, non-size-based, or had no detailed criteria
  • Diagnosis can be carried out by imaging, serological tests, and histology, the latter being the one with least differences between guidelines
  • Guidelines differ regarding the appropriateness of candidates for surgery
  • Interval for surveillance differs between guidelines
  • The participation of a multidisciplinary team including hepatologists, pathologists, radiologists, surgeons and oncologists is recommended by 3 of the guidelines

8.  Antiviral treatment to prevent reactivation of hepatitis B and (to a lesser extent) hepatitis C infection should start prior to SIRT and continue on maintenance therapy as per standard of care.

References: SIRT with resin microspheres in non-Asian regions

Article

Grade

Key Points

Jun et al. Hepatitis B virus reactivation after radiotherapy for hepatocellular carcinoma and efficacy of antiviral treatment: A multicenter study. PLoS One. 2018;13(7):e0201316. doi: 10.1371/journal.pone.0201316

B-NR

  • Retrospective multi-center (7) cohort study conducted in Korea on HBV-HCC patients treated with conformal radiotherapy or SBRT
  • HBV reactivation occurred in 12.7% of patients after RT
  • Incidence rates of HBV reactivation, hepatitis, and hepatitis due to HBV reactivation were lower for those on antiviral treatment than for those without antiviral treatment (7.5% vs 33%); thus, antiviral therapy can reduce HBV reactivation and complications after RT
  • No difference in incidence rates of RILD or RILD due to HBV reactivation for those on antiviral treatment and no antiviral treatment
  • Non-antiviral treatment and combined RT with TACE were associated with HBV reactivation
Jang et al. Risk of HBV reactivation according to viral status and treatment intensity in patients with hepatocellular carcinoma. Antivir Ther. 2011;16(7):969-77. doi: 10.3851/IMP1840

B-NR

  • Prospective multi-center cohort study (Korea) of patients with newly diagnosed HBV-related unresectable HCC
  • Patients were antiviral treatment naïve and allocated to 4 groups: TACE using adriamycin (n=93); TACE using epirubicin and cisplatin (n=26); RT+TACE-EC (n=43); or local ablation therapy (LAT, n=43; 7 with percurtaneous ethanol injection [PEIT] and 36 with RFA)
  • Median radiation dose was 49.8 Gy
  • 62 patients experienced HBV reactivation and 32 had HBV reactivation with hepatitis; all 32 patients received antiviral therapy and 10 developed hepatic decompensation; 1 died at 40 days after HBV reactivation of hepatic failure
  • Trend was found with increasing incidence of HBV reactivation with increasing intensity of LRT (P<0.001)
  • 22 of 30 patients with HBV reactivation only had antiviral therapy when clinically warranted
Kim et al. Hepatitis B virus reactivation after three-dimensional conformal radiotherapy in patients with hepatitis B virus-related hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2007;69(3):813-9. doi: 10.1016/j.ijrobp.2007.04.005

B-NR

  • Retrospective single-center cohort study (Korea)
  • The cumulative RILD rates were 12.5% and 21.8% for patients who received conformal radiotherapy (CRT) with and without antiviral medication, respectively
  • The cumulative rate of HBV reactivation was significantly higher in patients who did not received antiviral medication during CRT than those who did (21.8% vs 0%)
  • The cumulative rate of chronic hepatitis B exacerbation did not differ between patients treated with and without antiviral medication during CRT
  • Exacerbation of chronic hepatitis B in 4 patients had RILD features but differentiated by serum HBV DNA changes; 2 of these patients after CRT required antiviral therapy and recovered with lamivudine therapy
  • Chronic hepatitis B exacerbation should be considered in a differential diagnosis of RILD and antiviral therapy to prevent liver function deterioration after RT
Chou et al. Radiation-induced hepatitis B virus reactivation in liver mediated by the bystander effect from irradiated endothelial cells. Clin Cancer Res. 2007;13(3):851-7. doi: 10.1158/1078-0432.CCR-06-2459

C-LD

  • Cell-culture (Taiwan) and before/after radiation serology study
  • All HBV carriers received median dose of 45 Gy, range 40-50.4 Gy had an increase in viral load with a median post/preradiotherapy ratio of 4.8. 
  • Non-specific increase in IL-6 in patients undergoing liver directed radiotherapy and increase in HBV DNA correlated with cytokine activity changes
  • None of the HBV carriers had antiviral agents between sera collections
Huang et al. Risk factors for hepatitis B virus reactivation after conformal radiotherapy in patients with hepatocellular carcinoma. Cancer Sci. 2014;105(6):697-703. doi: 10.1111/cas.12400

C-LD

  • Retrospective multi-center (3) case series conducted in China
  • HBV reactivation rate after radiotherapy was 24.6% with the majority of reactivation occurring at 8 and 12 weeks (11.6% and 8.6%, respectively)
  • HBV reactivation-induced hepatitis rate was 21.7%, all of whom received lamivudine antiviral therapy 100 mg/day after diagnosis
  • HBV DNA level, normal liver volume, V20, and mean dose significantly correlated with HBV reactivation and were prognostic factors of HBV reactivation
Wang et al. Combined Yttrium-90 microsphere selective internal radiation therapy and external beam radiotherapy in patients with hepatocellular carcinoma: From clinical aspects to dosimetry. PLoS One. 2018;13(1):e0190098. doi: 10.1371/journal.pone.0190098

