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Popescu razvan gastric cancer locally advanced

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  • 1. Treatment  of     operable  gastric  cancer   Razvan  Popescu  MD,  MRCP(UK)  ESO  Balkan  Masterclass  in  Clinical  Oncology   11.5.2011-­‐  15.5.2011     Dubrovnik,  CroaKa  
  • 2. Gastric  Cancer  Incidence  in  Males  GLOBOCAN  2008,  Interna3onal  Agency  for  Research  on  Cancer   0                3.2                6.9                11.6                21.9                63     Age-­‐standardised  incidence  rates  per  100,000  
  • 3. Cancer  Incidence  in  Central  and  Eastern  Europe   GLOBOCAN  2008,  Interna3onal  Agency  for  Research  on  Cancer  
  • 4. Work-­‐up  of  Gastric  Cancer  •  Physical  examinaKon,  blood  count  and  differenKal,  liver   and  renal  funcKon  tests    •  Endoscopy  /  EUS    •  CT  scan  of  the  thorax,  abdomen  and  pelvis    •  Laparoscopy    (+  peritoneal  washings)   –  +ve  washings  not  independent  prognosKc  factor,  conversion  to  –ve   washings  up  to  1/3  with  preop  chemotherapy  (S.  Lorenzen  ASCO  GI  2010)  •  PET  scans   –  can  be  negaKve,  especially  in  paKents  with  mucinous   tumours  (up  to  30%)   –  If  posiKve  can  be  used  for  early  response  assessment  
  • 5. Gastric Cancer Survival 100% 91.6 82.0 79.2 Stage 0 66.9 Stage I 47.6 50 36.4 Stage II 21.9 14.7 Stage III 0 5 10 years   CADO,1985 Years after surgery
  • 6. EGJ  Cancers  and  Gastric  cancers     are  different  enKKes  !!   Distal esophagus GE junction Proximal stomach Distal stomach
  • 7. OGJ  Cancers  and  Gastric  cancers     are  different  !!  
  • 8. Treatment  of  M0  Gastric  Cancer  •  Surgical  resecKon  is  the  only  modality  that  is   potenKally  curaKve,  and  is  recommended  for  all  non-­‐ metastaKc  cancers  •  The  extent  of  opKmal  regional  lymphadenectomy  is   sKll  debated.  •  A  minimum  of  15  lymph-­‐nodes  should  be  recovered   (even  if  a  formal  D2  lymphadenectomy  is  not   performed)  
  • 9. Dutch  D1D2  surgical  trial  •  996  eligible  paKents  randomized  beteween  1989  and   1993  to  D1  or  D2  lymphadenectomy  •  771  paKents  underwent  assigned  treatment,  data   reanalysed  aaer  15  years   Outcome   D1   D2   P   15-­‐y  survival   21%   29%   0.34   Gastric  cancer  death   48%   37%   0.01   Local  recurrence   22%   12%   -­‐   OperaKve  mortality   4%   10%   0.004   ComplicaKons   25%   43%   0.001  
  • 10. Strategies  that  increase  cure  rate  in   potenKally  operable  gastric  cancer  •  Adjuvant  chemotherapy  •  Adjuvant  Chemo-­‐Radiotherapy  •  Peri-­‐operaKve  Chemotherapy  •  Pre-­‐operaKve  Chemotherapy,  postoperaKve   chemoradiotherapy  
  • 11. Benefit of adjuvant chemotherapy forresectable gastric cancer: a meta-analysis 17 RCT 3838 pts 5 year survival:Overall effort 55.3% vs. 49.6%HR: 0.82 (95% CI 0.76-0.91)P<0.0001 0.40 0.50 0.60 0.70 0.80 0.90 1.00 1.10 1.20 1.30 1.40 Any Hazard ratio Surgery chemotherapy better alone better JAMA. 2010 May 5;303(17):1729-3
