Treatment	  of	  	    operable	  gastric	  cancer	          Razvan	  Popescu	  MD,	  MRCP(UK)	  ESO	  Balkan	  Masterclass...
Gastric	  Cancer	  Incidence	  in	  Males	  GLOBOCAN	  2008,	  Interna3onal	  Agency	  for	  Research	  on	  Cancer	      ...
Cancer	  Incidence	  in	  Central	  and	  Eastern	  Europe	    GLOBOCAN	  2008,	  Interna3onal	  Agency	  for	  Research	 ...
Work-­‐up	  of	  Gastric	  Cancer	  •  Physical	  examinaKon,	  blood	  count	  and	  differenKal,	  liver	     and	  renal...
Gastric Cancer Survival 100%           91.6                              82.0                79.2                         ...
EGJ	  Cancers	  and	  Gastric	  cancers	  	         are	  different	  enKKes	  !!	                                 Distal e...
OGJ	  Cancers	  and	  Gastric	  cancers	  	             are	  different	  !!	  
Treatment	  of	  M0	  Gastric	  Cancer	  •  Surgical	  resecKon	  is	  the	  only	  modality	  that	  is	     potenKally	 ...
Dutch	  D1D2	  surgical	  trial	  •  996	  eligible	  paKents	  randomized	  beteween	  1989	  and	     1993	  to	  D1	  o...
Strategies	  that	  increase	  cure	  rate	  in	       potenKally	  operable	  gastric	  cancer	  •    Adjuvant	  chemothe...
Benefit of adjuvant chemotherapy forresectable gastric cancer: a meta-analysis                               17 RCT       ...
Challenges	  of	  adjuvant	  chemotherapy	  •  Efficacy	  of	  treatment	  is	  unknown	  for	  the	  individual	  paKent	  ...
Adjuvant chemotherapy: Percentage ofPatients achieving adequate dose intensity                                  PRE       ...
SAKK	  TCF	  preop	  vs.	  postop	  Trial	  •  4	  cycles	  TCF	  planned	  either	  pre-­‐	  or	     postoperaKvely	  •  ...
Strategies	  that	  increase	  cure	  rate	  in	       potenKally	  operable	  gastric	  cancer	  •    Adjuvant	  chemothe...
Postoperative Chemoradiotherapy For     Localised Gastric Cancer : INT-­‐0116SURGERY	    	   	   	   	                  	 ...
Postoperative Chemoradiotherapy For        Localised Gastric Cancer : INT-­‐0116•  Clear	  benefit	  in	  disease	  free	  ...
Postoperative Chemoradiotherapy For      Localised Gastric Cancer : INT-­‐0116•  Complex	  RT	  schedule	  with	  significa...
Impact	  of	  Extent	  of	  Surgery	  and	    PostoperaKve	  CRT	  on	  Recurrence	  Pamern	  •  Leyden	  retrospecKve	  a...
Strategies	  that	  increase	  cure	  rate	  in	       potenKally	  operable	  gastric	  cancer	  •    Adjuvant	  chemothe...
MAGIC TrialEligible patients:•  Adenocarcinoma of the stomach               Study entry and randomizationor lower third of...
MAGIC Trial                  CSC                         S                 N=250                      N=253  Commenced pre...
MAGIC Trial              Postoperative Morbidity/ Mortality                                  CSC          S Postoperative ...
MAGIC Trial Pathology	  Findings	  	  •  Median	  maximum	  diameter	  of	  the	  resected	     tumor	  was	  smaller	  in...
MAGIC Trial Survival                                                                               PFS*                   ...
Tests for Heterogeneity of Treatment Effect According to the Baseline Characteristics of the Patients         Cunningham D...
FNLCC 94012-FFCD 9703 Trial                                   Randomization N=224                       CT + S            ...
FNLCC 94012-FFCD 9703 Trial               PFS*             Overall                                                        ...
Pre-­‐operaKve	  CT:	  the	  EORTC	  40954	  trial	                                                       Surgery	        ...
Pre-­‐operaKve	  CT:	  the	  EORTC	  40954	  trial	                       Neoadjuvant	          Surgery	  	               ...
Pre-­‐operaKve	  CT:	  the	  EORTC	  40954	  trial	        DFS	                              OS	  
ResecKon	  Rates	                        MAGIC	                                                                           ...
Survival	  Hazard	  RaKos	              MAGIC	                                                 FFCD	                      ...
Summary	  pre-­‐	  /perioperaKve	                Chemotherapy	  •  All	  trials	  suggest	  a	  down	  sizing	  and	  down...
Strategies	  that	  increase	  cure	  rate	  in	       potenKally	  operable	  gastric	  cancer	  •    Adjuvant	  chemothe...
Pre-­‐	  /	  peri-­‐operaKve	  Chemotherapy,	         postoperaKve	  chemoradiotherapy	  •  RaKonale:	  sKll	  high	  rate...
How	  to	  improve	  benefit	  	                of	  systemic	  treatment	  •  Improve	  regimens	  •  Tailor	  treatment	  
Role	  of	  PET	  in	  idenKfying	  paKents	  who	  may	  benefit	  from	  neo-­‐adjuvant	  chemotherapy	  	  	            ...
How	  to	  improve	  benefit	  	                 of	  systemic	  treatment	  •  Improve	  regimens	  •  Tailor	  treatment	...
Summary	  •  Systemic	  treatment	  improves	  outcome	  of	     operable	  gastric	  cancer	  in	  all	  seqngs	  •  Preo...
Popescu razvan gastric cancer locally advanced
Popescu razvan gastric cancer locally advanced
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Popescu razvan gastric cancer locally advanced

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Popescu razvan gastric cancer locally advanced

  1. 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. 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. 3. Cancer  Incidence  in  Central  and  Eastern  Europe   GLOBOCAN  2008,  Interna3onal  Agency  for  Research  on  Cancer  
  4. 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. 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. 6. EGJ  Cancers  and  Gastric  cancers     are  different  enKKes  !!   Distal esophagus GE junction Proximal stomach Distal stomach
  7. 7. OGJ  Cancers  and  Gastric  cancers     are  different  !!  
  8. 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. 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. 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. 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. 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. 13. Adjuvant chemotherapy: Percentage ofPatients achieving adequate dose intensity PRE PRE-OP PRE PRE-OP POST POST-OP POST POST-OP
  14. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 31. Pre-­‐operaKve  CT:  the  EORTC  40954  trial   DFS   OS  
  32. 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. 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. 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. 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. 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. 37. How  to  improve  benefit     of  systemic  treatment  •  Improve  regimens  •  Tailor  treatment  
  38. 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. 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. 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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