Terapia Sistémica y Radioterapia en Cáncer Gástrico Resecable: Adyuvancia y neoadyuvancia

Prof. Dr. Paulo M. Hoff Centro de Oncologia

Surgery NOT Enough for Most Patients

The Problem

0%  

25%  

50%  

75%  

100%  

IA   IB   IIA   IIB   IIIA   IIIB   IIIC   IV  

 Survival  (%)    

3  years  

5  years   Just  Stage  I  Pts    have  a  higher  than  50/50  chance  to  

reach  5yrs  

More than 10,000 pts from 1973 to 2005

A  quarter  or  less  of    Stage  III  pts  

 are  alive  in  3  yrs  

SEER Data Base – Based on Seventh Edition AJCC Cancer Staging Manual

Adjuvant Chemoradiation

ITN 0116

Macdonald et al, NEJM, (345) 2001

556  Pts  Aug,  1991  –  Jul,  1998  

     3  to  6  weeks  aAer  Surgery     PS  0-­‐  2       Gastric  or  GEJ  IB  to  IVM0  

5-FU 425mg/m2 LCV 20 mg/m2 D1-D5

28 days

Radiotherapy CCT 5-FU 420mg/m2 LCV 20 mg/m2

D1-D4 D34–D36

275 pts

Follow up 281 pts

Macdonald et al, NEJM, (345) 2001

OS 36 x 27 months 3yS 50 x 41% HR 1.35 (1.09 – 1.66, p=0.005)

OS - HR 1.32 (p=0.004) All subsets, except diffuse histology

ITN 0116

Macdonald et al, NEJM, (345) 2001

   85%  had  node  mestastasis  

   20%  were  from  EGJ  

   Elderly  pts  were  included    87  years  old    –  oldest  

10% had a D2 ressection

More than 50% had LESS than a D1 ressection

ITN 0116

CALGB 80101

Fucks et al ASCO Annual Meeting 2011

MacMagic x Macdonald

546  Pts  

   OS    36.6  X    37.8  months  (p=0.8)     More  GIII-­‐IV  Toxic  effects    

Macdonald

ECF ECF

MAGIC TRIAL

Cunningham et al, NEJM, (355) 2006

503  Pts  Jul,  1994  –  Apr,  2002  

   Gastric,  GEJ,  lower  esophagus     ECOG-­‐  PS  0  -­‐  1     II  to  IVM0  (1998  AJCC)  

Surgery

Epirrubicin 50 mg/m2 Cisplatin 60 mg/m2 5-FU 200 mg/m2 Daily

D1 / 21d

250 pts

Surgery Only 253 pts

Cunningham et al, NEJM, (355) 2006

       Smaller  tumors  3  x  5  cm  (p<0.001)  

       Less  advanced  nodal  disease  (p=0.01)         Less  considered  non-­‐cura^ve  ressec^ons  (21%  x  30%)    

       Reduced  Local  and  Distal  Recurrence  

5yS 36.3 x 20.3 % HR 0.74 (p=0.008)

MAGIC TRIAL

To be remembered

   15%  lower  esophagus     12%  EGJ       20%  older  than  70  yo    

• 41%  completed  6  cycles  of  Chemo  

•  15%  Progressed  during  First  Phase  • 55%  re-­‐started  Chemo  aAer  Surgery

Cunningham et al, NEJM, (355) 2006

MAGIC TRIAL

FNCLCC - FFCD TRIAL

224  Pts  Nov,  1995  –  Dec,  2003  

   GEJ,  gastric,  lower  esophagus     ECOG-­‐  PS  0  -­‐  1     II  to  IVM0  (1998  AJCC)  

 65%  of  pts  had  dysphagia  

Cisplatin 100 mg/m2 D1 5-FU 800 mg/m2 D1-D5 28 days

113 pts

Surgery Only 111 pts

Ychou et al, JCO, (13) 2011

Ychou et al, JCO, (13) 2011

       More  R0  Ressec^on  84%  x  74%  (p<0.04)  

       Similar  postopera^ve  complica^ons  

5yS 38 x 24 % HR 0.69 (0.50 – 0.95, p=0.02)