  • 12. Challenges  of  adjuvant  chemotherapy  •  Efficacy  of  treatment  is  unknown  for  the  individual  paKent  •  Results  of  individual  trials  discouraging  –  Some  clearly   underpowered  to  detect  a  significant  survival  difference.   Other  trials  uKlized  inferior  surgical  techniques.  •  Commencement  of  post-­‐operaKve  treatment  may  be  delayed   by  slow  recovery  from  surgery  or  peri-­‐operaKve  morbidity,   problems  with  nutriKonal  status  •  Treatment  appears  to  be  less  well  tolerated  aaer  major   surgery  
  • 13. Adjuvant chemotherapy: Percentage ofPatients achieving adequate dose intensity PRE PRE-OP PRE PRE-OP POST POST-OP POST POST-OP
  • 14. SAKK  TCF  preop  vs.  postop  Trial  •  4  cycles  TCF  planned  either  pre-­‐  or   postoperaKvely  •  Trial  closed  due  to  slow  accrual  (70  pats  in  6  Y)  •  PreoperaKve  TCF  given  as  planned  in  74%  of   paKents,  but  only  34%  postoperaKvely  •  SAE  were  more  common  in  postoperaKve  arm   (23%  vs.  11%)  
  • 15. Strategies  that  increase  cure  rate  in   potenKally  operable  gastric  cancer  •  Adjuvant  chemotherapy  •  Adjuvant  Chemo-­‐Radiotherapy  •  Peri-­‐operaKve  Chemotherapy  •  Pre-­‐operaKve  Chemotherapy,  postoperaKve   chemoradiotherapy  
  • 16. Postoperative Chemoradiotherapy For Localised Gastric Cancer : INT-­‐0116SURGERY                        NO  TREATMENT  RANDOMIZED  N=  556                          5-­‐FU/FA  x  1  (Mayo)  STRATIFIED            infusional  5-­‐FU  /  45  Gy    T  1-­‐4              5-­‐FU/FA  x  1  (Mayo)    NODES  0,  1-­‐3,  >3       McDonald  JS  et  al.      N  Engl  J  Med  2001  Sep  6;345(10):725-­‐30
  • 17. Postoperative Chemoradiotherapy For Localised Gastric Cancer : INT-­‐0116•  Clear  benefit  in  disease  free  and  overall  survival  with  median  follow-­‐up  of   6  years.  Risk  reducKon  of  death  by  24%.  •  Surgery:  D2  resecKon  less  than  10%,  54  %  of  paKents  fewer  than  15  nodes   (less  than  D1)  •  Planning  of  RadiaKon  to  be  modified  aaer  central  review  in  35%  of  cases   due  to  protocol  deviaKons   McDonald  JS  et  al.      N  Engl  J  Med  2001  Sep  6;345(10):725-­‐30
  • 18. Postoperative Chemoradiotherapy For Localised Gastric Cancer : INT-­‐0116•  Complex  RT  schedule  with  significant  toxicity  •  SubopKmal  chemotherapy  schedule,  role  of  the  2  flanking   Mayo  5-­‐FU/FA  cycles  unclear    Not  an  approach  that  has  taken  root  in  Europe    In  the  context  of  subopKmal  surgery  or  if  preoperaKve  MDT  is   lacking  an  acceptable  approach  if  good  RT  available   McDonald  JS  et  al.      N  Engl  J  Med  2001  Sep  6;345(10):725-­‐30
  • 19. Impact  of  Extent  of  Surgery  and   PostoperaKve  CRT  on  Recurrence  Pamern  •  Leyden  retrospecKve  analysis  of  2  Dutch  trials  :  91   paKents  receiving  postop  CRT  vs.  Cohort  from  Dutch   Gastric  Cancer  Trial  (694)  split  by  D1  vs.  D2  resecKon  •  PaKents  with  D2  resecKon  had  as  good  an  outcome   as  paKents  receiving  postop.  CRT  •  Clear  benefit  for  D1  resected  paKents,  R1  resecKons   and  high  Maruyama  Index  of  unresected  disease   (computed  from  data  base  of  cases  giving  likelihood   of  involvement  of  unresected  LN  staKons)   JL  Dikken,  JCO  May  10,  2010  