C-LD

  • Retrospective single-center (Taiwan) case series 22 patients with unresectable HCC treated with EBRT after receiving SIRT (resin)
  • Patient characteristics include ECOG 0/1/2 (n=4/16/2) before EBRT, treatment naïve (n=4), prior treatment, including surgical resection, RFA, TACE and chemotherapy (n=18); chronic hepatitis B/C/B+C (n=17/2/2); Child Pugh A prior to SIRT (n=22)
  • SIRT was segmental (n=19) or whole liver (n=3)
  • Mean activity administered was 1.50 BGq; tumor absorbed dose was 115.8 Gy and dose to liver was 39.6 Gy
  • Mean days between SIRT and EBRT was 214 days
  • Mean prescribed dose of EBRT was 42.3 Gy in 14 fractions and targeted residual tumor (n=12), PVT (n=11, 6 should improvement after EBRT), and perihilar lymphadenopathies (n=4)
  • Actual delivered mean target and normal liver absorbed dose of EBRT was 42.3 Gy and 11.7 Gy; 3 patients did not complete RT
  • 1-, 2-, and 3-year overall survival at were 59.8%, 47.9%, and 47.9%
  • Median OS was 477 days
  • Median survival for Child Pugh A prior to EBRT was better than for Child Pugh B or C (P=0.01)
  • Tumor response 3 months after EBRT included PR (n=5), CR (n=4), PD (n=6) and new lesions were found in 7 patients
  • >Grade 2 liver toxicities developed in 8 patients; Grade 5 liver failure toxicity occurred in 5 patients
  • 7 patients had chronic hepatitis B infection and 1 had B+C; 6 were treated with antivirals, 1 had persistent low HBV titers
Taiwan groups. Management consensus guideline for hepatocellular carcinoma: 2016 updated by the Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan. J Formos Med Assoc 2018 May;117(5):381-403, doi: 10.1016/j.jfma.2017.09.007

C-EO

  • Clinical consensus statement by experts from Taiwan on HCC
  • BCLC should be used for prognostic prediction but other systems may be used in subgroups
  • Prevention: vaccination for HBV, antiviral therapy (HBV, HCV), nucleotide/nucleoside analogues and interferon-based therapies
  • SIRT is considered for:
  • BCLC C stage patients with PVT
  • Patients with major portal vein invasion, large tumor burden, or refractory to TACE
Park et al. Multidisciplinary Management of Nonresectable Hepatocellular Carcinoma. Oncology 2011;81 Suppl 1:134-40, doi: 10.1159/000333276

C-EO

  • Clinical consensus statement by experts from Asia-Pacific region on unresectable HCC
  • Unresectable HCC consists of subcategories of locally advanced HCC and the disease with extrahepatic spread
  • Locally advanced HCC was subdivided into 4 categories: nodular, massive with intrahepatic metastasis, diffuse, and vascular invasion (hepatic, portal vein). Clear definitions are needed
  • Preemptive antiviral therapy is key in combined therapies to prevent reactivation of HBV and exacerbation of viral hepatitis
  • There is a lack of evidence on multidisciplinary management of HCC with combinations of locoregional therapies
Asia–Pacific Working Party on Prevention of Hepatocellular Carcinoma. Prevention of hepatocellular carcinoma in the Asia–Pacific region: Consensus statements. J Gastroenterol Hepatol 2010 Apr;25(4):657-63, doi: 10.1111/j.1440-1746.2009.06167.x

C-EO

  • Clinical consensus statement by experts from Asia-Pacific region on HCC
  • Universal HBV vaccination is the most important preventive strategy against HBV-related HCC
  • Blood products should be tested for HBV and HCV and universal precautions should be taken to avoid transmission of blood-borne viruses in healthcare settings
  • Antiviral therapy is key in chronic HBV and HCV, although the latter maintains a higher risk
  • Antiviral therapy for hepatitis C complicating HCC can prevent late HCC recurrence after surgical resection
Korean Liver Cancer Study Group and Korean National Cancer Center. 2014 KLCSG-NCC Korea Practice Guideline for the Management of Hepatocellular Carcinoma. Gut Liver 2015 May 23;9(3):267-317, doi: 10.1110.5009/gnl14460

C-EO

  • Clinical practice guideline from experts in Korea on suspicious or newly diagnosed HCC
  • Staging followed mUICC system and BCLC was considered complementary
  • Antiviral therapy is recommended for HBV-infected patients undergoing TACE, HAIC, resection, or EBRT
  • Local ablation, TACE, and sorafenib are recommended for defined cases
  • Tumor response should be assessed with mRECIST and RECIST
  • SIRT can be performed safely in patients with PVTT, and outperforms TACE in downstaging HCC patients with UNOS T3 to T2
  • The role of SIRT is mentioned regarding downstaging and its safety for patients with PVTT but no recommendations are made on its use

References: SIRT with resin microspheres in non-Asian regions

Article

Grade

Key Points

Kamp et al. Direct-acting antivirals improve overall survival in interventional oncology patients with hepatitis c and hepatocellular carcinoma. J Vasc Interv Radiol. 2020;31(6):953-960. doi: 10.1016/j.jvir.2019.12.809

B-NR

  • This study (USA) did not identify SIRT specifically
  • HCV patients receiving direct-acting antivirals (DAA) had longer survival (49.2 months) than those not receiving DAA (18.5 months)
  • OS was longest (71.8 months) for patients who achieved 12-week sustained virologic response (SVR12) after DAA (26.7 months in the non-SVR12 group) 
  • Treatment type, DAA use and achieving SVR12 were independently associated with OS

9. Mitigation of toxicity and adverse events related to SIRT requires meticulous attention to patient selection, angiographic morphology, vascular optimization and accurate dosimetry.

10.  Determination of timing of downstaging to transplant or surgically resectable eligibility should be at the discretion of the surgeon.

11.  SIRT may extend the indications of embolic therapy beyond conventional TACE-eligible patients, subject to multidisciplinary review, such as patients with presence of a large tumors and/or portal vein invasion.