FNCLCC - FFCD TRIAL

Japonese Adjuvant Trial (ACTS-GT) – S1

Sakuramoto et al, NEJM, (357) 2007

1059  Pts  Oct,  2001  –  Dec,  2004  

   Stage  II  –  IIIb     All  pts  -­‐  D2  Surgery     EAST  ASIAN  

Follow up 530 pts

S-1 40mg/m2 4 weeks on 2 weeks off FOR ONE YEAR

529 pts

Sakuramoto et al, NEJM, (357) 2007

Most  pa^ents  N0  and  N1    Lower  impact  on  local  recurrence  65%  pts  Completed  Treatment  

3 yr OS: 81.1 x 70.1% HR for death 0.68, p=0.003

Japonese Adjuvant Trial (ACTS-GT) – S1

OR 0.8 (0.66-0.97)

Earle and Maroun, EJC, (35) 1999

The Gastric 17 trial 3838 pts OR 0.82 (0.76-0.92)

THE GASTRIC JAMA, (303) 2010

Bang et al, Lancet, (379) 2011

1035  Pts  Jun  2006  –  Jun,  2009  

   II  to  IIIB     ECOG-­‐  PS  0  -­‐  1     South  Korea,  Taiwan  and  China     Within  6  weeks  aAer  Surgery  

Capecitabine 2000 mg/m2/d– D1 to D14 Oxaliplatin 130 mg/m2 - D1

D1 / 21d

Surgery Only 515 pts

520 pts

CLASSIC

Bang et al, Lancet, (379) 2011

3y DFS 74% x 59% HR 0.56 (0.44 – 0.72, p<0.001)

CLASSIC

Bang et al, Lancet, (379) 2011

CLASSIC

   Only  2%  were  GEJ       More  than  90%  were  node  posi^ve  

   Primary  End  Point  :  3y  DFS  

   67%  Completed  the  Adjuvant  Chemo  

   56%  Toxicidade  G  III  e  GIV  

Bang et al, Lancet, (379) 2011

CLASSIC

ARTIST

458  Pts  Nov  2004  to    April  2008  

   Only  Gastric  Cancer     Most  were  Node  posi^ve  and  Diffuse    

   >  80%  completed  Chemoradia^on  Arm  

   Most  of  the  pa^ents  had  Dose  Modifica^on  

6 cycles XP (cisplatin 60 mg/m2)

XP Cct Capecitabine 1700 mg/m2/d

XP

Lee et al, JCO, (30) 2012

3y DFS 78 x 74 % p= 0.86

p= 0.0365

All Patients Node Positive

Non pre-planned

Analysis

ARTIST

Lee et al, JCO, (30) 2012

NO  DIFFERENCES  in  the  pajern  of  RECURRENCE

Lee et al, JCO, (30) 2012

ARTIST

ToGA trial design

HER2-positive advanced GC

(n=584)

5-FU or capecitabinea + cisplatin

(n=290)

R

5-FU or capecitabinea + cisplatin

+ trastuzumab

(n=294)   Stratification factors

−  advanced vs metastatic

−  GC vs GEJ

−  measurable vs non-measurable

−  ECOG PS 0-1 vs 2

−  capecitabine vs 5-FU

3807 patients screened 810 HER2-positive (22.1%)

OS in IHC2+/FISH+ or IHC3+ (exploratory analysis)

1.0

0.8

0.6

0.4

0.2

0.0

36 34 32 30 28 26 24 22 20 18 16 14 12 10 8 6 4 2 0

Time (months)

11.8 16.0

FC + T FC

Events

120 136

HR

0.65

95% CI

0.51, 0.83

Median OS

16.0 11.8

Event

0.1

0.3

0.5

0.7

0.9

Conclusions

" Even D2 surgery seems to be insufficient for most gastric cancers

" Adjuvant chemoradiotherapy and peri-operative chemotherapy are equally acceptable options at this point in time (level I)

" Chemotherapy alone is an acceptable alternative for selected cases, particularly those who are N0, or when the available radiotherapy is not ideal