  • 20. Strategies  that  increase  cure  rate  in   potenKally  operable  gastric  cancer  •  Adjuvant  chemotherapy  •  Adjuvant  Chemo-­‐Radiotherapy  •  Peri-­‐operaKve  Chemotherapy  •  Pre-­‐operaKve  Chemotherapy,  postoperaKve   chemoradiotherapy  
  • 21. MAGIC TrialEligible patients:•  Adenocarcinoma of the stomach Study entry and randomizationor lower third of the oesophagus(from 1999), suitable for curativeresection•  Non-metastatic disease S arm CSC arm•  Stage II or greater N=253 N=250Primary Surgery Pre-operative chemotherapy:Overall survival ECFx3SecondaryProgression-free survival 3-6 weeksSurgical resectabilityQuality of Life SurgeryChemotherapy (ECF): 6-12 weeksEpirubicin 50mg/m2, IV day 1Cisplatin 60mg/m2, IV day 15-FU 200mg/m2/day, continuous Post-operative chemotherapy:infusion, days 1-21 ECFx3(cycles repeated every 3 weeks)Recruitment: July 1994-April 2002    Cunningham et al NEJM 2006
  • 22. MAGIC Trial CSC S N=250 N=253 Commenced pre-operative chemotherapy N=237 (95%) Completed pre-operative chemotherapy N=215 (86%) Proceeded to surgery Proceeded to surgery N=219 (88%) N=240(95%)Cunningham et al NEJM 2006
  • 23. MAGIC Trial Postoperative Morbidity/ Mortality CSC S Postoperative deaths 6% 6% (14/219) (15/240) Postoperative complications 46% 46% Median duration of 13 days 13 days post-operative hospital stayCunningham et al NEJM 2006
  • 24. MAGIC Trial Pathology  Findings    •  Median  maximum  diameter  of  the  resected   tumor  was  smaller  in  the  perioperaKve-­‐ chemotherapy  group  than  in  the  surgery  group    (3  cm  vs.  5  cm,  P<0.001)  •  a  greater  proporKon  of  stage  T1  and  T2  tumors  in   the  perioperaKve-­‐chemotherapy  group  than  in   the  surgery  group  (51.7  %  vs.  36.8  %,  P=0.002).    •  less  advanced  nodal  disease  (i.e.,  N0  or  N1)  in  the   perioperaKve-­‐chemotherapy  group  than  in  the   surgery  group  (84.4  %  vs.  70.5  %,  P=0.01)  
  • 25. MAGIC Trial Survival PFS* Overall 1.0   1.0 0.9   Logrank p-value = 0.0001 0.9 Logrank p-value = 0.009 Progression-free Survival rate 0.8   Hazard Ratio = 0.66 0.8 Hazard Ratio = 0.75 0.7   (95% CI 0.53 - 0.81) 0.7 (95% CI 0.60 - 0.93) Survival rate 0.6   0.6 0.5   0.5 0.4   0.4 0.3   0.3 Events  Total   Events   Total   0.2   0.2 163   250   CSC   149   250   CSC   0.1   S   0.1 170   253   S   190   253   0.0   0.0 0   12   24   36   48   60   72   0 12 24 36 48 60 72 Months from randomisation   Months from randomisation 2 year 5 year Median   On multivariate analysis, survival survival survival treatment effect unchanged after CSC 50% 36% 24 mo adjustment for age, performance status, site of primary and gender S 41% 23% 20 mo   Hazard ratio for death Benefit to CSC 9% 13% 4 mo   Adjusted: 0.74 (95%CI: arm 0.59-0.93)   Unadjusted: 0.75 Cunningham et al NEJM 2006*Included relapse, PD and death from any cause.