References: SIRT with resin microspheres in Asian regions

Article

Grade

Key Points

Zhang et al. Transarterial Y90 radioembolization versus chemoembolization for patients with hepatocellular carcinoma: A meta-analysis. Biosci Trends 2015 Oct;9(5):289-98, doi: 10.5582/bst.2015.01089

B-NR

  • Systematic review and meta-analysis of studies (USA, China, Germany, and Egypt) on intermediate- and advanced-stage HCC
  • In most cases, HCC was a result of HCV (ranging 13%–86%) and alcohol
  • Y90 SIRT improved survival compared with TACE, reducing risk of death by 26% and leading to higher 3-year OS (no differences in 1- and 2-year OS) 
  • No statistical difference was found in tumor control between SIRT and TACE
  • Hospitalization time with SIRT was shorter than with TACE
  • Time to progression was better with SIRT, with a 39% risk reduction
  • SIRT led to lower abdominal pain than TACE
Ho et al. Partition model for estimating radiation doses from yttrium-90 microspheres in treating hepatic tumours. Eur J Nucl Med. 1996;23:947–52. doi: 10.1007/BF01084369

C-LD

  • Single-center (Hong Kong) case series of 14 patients with HCC treated with SIRT (resin)
  • 99mTc MAA scintigraphy is used to estimate percentage of activity shunted to the lung and the T/N ratio
  • MIRD was used to compute radiation doses
  • The partition model was used for estimating the radiation doses to the tumor and normal liver
  • Total activity of Y90 administered ranged from 2 to 7 GBq with a median of 3 GBq. Estimated activity shunted into the pulmonary system ranged 0.044–0.798 GBq, with a median of 0.219 GBq
Chen et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with intermediate and advanced/relapsed hepatocellular carcinoma. Ann Oncol 2020 Mar;31(3):334-351, doi: 10.1016/j.annonc.2019.12.001

C-LD

  • Clinical practice guideline on intermediate and advanced/relapsed HCC by experts from Asia and Europe
  • SIRT can be considered for:
  • Intermediate- or advanced-stage HCC without extrahepatic disease: as first-line therapy alternative to TACE
  • As an alternative for selected TACE-failed BCLC B or non-metastatic BCLC C patients. SIRT results in similar survival outcomes and better ORR and QoL compared to sorafenib in these patients
  • For non-metastatic HCC with macrovascular invasion, which has shown benefit in some Asian studies, as well as other locoregional therapies (TACE, resection, HAIC)
  • Advanced, non-metastatic patients: as locoregional therapy
  • There is limited evidence on the improved benefit of using mRECIST over RECIST for predicting overall survival
Park et al. Consensus for Radiotherapy in Hepatocellular Carcinoma from The 5th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014): Current Practice and Future Clinical Trials. Liver Cancer 2016;5:162-174. doi: 10.1159/000367766

C-LD

  • Clinical consensus statement on unresectable HCC by experts from China, Hong Kong, South Korea, Singapore, Taiwan

SIRT is considered in the following cases:

  • Early-stage HCC (BCLC A): for bridging treatment for liver transplantation
  • Intermediate-stage HCC (BCLC B: for bilobar, multinodular or large tumor burden, and also to treat patients after conventional TACE has failed. SIRT is also mentioned as a possible neoadjuvant treatment but there is limited data
  • Advanced-stage HCC (BCLC C): for patients with vascular invasion and liver-dominant metastatic HCC

SIRT is also acknowledged as:

  • Leading to favorable results regarding downsizing and objective response compared to TACE in some studies (intermediate HCC)
  • Not associated with a strong embolic effect and, therefore, not contraindicated for patients with tumor thrombosis of major portal veins (advanced HCC)

Adverse events less likely with SIRT than TACE, but there are SIRT-specific complications

  • SIRT contraindicated in tumor/normal liver ratios and high hepatopulmonary shunts
Omata et al. Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int (2017) 11:317–370, doi: 10.1007/s12072-017-9799-9

C-LD

  • Clinical practice guideline by experts from Japan, Taiwan, South Korea, China, India, Pakistan, Indonesia, Philippines on HCC
  • TACE was mainly recommended for patients with unresectable, large/multifocal HCC with no vascular invasion or extrahepatic spread; also, for patients with small tumors in whom ablation is complicated
  • SIRT with Y-90 may be used as an alternative to TACE for unresectable HCC
  • SIRT is considered for:
  • Unresectable HCC: as an alternative locoregional therapy
  • Patients who are not suitable candidates for TACE due to bulky tumor and/or portal vein invasion

References: SIRT with resin microspheres in non-Asian regions

Article

Grade

Key Points

Pitton et al. Randomized comparison of selective internal radiotherapy (SIRT) versus drug-eluting bead transarterial chemoembolization (DEB-TACE) for the treatment of hepatocellular carcinoma. Cardiovasc Intervent Radiol. 2015;38(2):352-60. doi: 10.1007/s00270-014-1012-0

B-R

  • Single-center (Germany) pilot RCT of patients with unresectable HCC treated with SIRT (resin) or DEB-TACE
  • Patient characteristics included hepatitis B/C (SIRT, n=0/5; TACE, n=1/4); Child Pugh A/B/C (SIRT, n=10/2/0; TACE, n=9/3/0); BCLC A/B (SIRT, n=0/12; TACE, n=1/11)
  • Body surface model used to calculate activity to treat lobes, either singly (n=4) sequential treatments (n=8) were 4 weeks apart
  • DEB-TACE performed with maximal 150 mg doxorubicin per session for a median of 3.8 session within an interval of 48.2 days between session
  • Administer activity for SIRT was 1.847 GBq
  • No differences in TTP, PFS and OS between groups
Casadei Gardini  et al. Radioembolization versus chemoembolization for unresectable hepatocellular carcinoma: a meta-analysis of randomized trials. Onco Targets Ther. 2018;11:7315-7321. doi: 10.2147/OTT.S175715

B-R

  • Meta-analysis of RCTs (USA and Europe) of patients with unresectable HCC treated with SIRT (resin or glass) or TACE
  • 3 studies identified HCC patients treated with SIRT (n=49) or TACE (n=48)
  • Significant heterogeneity was found between the trials for PFS and no heterogeneity was found for OS, DCR or transplantation rate
  • No significant differences were found between outcomes (PFS, OS, DCR or transplantation rates for patients treated with either
Facciorusso et al. Transarterial radioembolization vs chemoembolization for hepatocarcinoma patients: A systematic review and meta-analysis. World J Hepatol. 2016;8(18):770-8. doi: 10.4254/wjh.v8.i18.770

