La terapia adiuvante e neoadiuvante del cancro gastrico avanzato - Gastrolearning®
-
Upload
gastrolearning -
Category
Education
-
view
370 -
download
0
description
Transcript of La terapia adiuvante e neoadiuvante del cancro gastrico avanzato - Gastrolearning®
TERAPIA ADIUVANTE, TERAPIA ADIUVANTE, NEOADIUVANTE E DELLA NEOADIUVANTE E DELLA
MALATTIA AVANZATA NEL MALATTIA AVANZATA NEL CARCINOMA GASTRICOCARCINOMA GASTRICO
Sara LonardiSara Lonardi
Oncologia Medica 1Oncologia Medica 1
Istituto Oncologico VenetoIstituto Oncologico Veneto
PadovaPadova
GC mortality in Italy derived from population based cancer registries
AIRTUM, 2013
Carcinoma gastrico: chemioradioterapia adiuvante
Macdonald, N Engl J Med 2001
556 resected stage IB-IV M0 gastric cancer
Random
Observation
5FU/LV + RT
Carcinoma gastrico: chemioradioterapia adiuvante
Relapse-free Survival by treatment arm
Overall Survival by treatment arm
HR 1.35 (95% CI: 1.09-1.66)P=0.005mOS 36 vs 27 months
HR 1.52 (95% CI: 1.23-1.86)P<0.001mRFS 30 vs19 months
Macdonald, N Engl J Med 2001
Carcinoma gastrico: chemioradioterapia adiuvante
Major critic: surgery inadequate
Macdonald, N Engl J Med 2001
Carcinoma gastrico: chemioterapia adiuvante – nuovi studi
Reference Stage Treatment N of patients
5-yr survival
P
Bajetta, 2002 pT3-4/N+ EAP x 2 → 5FU x 2Surgery alone
135136
5248
NS
Bouché, 2005 II-IV M0 PF x 5Surgery alone
138140
46.641.9
NS
Nitti, 2006 IB-IV M0 FAMTX or FEMTX x 6Surgery alone
194203
4344
NS
De Vita, 2007 IB-IIIB ELFE x 6Surgery alone
113112
4843.5
NS
Di Costanzo, 2008 IB- IV M0 PELF x 4Surgery alone
130128
47.648.7
NS
Cascinu, 2007 II-IV M0 PELFw x 85FU bolus x 6
201196
5250
NS
Carcinoma gastrico: chemioterapia adiuvante –metanalisi
Reference N. of studies
N of patients
HR 95% CI Reduction of Mortality
Bajetta, 2008 15 3514 0.82 NR 7%
Boku, 2008 14 3293 0.81 0.73-0.89 7%
GASTRIC, 2010 16 3710 0.83 0.76-0.91 6.5%
Carcinoma gastrico: chemioterapia adiuvante –metanalisi
GASTRIC, JAMA 2010
Chemioterapia adiuvante: XELOX
Chemioterapia adiuvante: fattibilità
CT adiuvante e perioperatoriastudi di fase III
Autore Sakuramoto 2007(ACTS-CG)
Cunningham 2006(MAGIC)
Ychou 2011(FNCLCC/FFCD)
Stato Giappone UK Francia
Stadio II/III II/III III
N. Pz 529/530 250/253 113/111
Strategia Adiuvante Perioperatoria Perioperatoria
Tratt sperimentale
S1 post ECFx3 preop+post
FPx3 preop+post
controllo Follow-up Follow-up Follow-up
Loc gastrico/AEG NA 74%/26% 25%/75%
HR 0.68 P=0.003 0.75P=0.009 0.69P=0.02
Braccio di controllo :chirurgia
5-year OS in advanced GC (aGC): a sad starting point!
What are the aims of CT in this setting?
• Symptomatic control
• Improve of QoL or avoid its deterioration
• Delay tumor progression
• Prolong survival
Should pts with aGC receive CT?
Wagner AD, JCO 2006
Effect of combination vs BSC on overall survival
Glimelius B, Ann Oncol 1994
When should pts with aGC receive CT?
Should pts with aGC receive mono or poliCT?
