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  

Quick  Summary   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  

Study  design   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  

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

Interven7on:  DEB  +  TACE    50  pa7ents     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  

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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  

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

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

Outcome

   

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.    

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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