B-NR

  • Meta-analysis of 2 RCTs and 8 observational studies with clinical data for 1557 HCC patients treated with SIRT (n=461) (glass or resin) or TACE (n=1096)
  • The 2-year and 3- year survival rates were longer for patients treated with SIRT than with TACE (P=0.01, P=0.04)
  • PFS rate was higher for patients treated with SIRT than with TACE at 1 year (P=0.02)
  • Tumor response was dependent on a number of variables, including radiologic criteria, local expertise, imaging techniques, and time of response evaluation
  • Toxicity had a high level of heterogeneity
Auer et al. Trans-arterial chemoembolization with degradable starch microspheres (DSM-TACE) versus selective internal radiation therapy (SIRT) in multifocal hepatocellular carcinoma. Acta Radiol. 2020 Jun 4:284185120926474. doi: 10.1177/0284185120926474

B-NR

  • Retrospective single-center (Germany) analysis of patients with multifocal HCC treated with SIRT (resin) (n=18) or DSM-TACE (n=18)
  • Overall median survival (OS) for the entire cohort was 9.5 months (95% CI 8.3—16.2 months) and median progression-free survival (PFS) for the entire group was 5.0 months (95% CI 4.8-11.9 months)
  • Median local tumor control (LRT) for the entire cohort was 5.5 months (95% CI 5.1—12.1)
  • Subgroup analysis showed no significant differences between SIRT-treated and DSM-TACE-treated patients in OS, PFS, or LRT
  • The toxicity profiles and adverse events for SIRT treatment and DSM-TACE treatment groups were similar, with the only significant difference being an increased incidence of nausea/vomiting in DSM-TACE-treated patients (16.5% incidence in the DSM-TACE-treatment group vs 55.5% in the SIRT-treatment group, p=0.015)
  • DSM-TACE may offer an alternative to SIRT for treatment of multifocal HCC, as efficacy and safety appear similar to that of SIRT for this patient population
Abdel-Rahman and Elsayed. Yttrium-90 microsphere radioembolisation for unresectable hepatocellular carcinoma. Cochrane Systematic Review 2020, Jan 24;1(1):CD011313, doi: 10.1002/14651858.CD011313.pub3

B-NR

  • Systematic review and meta-analysis of low-quality RCTs on unresectable HCC
  • Radioembolization seemed to achieve equivalent survival with fewer adverse events compared with sorafenib, although certainty of the authors about the findings was low
  • Radioembolization did not seem to differ from chemoembolization in serious adverse events or quality of life, although certainty of the authors about the findings was low
  • Unable to determine if radioembolization plus sorafenib vs sorafenib alone affects all-cause mortality or adverse events
  • Evidence comparing radioembolization and chemoembolization is highly insufficient
Katsanos et al. Comparative Effectiveness of Different Transarterial Embolization Therapies Alone or in Combination With Local Ablative or Adjuvant Systemic Treatments for Unresectable Hepatocellular Carcinoma: A Network Meta-Analysis of Randomized Controlled Trials. PLoS One 2017 Sep 21;12(9):e0184597, doi: 10.1371/journal.pone.0184597

B-NR

  • Systematic review of TACE alone or combined with ablative or adjuvant systemic therapies for treating patients with unresectable HCC
  • Survival benefit was similar between TACE and TAE, with providing a significant benefit over best supportive therapy.
  • TACE combined with either radiotherapy or ablation performed better than TACE alone
  • TACE and TAE resulted in a strong response rate compared to control treatment. TACE combined with chemotherapy or ablation was better than TACE alone
  • SIRT was the safest treatment; TACE combined with adjuvant systemic therapies had the highest risk
  • TACE, DEB-TACE, SIRT, and adjuvant systemic agents neither improved tumor objective response nor conferred patient survival compared to TAE
Soydal et al. Comparison of survival, safety, and efficacy after transarterial chemoembolization and radioembolization of Barcelona Clinic Liver Cancer stage B-C hepatocellular cancer patients. Nucl Med Commun. 2016 Jun;37(6):646-9. doi: 10.1097/MNM.0000000000000486

B-NR

  • Retrospective single-center (Turkey) analysis of 80 patients who underwent SIRT (n=40) (resin) or TACE (n=40) for treatment of HCC (stage BCLC B or C)
  • Although treatment groups were similar in most baseline characteristics, there was a significantly higher rate of chronic liver disease in the TACE treatment group (85%) than in the SIRT treatment group (55%), p=0.003. Rates of HCV/HBV infection were not given
  • Mean OS Of the SIRT-treated group was significantly longer than mean OS of the TACE-treated group: 39.24±4.62 months (95% CI, 30.18–48.29 months) vs 30.63±3.68 months (95% CI, 23.42–37.84 months); p=0.014 and 2-year survival rates were 72% and 74% for the SIRT-treatment group and 47% and 59% for the TACE treatment group
  • There was no significant difference between rates of disease recurrence or chronic complications between the two treatment groups
  • For the SIRT treatment group, dimension of the largest lesion was a significant predictor of survival, while for the TACE treatment group, BCLC stage and female sex were significant predictors of survival
  • Although there was a significantly longer mean OS for the SIRT treatment group vs the TACE treatment group, the significantly higher rate of chronic liver disease in the TACE treatment group should be considered as a factor that may influence survival
Kooby et al. Comparison of yttrium-90 radioembolization and transcatheter arterial chemoembolization for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol. 2010;21(2):224-30. doi: 10.1016/j.jvir.2009.10.013

B-NR

  • Retrospective single-center cohort study (USA) of patients with unresectable HCC treated with SIRT (resin) or TACE
  • Patient characteristics included hepatitis C (SIRT, n=10; TACE, n=25); Child Pugh A/B (SIRT, n=13/14; TACE n=22/22); MELD score (SIRT, 10.0; TACE, 10.4); Okuda I/II/III (SIRT, n=13/13/1; TACE, n=15/27/3); vascular invasion (SIRT, n=14; TACE n=13); mean AFP level ug/L (SIRT, 801; TACE, 690)
  • Activity calculated by BSA method
  • Using RECIST and evaluated after 4 and then every 12 weeks, CR/PR/SD/PD were 0/3/11/9 for SIRT and 1/2/16/16 for TACE
  • Median survival was 6.0 months for both SIRT and TACE
  • No differences were found for any complications or major complications between groups. Hematologic specific complications different between treatments: SIRT had 0 and TACE had 10
Lobo et al. Unresectable hepatocellular carcinoma: Radioembolization versus chemoembolization: a systematic review and meta-analysis. Cardiovasc Intervent Radiol. 2016;39(11):1580-1588. doi: 10.1007/s00270-016-1426-y