Wagner AD, JCO 2006
Effect of combination vs single-agent CT on OS
Recent phase III trials in aGC
Non-inferior
Study N 1st EP CT scheme mOS
REAL-2 964 OSECF vs EOF vs
ECX vs EOX9.9 vs 9.9 vs 9.3 vs 11.2
ML17032 316 PFS XP vs CF 10.5 vs 9.3
JCOG9912 704 OS S1 vs FU 11.5 vs 10.8
Superior
Study N 1st EP CT scheme mOS
V325 457 TTP DCF vs CF 9.2 vs 8.4
V306 333 TTP IF vs CF 9.0 vs 8.7
JCOG9912 704 OS IP vs FU 12.3 vs 10.8
SPIRITS 305 OS S1P vs S1 13 vs 11
TOP-002 326 OS IS1 vs S1 12.8 vs 10.5
FLAGS 1053 OS S1P vs CF 8.6 vs 7.9
START 639 OS DS1 vs S1 12.5 vs 10.8
Oxaliplatin is as effective than cisplatin
Cunningham D, NEJM 2008
Al Batran SE, JCO 2008
Oral fluoropyrimidines can replace 5-FU: Capecitabine
Okines, Ann Oncol 2009
HR 0.87(p=0.027)
DCF improves CT efficacy over CF
Van Cutsem E, JCO 2006
Best overall response rate
(A)TTP and (B) OS among pts treated with DCF or CF
BUT…
…Toxicity
Van Cutsem E, JCO 2006
Hematologic and nonhematologic toxicities
Alternative Docetaxel-containing regimen
Tebutt NC, Br J Cancer 2010
Total events
Heterogeneity: ChP = 10.76, df = 11 (P = 0.46); P = 0%
Test for overall effect: Z = 4.67 (P < 0.00001)
Total events
Heterogeneity: ChP = 10.76, df = 11 (P = 0.46); P = 0%
Test for overall effect: Z = 4.67 (P < 0.00001)
DCF regimens increase ORR compared with non- docetaxel containing CT
Cheng XL, Plos One 2013
DCF Control Risk Ratio
Study or subrgroup Events Total Events Total Weight M-H, Fixed, 95% CI Year
Sadighi S, et al 18 44 17 42 10.5% 1.01 (0.61. 1.68) 2006
Chu JH, et al 9 20 3 20 1.8% 3.00 (0.95. 9.48) 2006
Van CE, et al 81 221 57 224 34.0% 1.44 (1.08. 1.91) 2006
Roth AD, et al 15 41 10 40 6.1% 1.46 (0.75. 2.86) 2007
Li XQ, et al 22 30 19 30 11.4% 1.16 (0.82. 1.64) 2007
Zhang FL, et al 12 25 5 25 3.0% 2.40 (0.99. 5.81) 2007
Wu GC, et al 21 32 10 26 5.5% 1.71 (0.99. 2.95) 2008
Hou AJ, et al 10 19 3 17 1.9% 2.98 (0.98. 9.07) 2009
Shen YC, et al 11 24 9 24 5.4% 1.22 (0.62. 2.40) 2009
Zhao F, et al 16 31 15 32 8.9% 1.10 (0.67. 2.40) 2009
Liang B, et al 11 30 8 28 5.0% 1.28 (0.61. 2.72) 2010
Gao H, et al 18 32 9 32 5.4% 2.00 (1.06. 3.76) 2010
Total (95% CI) 549 540 100.0% 1.45 (1.24, 1.69)
165165244244
Risk Ratio
M-H, Fixed, 95% CI
Risk Ratio
M-H, Fixed, 95% CI
220.50.5 0.70.7 11 1.51.5
Favours DCFFavours DCFFavours ControlFavours Control
Forest plot of overall response rate
Overall Response Rate of triplet CT Data from randomized trials
EOXEOX
Overall Response Rate Overall Response Rate
ECXECX
ECFECF
DCFDCF
48%48%
46%46%
45%45%
35%35%
Time (months)
294290
277266
246223
209185
173143
147117
11390
9064
7147
5632
4324
3016
2114
137
126
65
40
10
00
No. at risk
11.1 13.8
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Event
FC + T
FC
Events
167182
HR
0.74
95% CI
0.60, 0.91
p value
0.0046
MedianOS
13.811.1
ToGA primary end point: OS
Bang, Lancet 2010
Targeting HER-2ToGA Trial: OS
1.0
0.8
0.6
0.4
0.2
0.0
363432302826242220181614121086420
11.8 16.0
FC + TFC
Events
120136
HR
0.65
95% CI
0.51, 0.83
MedianOS
16.011.8
4.2
0.1
0.3
0.5
0.7
0.9
Months
113
218198
40
53
124
2011
228218
196170
170141
142112
12296
10075
8453
6539
5128
10
00
3920
2813
No. at risk
Probability of survival
Exploratory analysis
Targeting HER-2ToGA Trial: OS in pts with IHC 2+/FISH+ or IHC 3+ disease(exploratory analysis)
Bang, Lancet 2010
Second-line CT is effective in aGC
COUGAR-02
Kim HS, Ann Oncol 2013
HR for death comparing 2nd line docetaxel with BSC
HR for death comparing 2nd line CT with BSC
HR for death comparing 2nd line irinotecan with BSC
Second-line CT is effective in aGC
Second-line CT is effective in aGC
HR (95% CI) = 0.807 (0.678, 0.962)
Stratified log rank p-value = 0.0169
RAM + PAC PBO + PAC
Patients / Events 330 / 256 335 / 260
Median(mos) (95% CI)
9.63 (8.48, 10.81)
7.36 (6.31, 8.38)
6-month OS 72% 57%
12-month OS 40% 30%
RAM + PAC 330 308 267 228 185 148 116 78 60 41 24 13 6 1 0
PBO + PAC 335 294 241 180 143 109 81 64 47 30 22 13 5 2 0
No. at risk
Censored
mOS = 2.3 months
REGARD Trial
RAIMBOW Trial
Wilke H, ASCO GI 2014
Fuchs CS, ASCO GI 2013
Which pts should receive CT?PS 2 pts present a very poor outcome
Shitara K,Gastr Cancer Res 2009
OSTTP
Chau I, JCO 2004
PS2
Liver mets
Peritoneal mets
Alkaline Phosphatase
Overall survival by prognostic index
Which pts should receive CT?Different risk groups
Does CT improve/impair QoL?QoL and efficacy outcomesin phase III trials
Al Batran SE Cancer,2010
How we will make any progress in the treatment of advanced GC ?