  • 26. Tests for Heterogeneity of Treatment Effect According to the Baseline Characteristics of the Patients Cunningham D et al. N Engl J Med 2006;355:11-20
  • 27. FNLCC 94012-FFCD 9703 Trial Randomization N=224 CT + S S FP (*) x 2/3 every 28 days Within 4 weeks 4 - 6 weeks Resection Resection 4 – 6 weeks FP x 3/4 or no treatment Follow-up Trial accrual 1995-2003*5-Fluorouracil 800 mg/m2 d1-5* Median FU 5.7 yrs+ Cisplatin 100 mg/m2 day 1 BOIGE et al ASCO 2007
  • 28. FNLCC 94012-FFCD 9703 Trial PFS* Overall Logrank p value = 0.021 Hazard Ratio = 0.69 ___ S (95% CI 0.50-0.95) RFS   OS   ___ CT + S 2 year 5 year Median survival survival survival   On multivariate analysis, treatment effect unchanged after adjustmentPeriop CT 58% 38% 29 mo for age, performance status, site of primary and genderSurgery 47% 24% 20 mo   Prognostic variables in Cox multivariate analysis:Benefit to CSC 10% 14% 9 mo   Preoperative CTarm   Gastric location Median follow up: 5.7 years
  • 29. Pre-­‐operaKve  CT:  the  EORTC  40954  trial   Surgery   144  paSents   N=  72  resectable  adenoca.  of   the  stomach   R   Surgery   N=  72   PLF  x  1   Restaging   cycle   If  NO  PD/tox/WHO  2   PLF  x  1   cycle   Surgery  144  paSents  randomized  /360  in  4  years  Study  prematurely  closed  because  of  poor  accrual  
  • 30. Pre-­‐operaKve  CT:  the  EORTC  40954  trial   Neoadjuvant   Surgery     p   Arm   arm  R0  resecSon   59  (81.9%)   48  (66.7%)   0.036  N0  node   27  (38.6%)   13  (19.1%)   0.018  
  • 31. Pre-­‐operaKve  CT:  the  EORTC  40954  trial   DFS   OS  
  • 32. ResecKon  Rates   MAGIC   FFCD   EORTC   (n=503)   (n=224)   (n  =  114)   S                    Chemo+S   S                    Chemo+S   S                    Chemo+S  96%                              92%                                 99%                              96%                                 94%                              96%                                
  • 33. Survival  Hazard  RaKos   MAGIC   FFCD   EORTC   (n=503)   (n=224)   (n  =  114)  S                    Chemo+S   S                    Chemo+S   S                    Chemo+S   0.75   0.69   0.84  
  • 34. Summary  pre-­‐  /perioperaKve   Chemotherapy  •  All  trials  suggest  a  down  sizing  and  down   staging  of  gastric  cancers,  no  relevant  risk  of   progression  whilst  on  chemotherapy,  no   increased  complicaKons  perioperaKvely  and   improved  PFS  and  OS  •  No  standard  chemotherapy  regimen  –  choose   best  advanced  chemotherapy  available  
  • 35. Strategies  that  increase  cure  rate  in   potenKally  operable  gastric  cancer  •  Adjuvant  chemotherapy  •  Adjuvant  Chemo-­‐Radiotherapy  •  Peri-­‐operaKve  Chemotherapy  •  Pre-­‐operaKve  Chemotherapy,  postoperaKve   chemoradiotherapy  
  • 36. Pre-­‐  /  peri-­‐operaKve  Chemotherapy,   postoperaKve  chemoradiotherapy  •  RaKonale:  sKll  high  rates  of  local  failure,  may  be   improved  by  postoperaKve  RT,  now  combined  to   modern  preoperaKve  chemotherapy  (mostly  ECF   or  modificaKons  thereof)  •  Trials  ongoing  •  Not  standard,  may  be  appropriate  in  paKents   with  expected  poor  surgical  results  (e.g.   insufficient  LN  dissecKon,  high  number  /raKo  of   involved  /  resected  LN)  
  • 37. How  to  improve  benefit     of  systemic  treatment  •  Improve  regimens  •  Tailor  treatment  
  • 38. Role  of  PET  in  idenKfying  paKents  who  may  benefit  from  neo-­‐adjuvant  chemotherapy       PET  -­‐Responders   PET  -­‐Responders   PET  –NON  Responders   PET  –NON  Responders  
  • 39. How  to  improve  benefit     of  systemic  treatment  •  Improve  regimens  •  Tailor  treatment  •  Establish  working  mulKdisciplinary  teams  that   meet  regularly  and  mandate  that  oncological   treatment  should  be  first  discussed  in  an  MDT  
  • 40. Summary  •  Systemic  treatment  improves  outcome  of   operable  gastric  cancer  in  all  seqngs  •  PreoperaKve  approaches  are  preferred     –  Bemer  delivery  of  treatment   –  Monitoring  of  response     –  Downstaging  and  downsizing  of  tumor    •  Ongoing  research  regarding  opKmal  regimen   and  tailoring  of  treatment    •  MDT  essenKal  in  improving  management  

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