C-LD

  • Meta-analysis of observational studies on unresectable HCC treated with SIRT (resin or glass) or TACE
  • Survival data were available 269 patients treated with SIRT and for 284 patients undergoing TACE; overall 1-year survival did not differ between treatments (46% vs 41% P=0.33) but at 2 years, survival rate was lower for SIRT than TACE (18% vs 27%, P=0.02)
  • Tumor responses for CR, PR, SD or PD did not differ between treatments at 3 months
  • ≥Grade 3 AE differed between SIRT and TACE: Pain was less but more fatigue was reported for SIRT
Rodriguez et al. A descriptive analysis of remnant activity during 90Y resin microspheres radioembolization of hepatic tumors: Technical factors and dosimetric implications. Ann Nucl Med. 2016;30(3):255-61. doi: 10.1007/s12149-015-1052-9

C-LD

  • Single-center retrospective case series of patients with unresectable HCC (n=70) or liver metastases (n=7) treated with SIRT (resin)
  • Administered activity was calculated using the partition model (n=73) or BSA method (n=4), and calculated absorbed dose loss to implanted tumor was 12.2 Gy
  • Median IQR total activity was 1.3 GBq and total median loss was 0.1 GBq and increased 0.244 GBq when given in 3 split doses (<0.0001)
  • Split activity numbers were 1 (n=34) , 2 (n=33) or 3 (n=10)
  • No patient had visible stasis
Cappelli et al. Transarterial radioembolization in patients with hepatocellular carcinoma of intermediate B2 substage. Eur J Nucl Med Mol Imaging. 2019 Mar;46(3):661-668. doi: 10.1007/s00259-018-4152-7

C-LD

  • Retrospective multi-center (Spain, Germany, Italy) survival analysis of 126 patients with BCLC-B2 substage HCC treated with SIRT (resin) as either first-line therapy or second-line therapy or above
  • Overall survival (OS) did not differ significantly in relation to presence of single large tumor vs multiple tumors. Median OS was 19.35 months (95% CI 8.27–30.42 months) in patients with a single large (>7 cm) tumor vs 18.43 months (95% CI 15.08–21.77 months) in patients with multiple tumors (p = 0.27). 
  • Patients with a single large tumor had better long-term survival rates at 24 and 36 months (36.3 and 29%, respectively) than patients with multinodular HCC (34.6
    and 16.8%, respectively
  • BCLC-B2 substage HCC patients with a single large tumor might particularly benefit from SIRT, as TACE has shown poor efficacy in the treatment of large tumors

12.  Modulation of dosimetry can be achieved through use of pre-calibration (i.e., FLEXdose) in situations where optimization of microsphere distribution may result in optimal outcomes.

13.  Patient follow-up after SIRT treatment should consist on imaging every 2–3 months (MRI, CT, PET/CT) and lab work starting 4 weeks post-SIRT (AFP, viral load, and liver function tests) for a minimum of 1 year, in order to identify best response.

References: SIRT with resin microspheres in Asian regions

Article

Grade

Key Points

Chow et al. SIRveNIB: Selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol. 2018;36(19):1913-1921. doi: 10.1200/JCO.2017.76.0892

B-R

  • Multi-center open-label RTC of SIRT (resin) vs sorafenib for Asian patients with locally advanced HCC
  • Liver function parameters for inclusion: total bilirubin < 2.0mg/dL; INR ≤ 2.0; ALP ≤ 5 x institutional ULN; AST and ALT ≤ 5 x institutional ULN; albumin ≥ 2.5g/dL
  • No difference in OS between SIRT and sorafenib, but better safety profile for SIRT than sorafenib
  • Patient characteristics included ECOG 0/1 (SIRT, n=135/47; sorafenib, n=141/37) BCLC A/B/C (SIRT, n=0/93/88; sorafenib, n=1/97/80); Child Pugh A/B (SIRT, n=165/14; sorafenib, n=160/16); hepatitis B/C/B+C (SIRT, n=93/26/4; sorafenib, n=104/19/5)
  • Activity administered was calculated by BSA or partition model and mean activity was 1.8 GBq
  • Response was evaluated with RECIST 1.1
  • Median daily dose was 644.5 mg sorafenib for patients who were planned to receive 400 mg twice daily
  • ITT Median OS was 8.8 months for SIRT and 10.0 months for sorafenib; PP median OS was 11.3 month and 10.4 months; median PFS at any site was 5.8 and 5.1 respectively  
  • AFP was measured at 12 weeks post-SIRT; liver function, every 4 weeks until week 12, then 12-weekly thereafter
  • BCLC C treated population had median OS of 9.2 months for SIRT and 5.8 months for sorafenib (P=0.0475)
  • Reported AEs were 437 events for SIRT and 1031 events for sorafenib
  • Fewer SIRT patients than sorafenib patients experienced one or more AEs: 78 (60.0%) of 130 patients and 137 (84.6%) of 162 patients; AEs of grade ≥ 3: 36 (27.7%) and 82 (50.6%); or serious AEs (SAEs): 27 (20.8%) and 57 (35.2%)
Lim et al. Alpha-fetoprotein, des-gamma-carboxy prothrombin (DCP), and modified RECIST response as predictors of survival after transarterial radioembolization for hepatocellular carcinoma. J Vasc Interv Radiol. 2019 Aug;30(8):1194-1200.e1. doi: 10.1016/j.jvir.2019.03.016