5-FU monotherapy5-FU monotherapy
EOXEOX
Median overall survival in advanced gastric cancerMedian overall survival in advanced gastric cancer
5-FU + LV +Oxaliplatin (FLO)
5-FU + LV +Oxaliplatin (FLO)
Capecitabine +Cisplatin (XP)
Capecitabine +Cisplatin (XP)
SP SP
Docetaxel +Cisplatin + 5FU
Docetaxel +Cisplatin + 5FU
11.2 mo11.2 mo
10.7 mo10.7 mo
10.5 mo10.5 mo
9.2 mo9.2 mo
7.0 mo7.0 mo
8.6 mo8.6 mo
13 mo13 moX/FP+ TX/FP+ T HER2 +
16 mo16 moHER2 IHC 3+ or IHC 2+/FISH +X/FP+ TX/FP+ T
Best supportive care
Best supportive care
4.0 mo4.0 mo
Shah MA, Clin Canc Res 2011
6926
6926345
115
345115
3618
3618365
166
365166
11564
11564
488221
488221
72478110
72478110up
down
updown
7520
7520
Type 2 - normalType 1 - normal
Type 3 - normal
GC: a single tumor or an heterogeneous disease?
•GC treated uniformly, despite epidemiologic, anatomic, and histopathologic distinctions between subtypes
•Proximal non-diffuse, diffuse, and distal non-diffuse gastric cancers can be distinguished by gene signatures
Targets in advanced GC
MET
FGFR2
EGFR
HER2
PI3K/mTOR
VEGF
1stL
Study Target N 1st EP CT scheme mOS (m) ORR
TOGA HER2 594 OSCX
CX + Trastu11.1
13.8 (16.0)34.5%47.3%
LOGIC HER2 497 OSCAPEOX
CAPEOX + Lapatinib10.512.2
40%53%
AVAGAST VEGF 774 OSCX
CX + Beva10.112.1
37%46%
REAL-3 EGFR553
(76%)OS
EOCmEOC-Pani
11.38.8
42%46%
EXPAND EGFR 904 PFSCX
CX-Cetuximab10.79.4
29%30%
AMG102 MET 118PFS (phase
II)ECX
ECX-Rilotu8.9
11.1
2ndL
GRANITE mTOR 656 PFSPlacebo
Everolimuns4.345.39
2.1%4.5%
REGARD VEGFR-2 355 OSPlacebo
Ramucirumab3.85.2
2.6%3.4%
RAINBOW VEGFR-2 665 OSPaclitaxel +/-Ramucirumab
7.369.63
16%28%
RAINBOWRAINBOW
TOGATOGA
AMG102AMG102
REGARDREGARD
Target therapy in GC: results
No patient selection based on PI3K/mTOR status
Targeting PI3K/mTORGRANITE-1 Trial: OS
Ohtsu A, JCO 2013
Target therapies
• Targeting right patients with targeted agents based on good biomarker in gastric cancer is important
• To better patient selection molecular selection is needed
• More knowledge
• Better technique
• Better design of trials
• Targeting right patients with targeted agents based on good biomarker in gastric cancer is important
• To better patient selection molecular selection is needed
• More knowledge
• Better technique
• Better design of trials
Take-home messages
- CT adiuvante: si, beneficio assoluto del 7%- CT-RT adiuvante: in casi selezionati (linfadenectomia)- CT perioperatoria: si, meglio tollerata
- CT per malattia avanzata: si, prima possibile (PS 2: ?)- CT a due farmaci: si, platinum-based- CT a tre farmaci: in casi selezionati (bulky, sintomatici)- CT target: si, trastuzumab in HER2 +- CT di seconda linea: si, in pazienti a buon PS
1st-line treatment algorithm in aGC
Immunohistochemistry (IHC) for Her2
FISH-Test for Her2
IHC Score 3+IHC Score 0/1+ IHC Score 2+
FISH +FISH -
Trastuzumab +Cisplatin-Fluoropyrimidine
Platin-Fluoropyrimidin(Docetaxel/Epirubicin)
Post-progression chemotherapy
ECOG PS 0-1(2) ECOG PS 3-4
Best Supportive care
Irinotecan or Taxane+
best supportive care
Second-line treatment algorithm in aGC