Open-­‐Label  Single-­‐Arm  Phase  II  Trial  of  Sorafenib  Therapy  with  Drug-­‐elu=ng  Bead  Transarterial  Chemoemboliza=on  in  Pa=ents  with  Unresectable  Hepatocellular  Carcinoma:  Clinical  Results  SIR-­‐RFS  Journal  Club  

BOTTOM  LINE  •  Based   on   a   prospective   study   on   50   patients,   combined   continuous   sorafenib   therapy   and   on-­‐

demand  drug-­‐eluting  (DEB)  transarterial  chemoembolization  (TACE)   in  patients  with  unresectable  hepatocellular  carcinoma  (HCC)  provided  successful  disease  control  and  may  have  a  survival  beneJit  in  patients  with  advanced  HCC  

MAJOR  POINTS    •  The  6-­‐month  disease  control  rate  (complete  response  plus  partial  response  plus  stable  disease)  was  

94%  •  Median  time  to  progression  (TTP)  was  13.0  months  •  Overall  survival  (OS)  was  20.4  months    

CRITICISM    

•  Confounding   of   overall   survival   when   considered   for   other   standards   of   care   once   patients   were  removed  from  study  having  already  undergone  therapeutic  interventions  

•  Patients  with  macrovascular   invasion  and  asymptomatic  extrahepatic  disease  and  ECOG  score  of  1  were  included  in  order  to  reJlect  the  patient  population  of  US  tertiary  care  centers  

•  No  other  criticisms  mentioned    

Quick  Summary  

SINGLE  CENTER  SINGLE-­‐ARM,  OPEN-­‐LABEL  PHASE  II  TRIAL  •  50  patients  with  unresectable  HCC  treated  with  DEB  TACE  from  March  2009-­‐

January  2012,  treated  in  six-­‐week  cycles  INCLUSION  CRITERIA  •  Age  greater  than  18  •  Diagnosis  of  unresectable  HCC  on  the  basis  of  histologic  conJirmation,  a  

hypervascular  lesion  within  a  cirrhotic  liver  at  cross-­‐sectional  imaging  or  an  alpha-­‐fetoprotein  level  of  200ng/mL  or  greater  

•  ECOG  performance  status  of  0-­‐1,  Child-­‐Pugh  liver  function  class  of  A-­‐B7,  life  expectancy  greater  than  12  weeks  

•  Total  bilirubin  less  than  3mg/dL  and  serum  albumin  level  greater  than  2.0mg/dL    

•  Adequate  cardiac,  bone  marrow  and  renal  function  EXCLUSION  CRITERIA  •  Symptomatic  extrahepatic  disease,  hepatic  tumor  burden  greater  than  70%  of  

the  total  liver  volume,  complete  occlusion  of  the  portal  venous  system,  uncontrolled  hypertension,  evidence  of  bleeding  diathesis  or  coagulopathy  and  active  second  primary  malignancy  

 

Study  design  

To  determine  the  ef-icacy  of  combined  continuous  sorafenib  therapy  and  drug-­‐eluting  bead  (DEB)  transarterial  chemoembolization  (TACE)  in  patients  with  unresectable  HCC  

Purpose  

All  subjects  had  unresectable  HCC    Tumor  Evaluation:  

»  Baseline  recorded  as  :        Liver  mass  >  1cm  on  CT  or  MR    

§  Tumor  Response  on  follow  up  triphasic    CT  /  MR,  clinical  examination  and  serum  biochemistry  1  month  following  treatment  and  at  subsequent  3-­‐month  intervals  for  Jirst  year  and  then  biannually  with  coinciding  clinical  exam  and  imaging    

DEB  TACE:  »  Treatment  consisted  of  6  week  cycles,  one  with  continuous  sorafenib  therapy  (400mg  twice  daily  oral  dosing  one  week  

prior  to  DEB  TACE)  and  DEB  TACE  performed  during  week  2  of  each  cycle  

»  DEB  TACE  consisted  of  100mg  doxorubicin  per  procedure  loaded  onto  100-­‐300  micron  LC  beads    

»  Total  dose  delivered  determined  by  vascularity  of  tumor  on  hepatic  angiography  

»  End  point  was  either  complete  delivery  of  DEB  TACE  or  reduced  Jlow  of  the  feeding  artery  

»  Maximum  of  four  procedures  over  six  months  

Analysis:  »  Primary  end  point  was  safety,  secondary  end  points  were  assessment  of  response,  TTP  and  survival  

»  Complete  responses  was  deJined  as  100%  tumor  necrosis,  partial  response  >50%  tumor  necrosis,  progressive  disease  was  deJined  as  an  increase  in  tumor  enhancement  by  more  than  25%,  stable  disease  present  if  other  criteria  not  met  

»  Disease  control  rate  was  deJined  as  complete  response  plus  partial  response  plus  stable  disease  

»  TTP  deJined  as  interval  from  start  of  therapy  to  progression  of  lesions  targeted  by  DEB  TACE    

»  OS  assessed  with  Kaplan-­‐Meier  estimates  of  survival,  and  Mantel-­‐Cox  log-­‐rank  test  used  to  determine  differences  in  survival  

»  All  patients  who  received  at  least  one  dose  of  sorafenib  were  included  in  the  analysis  

»  Analyses  carried  out  with  STATA  version  12.0  and  two  sided  P  value  of  <0.05  used  

Interven7on:  DEB  +  TACE    50  pa7ents    

Overall  survival  was  20.4  months.    Median  survival  was  45.6  months  for  BCLC  stage  A  disease  and  29.7  months  for  BCLC  stage  B  disease  and  8.0  months  for  BCLC  stage  C  disease.  For  those  who  

underwent  greater  than  6  months  sorafenib  therapy,  survival  was  21  months  compared  to  those  who  

underwent  therapy  for  less  than  6  months  at  6.8  months.  

 

Outcome    

Median  TTP  in  all  subjects  was  13.9  months.    When  BCLC  

strati-ied,  median  TTP  was  9.5  months  for  patients  with  stage  C  disease,  24.7  months  for  patients  with  stage  B  disease  and  27.6  

months  for  patients  with  stage  A  disease.      

Credits  

SUMMARY  BY:    Alyson  Kil  M.D.,  PGY2  Department  of  Radiology  Walter  Reed  National  Military  Medical  Center/National  Capital  Consortium    FULL  CITATION:  Cosgrove,  David  P.,  Reyes,  Diane  K.,  Pawlik,  Timothy  M.,  Feng,  Allen  L.,  Kamel,  Ihab  R.,  Jean-­‐Francois,  H.  Geschwind..  “Comparison  of  Combination  Therapies  in  the  Management  of  Hepatocellular  Carcinoma"      Journal  of  Vascular  and  Interventional  Radiology.  26.3  (2015):  330-­‐341.  

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