C-LD

  • Retrospective single-center (Korea) case series of patients with HCC and elevated AFP and DCP treated with SIRT (resin or glass)
  • MIRD was used to calculate prescribed activity for glass and partition model was used for resin
  • Average activity was 2.1 GBq; average lung dose was 11.3 Gy; average liver dose was 48 Gy and tumor resin dose was 149.9 Gy; average target dose for glass was 134.5 Gy
  • AFP, DCP and mRECIST response at 3 months occurred in 68.5%, 66.0% and 45.4% and were predictive of OS 
  • Median OS was longer for responders than non-responders
Chen et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with intermediate and advanced/relapsed hepatocellular carcinoma. Ann Oncol 2020 Mar;31(3):334-351, doi: 10.1016/j.annonc.2019.12.001

C-EO

  • Clinical practice guideline on intermediate and advanced/relapsed HCC by experts from Asia and Europe
  • SIRT can be considered for:
  • Intermediate- or advanced-stage HCC without extrahepatic disease: as first-line therapy alternative to TACE
  • As an alternative for selected TACE-failed BCLC B or non-metastatic BCLC C patients. SIRT results in similar survival outcomes and better ORR and QoL compared to sorafenib in these patients
  • For non-metastatic HCC with macrovascular invasion, which has shown benefit in some Asian studies, as well as other locoregional therapies (TACE, resection, HAIC)
  • Advanced, non-metastatic patients: as locoregional therapy
  • There is limited evidence on the improved benefit of using mRECIST over RECIST for predicting overall survival

References: SIRT with resin microspheres in non-Asian regions

Article

Grade

Key Points

Vilgrain et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2017;18(12):1624-1636. doi: 10.1016/S1470-2045(17)30683-6

B-R

  • Multi-center open-label RCT conducted in France on SIRT (with resin microspheres) vs sorafenib on locally advanced and unresectable HCC after unsuccessful TACE 
  • No significant difference in OS between SIRT and sorafenib
  • Compared sorafenib 400 mg twice daily with SIRT to lobe, sector or segment
  • Activity was calculated using BSA method
  • Patient characteristics included hepatitis C/B (SIRT, n=55/13; sorafenib, n=49/15); ECOG 0/1 (SIRT, n=145/92; sorafenib, n=139/83); BCLC A/B/C (SIRT, n=9/66/162; sorafenib n=12/61/149); Child Pugh A(5-6)/B7/unknown (SIRT, n=196/39/2; sorafenib, n=187/35/0); bilobar (SIRT, n=50; sorafenib, n=35); macrovascular invasion (SIRT, n=149; sorafenib, n=128); AFP (SIRT, median 87 ng/mL, sorafenib, median 80.0 ng/mL)
  • Activity delivered per patient was 1.394 GBq
  • Median follow-up was 27.9 months in the SIRT group, 28.1 months in sorafenib group
  • Response was evaluated with RECIST 1.1
  • Median OS and PFS was 8.0 and 4.1 months for SIRT and 9.9 and 3.7 months for sorafenib
  • Best overall response include CR (SIRT, n=5; sorafenib, n=2), PR (SIRT, n=31; sorafenib, n=21), SD (SIRT, n=93; sorafenib, n=131), PD (SIRT, n=60; sorafenib, n=44)
  • 1088 serious adverse events were reported (SIRT, n=518 events; sorafenib, n=570 events)
Birgin et al. Contralateral liver hypertrophy and oncological outcome following radioembolization with 90Y-microspheres: A systematic review. Cancers (Basel). 2020 Feb; 12(2): 294. doi: 10.3390/cancers12020294

B-NR

  • Systematic review of 16 papers comprising 602 patients treated with SIRT (resin or glass): 81% had primary liver cancer and 22% secondary malignancies
  • The ratio of the future liver remnant to the total liver volume ranged between 23.4% and 49.6% at baseline and between 27% and 68.6% after SIRT
  • Evidence of SIRT-induced liver hypertrophy was based mainly on retrospective studies, which had low Methodological Index for Non-Randomized Studies scores
  • Only 1 prospective study of 24 patients treated with SIRT for palliative care of advanced HCC was identified; however, it was too small to report on subgroup analyses of patients at high risk for poor hypertrophy 
  • Mean degree of relative hypertrophy in the studies ranged from 7% to 43.4%
  • Mean SIRT delivered dose ranged from 112 Gy to 154 Gy
  • Mean follow-up ranged from 4 weeks to 12 months
Golfieri et al. Comparison of the survival and tolerability of radioembolization in elderly vs. younger patients with unresectable hepatocellular carcinoma. J Hepatol. 2013 Oct;59(4):753-61. doi: 10.1016/j.jhep.2013.05.025

C-LD

  • Prospective multi-center (Spain, Italy, Germany) study comparing SIRT-treatment (resin) outcomes in 128 elderly patients (range: 70-87 years) versus 197 patients <70 years 
  • The younger group presented a higher hepatitis B infection rate compared to the elderly (7.8% vs 16.3%); hepatitis C infection rates were similar in both groups (43.1% vs 46.1%)
  • No significant difference in overall survival between the two age groups, with similar survival times seen in early, intermediate, and advanced BCLC stage disease
  • SIRT treatment equally well-tolerated in both age groups
  • Procedure-related events were followed for 1–7 days post-SIRT. Laboratory changes and radiation-related events were followed for 3 months
Klompenhouwer et al. Transarterial radioembolization following chemoembolization for unresectable hepatocellular carcinoma: Response based on apparent diffusion coefficient change is an independent predictor for survival. Cardiovasc Intervent Radiol. 2018;41(11):1716-1726. doi: 10.1007/s00270-018-1991-3

C-LD

  • Retrospective single-center (Belgium) case series (prospectively collected data) of 29 patients with HCC treated with SIRT (resin) and previously treated with DEB-TACE
  • Patient characteristics include hepatitis B/C (n=8); Child Pugh A (n=15), B (n=8); BCLC B (n=15), C (n=14); mean MELD 9.4; unilobar (n=10); mean AFP 267.2 ug/L; prior treatments (n=14)
  • Follow up at 1 month and then every 3 months after SIRT
  • mRECIST criteria was used and identified 0 CR, 11 PR, 8 SD, and 10 PD.
  • Median survival was 26.5 months and 8.9 months for responders and non responders (P=0.057)
  • Factors that had worse survival included female gender, BCLC C, and more prior treatments
  • Apparent diffusion coefficient ratio at DWI MRI following TARE is an independent predictor for survival in patients who previously underwent DEB-TACE
Kucuk et al. Selective intraarterial radionuclide therapy with Yttrium-90 (Y-90) microspheres for unresectable primary and metastatic liver tumors. World J Surg Oncol. 2011 Aug 6;9:86. doi: 10.1186/1477-7819-9-86

C-LD

  • Retrospective single-center (Turkey) analysis of 78 patients treated with SIRT (resin) for unresectable liver tumors from primary HCC (etiology not specified, n=25) or unresectable hepatic metastases from other primary tumors (colorectal: 35; gastric: 7; breast: 4; malign melanoma: 1; pancreas: 1; renal cell: 1; esophagus: 1; neuroendocrine: 3) 
  • Patients were classified into two groups according to their disease stage: those with only liver metastases (H) and those in which metastases had spread to other organs (EH)
  • As assessed by FDG-PET/CT in the sixth week after SIRT treatment, 55% of patients showed a metabolic treatment response while 45% of patients were classified as non-responders
  • 31% of non-responding patients had H disease (tumors restricted to the liver i.e. no extrahepatic metastases) but 69% of responders had H disease (p < 0.05) 
  • The mean overall survival of those in the “responders” group was significantly longer than those in the non-responding group: 25.63 ± 1.52 months vs 20.45 ± 2.11 months, respectively (p = 0.04)
  • SIRT may be a useful treatment for patients with both primary and metastatic unresectable liver tumors, and FDG-PET/CT may be a successful imaging method for evaluating treatment response and predicting survival time

14. Efficacy of SIRT should be measured by evaluating tumor response using RECIST 1.1 and/or mRECIST.

References: SIRT with resin microspheres in Asian regions

Article

Grade

Key Points

Chow et al. SIRveNIB: Selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol. 2018;36(19):1913-1921. doi: 10.1200/JCO.2017.76.0892

B-R

  • Multi-center open-label RTC of SIRT (resin) vs sorafenib for Asian patients with locally advanced HCC
  • Liver function parameters for inclusion: total bilirubin < 2.0mg/dL; INR ≤ 2.0; ALP ≤ 5 x institutional ULN; AST and ALT ≤ 5 x institutional ULN; albumin ≥ 2.5g/dL
  • No difference in OS between SIRT and sorafenib, but better safety profile for SIRT than sorafenib
  • Patient characteristics included ECOG 0/1 (SIRT, n=135/47; sorafenib, n=141/37) BCLC A/B/C (SIRT, n=0/93/88; sorafenib, n=1/97/80); Child Pugh A/B (SIRT, n=165/14; sorafenib, n=160/16); hepatitis B/C/B+C (SIRT, n=93/26/4; sorafenib, n=104/19/5)
  • Activity administered was calculated by BSA or partition model and mean activity was 1.8 GBq
  • Response was evaluated with RECIST 1.1
  • Median daily dose was 644.5 mg sorafenib for patients who were planned to receive 400 mg twice daily
  • ITT Median OS was 8.8 months for SIRT and 10.0 months for sorafenib; PP median OS was 11.3 month and 10.4 months; median PFS at any site was 5.8 and 5.1 respectively 
  • BCLC C treated population had median OS of 9.2 months for SIRT and 5.8 months for sorafenib (P=0.0475)
  • Reported AEs were 437 events for SIRT and 1031 events for sorafenib
  • Fewer SIRT patients than sorafenib patients experienced one or more AEs: 78 (60.0%) of 130 patients and 137 (84.6%) of 162 patients; AEs of grade ≥ 3: 36 (27.7%) and 82 (50.6%); or serious AEs (SAEs): 27 (20.8%) and 57 (35.2%)
Yang et al. Yttrium-90 transarterial radioembolization versus conventional transarterial chemoembolization for patients with hepatocellular carcinoma: a systematic review and meta-analysis. Cancer Biol Med. 2018;15(3):299-310. doi: 10.20892/j.issn.2095-3941.2017.0177

B-NR

  • Meta-analysis of 2 RCTs and 9 observational studies conducted in Germany, Spain, China, Egypt, Turkey, USA: 1652 patients with unresectable HCC treated with SIRT (resin and/or glass)
  • HBV: 14.1% in TACE, 12.9% in SIRT; HCV: 32.1% in TACE, 40.7% in SIRT
  • Liver function was assessed and reported for each paper; no differences were found in patient characteristics among the trials
  • 1-year and 2-year survival rates were analyzed based on observational or RCT study design; 1-year rates were similar, but 2-year rates were higher for SIRT than TACE treated patients
  • Tumor responses were assess using either WHO (n=4) or mRECIST (n=5), the significant differences varied depending on type of analysis used (mRECIST)
  • Serious AEs (≥grade 3) were rare and did not differ between treatments

She et al. Survival analysis of transarterial radioembolization with yttrium-90 for hepatocellular carcinoma patients with HBV infection. Hepatobiliary Surg Nutr. 2014;3(4):185-93. doi: 10.3978/j.issn.2304-3881.2014.07.09

B-NR

  • Retrospective single-center cohort study (Hong Kong) of patients with unresectable advanced HCC treated with SIRT (resin) or TACE 
  • Patient characteristics included BCLC A/B (SIRT, n=15/1; TACE, n=14/2); hepatitis B/C (SIRT, n=12/0; TACE, n=13/3), AFP ng/mL (SIRT, 38; TACE, 242.5); albumin g/L (SIRT, n=40; TACE n=36.5); MELD (SIRT, 7.5; TACE 8.5); no portal invasion (SIRT, n=8; TACE, n=8)
  • Using mRECIST and evaluating in 2 months, CR/PR/SD/PD were 0/4/5/7 for SIRT and 0/2/5/9 for TACE
  • Median OS was 19.9 months for SIRT and 14.0 months for TACE (P=0.615)
  • Despite title, not all patients had HBV (75% SIRT and 81.3% TACE)
Song et al. Transarterial radioembolization versus concurrent chemoradiation therapy for locally advanced hepatocellular carcinoma: A propensity score matching analysis. Int J Radiat Oncol Biol Phys. 2017;99(2):396-406. doi: 10.1016/j.ijrobp.2017.05.049

B-NR

  • Retrospective single-center (Korea) cohort study of patients with unresectable advanced HCC treated with either SIRT (resin) or SIRT with concurrent chemoradiation therapy (CCRT)
  • Patient characteristics for the propensity score matching cohort included cirrhosis (SIRT, n=37; CCRT, n=35), Child Pugh B (SIRT, n=7; CCRT, n=2); BCLC B/C (SIRT, n= 12/50; CCRT, n=14/48); hepatitis B/C (SIRT, n=52/6; CCRT, n=50/2); AFP ng/mL (SIRT, n=216; CCRT, n=1291); PVT (SIRT, n=24; CCRT, n=33)
  • Using mRECIST, tumor response was determined at 1, 3, 6 months and 1 year after treatment
  • Response was better in the CCRT than SIRT arm at 1 month (P<0.001) but was better in the SIRT arm than the CCRT at 3 months (P=0.04)
  • By 6 months no differences were detected in tumor responses
  • Median OS was 14.0 for SIRT and 13.2 for CCRT (P=0.435)
  • Biochemical AEs were different between treatment groups. Overall, AEs occurred more frequently in the CCRT group than in the SIRT group

References: SIRT with resin microspheres in non-Asian regions

Article

Grade

Key Points

Vilgrain et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2017;18(12):1624-1636. doi: 10.1016/S1470-2045(17)30683-6

B-R

  • Multi-center open-label RCT conducted in France on SIRT (with resin microspheres) vs sorafenib on locally advanced and unresectable HCC after unsuccessful TACE 
  • No significant difference in OS between SIRT and sorafenib
  • Compared sorafenib 400 mg twice daily with SIRT to lobe, sector or segment
  • Activity was calculated using BSA method
  • Patient characteristics included hepatitis C/B (SIRT, n=55/13; sorafenib, n=49/15); ECOG 0/1 (SIRT, n=145/92; sorafenib, n=139/83); BCLC A/B/C (SIRT, n=9/66/162; sorafenib n=12/61/149); Child Pugh A(5-6)/B7/unknown (SIRT, n=196/39/2; sorafenib, n=187/35/0); bilobar (SIRT, n=50; sorafenib, n=35); macrovascular invasion (SIRT, n=149; sorafenib, n=128); AFP (SIRT, median 87 ng/mL, sorafenib, median 80.0 ng/mL)
  • Activity delivered per patient was 1.394 GBq
  • Median follow-up was 27.9 months in the SIRT group, 28.1 months in sorafenib group
  • Response was evaluated with RECIST 1.1
  • Median OS and PFS was 8.0 and 4.1 months for SIRT and 9.9 and 3.7 months for sorafenib
  • Best overall response include CR (SIRT, n=5; sorafenib, n=2), PR (SIRT, n=31; sorafenib, n=21), SD (SIRT, n=93; sorafenib, n=131), PD (SIRT, n=60; sorafenib, n=44)
  • 1088 serious adverse events were reported (SIRT, n=518 events; sorafenib, n=570 events)
Kolligs et al. Pilot randomized trial of selective internal radiation therapy vs. chemoembolization in unresectable hepatocellular carcinoma. Liver Int. 2015;35(6):1715-21. doi: 10.1111/liv.12750

C-LD

  • Multi-center open-label pilot RCT conducted in Germany on patients with unresectable HCC receiving SIRT with resin microspheres
  • Patients randomized to receive either SIRT (n=13) or TACE (n=15)
  • Patient characteristics included ECOG 0/1 (SIRT, n=10/3; TACE, n=12/3); Child Pugh 5/6/7 (SIRT, n=9/3/1; TACE, n=9/4/2); AFP mean (SIRT, 636 ng/dL; TACE, 2624.7 ng/dL); total bilirubin median IQR (SIRT 1; TACE 1.08); Albumin median IQR (SIRT 3.63; TACE 4.20); BCLC A/B/C (SIRT, n=5/5/3; TACE, n=4/8/3)
  • Median activity 1.6 GBq delivered to whole (n=7), lobe (n=5), or segment (n=1)
  • No difference in QoL measures were detected 12 weeks after treatment
  • Using RECIST 1.0, PR was 30.8% for SIRT and 13.3% for TACE; 2 patients in each group were downstaged for LT (n=3) or RFA (n=1)
  • Median PFS was 3.6 months for SIRT and 3.7 months for TACE
  • No differences in frequency of AE between groups; only GI events occur more frequently in SIRT group; SAE occurred in 7 and 5 patients, respectively
Kooby et al. Comparison of yttrium-90 radioembolization and transcatheter arterial chemoembolization for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol. 2010;21(2):224-30. doi: 10.1016/j.jvir.2009.10.013

C-LD

  • Retrospective single-center cohort study (USA) of patients with unresectable HCC treated with SIRT (resin) or TACE
  • Patient characteristics included hepatitis C (SIRT, n=10; TACE, n=25); Child Pugh A/B (SIRT, n=13/14; TACE n=22/22); MELD score (SIRT, 10.0; TACE, 10.4); Okuda I/II/III (SIRT, n=13/13/1; TACE, n=15/27/3); vascular invasion (SIRT, n=14; TACE n=13); mean AFP level ug/L (SIRT, 801; TACE, 690)
  • Activity calculated by BSA method
  • Using RECIST and evaluated after 4 and then every 12 weeks, CR/PR/SD/PD were 0/3/11/9 for SIRT and 1/2/16/16 for TACE
  • Median survival was 6.0 months for both SIRT and TACE
  • No differences were found for any complications or major complications between groups. Hematologic specific complications different between treatments: SIRT had 0 and TACE had 10

End of "SIRT Delivery" section