TERAPIA ADIUVANTE,
NEOADIUVANTE E DELLA
MALATTIA AVANZATA NEL
CARCINOMA GASTRICO
Sara Lonardi
Oncologia Medica 1
Istituto ...
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
R...
Carcinoma gastrico: chemioradioterapia adiuvante
Relapse-free Survival
by treatment arm
Overall Survival
by treatment arm
...
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,...
Carcinoma gastrico: chemioterapia adiuvante –metanalisi
Reference N. of
studies
N of
patients
HR 95% CI Reduction of
Morta...
Carcinoma gastrico: chemioterapia adiuvante –metanalisi
GASTRIC, JAMA 2010
Chemioterapia adiuvante: XELOX
Chemioterapia adiuvante: fattibilità
CT adiuvante e perioperatoria
studi di fase III
Autore Sakuramoto 2007
(ACTS-CG)
Cunningham 2006
(MAGIC)
Ychou 2011
(FNCLC...
5-year OS in advanced GC (aGC):
a sad starting point!
What are the aims of CT in this setting?
• Symptomatic control
• Imp...
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 OS
ECF vs EOF vs
ECX vs EOX
9.9 vs 9.9...
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 wit...
…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)
DCF re...
Overall Response Rate of triplet CT
Data from randomized trials
EOX
Overall Response Rate
ECX
ECF
DCF
48%
46%
45%
35%
Time (months)
294
290
277
266
246
223
209
185
173
143
147
117
113
90
90
64
71
47
56
32
43
24
30
16
21
14
13
7
12
6
6
5
4
0...
1.0
0.8
0.6
0.4
0.2
0.0
363432302826242220181614121086420
11.8 16.0
FC + T
FC
Events
120
136
HR
0.65
95% CI
0.51, 0.83
Med...
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 f...
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 +...
Which pts should receive CT?
PS 2 pts present a very poor outcome
Shitara K,Gastr Cancer Res 2009
OS
TTP
Chau I, JCO 2004
PS2
Liver mets
Peritoneal mets
Alkaline Phosphatase
Overall survival by prognostic index
Which pts shoul...
Does CT improve/impair QoL?
QoL and efficacy outcomes
in phase III trials
Al Batran SE Cancer,2010
How we will make any progress in the
treatment of advanced GC ?
5-FU monotherapy
EOX
Median overall survival in advanced g...
Shah MA, Clin Canc Res 2011
69
26
345
115
36
18
365
166
115
64
488
221
7247
8110
up
down
75
20
Type 2 - normalType 1 - nor...
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 OS
CX
CX + Trastu
11.1
13.8 (16.0)
34.5%
47.3%
LOGIC HER2 4...
No patient selection based on PI3K/mTOR status
Targeting PI3K/mTOR
GRANITE-1 Trial: OS
Ohtsu A, JCO 2013
Target therapies
• Targeting right patients with targeted agents based
on good biomarker in gastric cancer is important
• ...
Take-home messages
- CT adiuvante: si, beneficio assoluto del 7%
- CT-RT adiuvante: in casi selezionati (linfadenectomia)
...
1st-line treatment algorithm in aGC
Immunohistochemistry (IHC) for Her2
FISH-Test for Her2
IHC Score 3+IHC Score 0/1+ IHC ...
Post-progression chemotherapy
ECOG PS 0-1(2) ECOG PS 3-4
Best
Supportive care
Irinotecan or Taxane
+
best supportive care
...
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La terapia adiuvante e neoadiuvante del cancro gastrico avanzato - Gastrolearning®

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Gastrolearning II modulo/10a lezione
La terapia adiuvante e neoadiuvante del cancro gastrico avanzato
Dott.ssa S. Lonardi - Università di Ancona

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  • 25
  • Nei campioni istologici di adenocarcinoma gastrico, i tumori HER2-positivi possono mostrare una reattività completa, basolaterale o laterale di membrana.


  • Nei campioni istologici di adenocarcinoma gastrico, i tumori HER2-positivi possono mostrare una reattività completa, basolaterale o laterale di membrana.


  • La terapia adiuvante e neoadiuvante del cancro gastrico avanzato - Gastrolearning®

    1. 1. TERAPIA ADIUVANTE, NEOADIUVANTE E DELLA MALATTIA AVANZATA NEL CARCINOMA GASTRICO Sara Lonardi Oncologia Medica 1 Istituto Oncologico Veneto Padova
    2. 2. GC mortality in Italy derived from population based cancer registries AIRTUM, 2013
    3. 3. Carcinoma gastrico: chemioradioterapia adiuvante Macdonald, N Engl J Med 2001 556 resected stage IB-IV M0 gastric cancer R a n d o m Observation 5FU/LV + RT
    4. 4. 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=0.005 mOS 36 vs 27 months HR 1.52 (95% CI: 1.23-1.86) P<0.001 mRFS 30 vs19 months Macdonald, N Engl J Med 2001
    5. 5. Carcinoma gastrico: chemioradioterapia adiuvante Major critic: surgery inadequate Macdonald, N Engl J Med 2001
    6. 6. 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 2 Surgery alone 135 136 52 48 NS Bouché, 2005 II-IV M0 PF x 5 Surgery alone 138 140 46.6 41.9 NS Nitti, 2006 IB-IV M0 FAMTX or FEMTX x 6 Surgery alone 194 203 43 44 NS De Vita, 2007 IB-IIIB ELFE x 6 Surgery alone 113 112 48 43.5 NS Di Costanzo, 2008 IB- IV M0 PELF x 4 Surgery alone 130 128 47.6 48.7 NS Cascinu, 2007 II-IV M0 PELFw x 8 5FU bolus x 6 201 196 52 50 NS
    7. 7. 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%
    8. 8. Carcinoma gastrico: chemioterapia adiuvante –metanalisi GASTRIC, JAMA 2010
    9. 9. Chemioterapia adiuvante: XELOX
    10. 10. Chemioterapia adiuvante: fattibilità
    11. 11. CT adiuvante e perioperatoria studi 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
    12. 12. 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 95 85 70 50 20 2 0 20 40 60 80 100 % Ia Ib II IIIa IIIb IV
    13. 13. Should pts with aGC receive CT? Wagner AD, JCO 2006 Effect of combination vs BSC on overall survival
    14. 14. Glimelius B, Ann Oncol 1994 When should pts with aGC receive CT?
    15. 15. Should pts with aGC receive mono or poliCT? Wagner AD, JCO 2006 Effect of combination vs single-agent CT on OS
    16. 16. Recent phase III trials in aGC Non-inferior Study N 1st EP CT scheme mOS REAL-2 964 OS ECF vs EOF vs ECX vs EOX 9.9 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
    17. 17. Oxaliplatin is as effective than cisplatin Cunningham D, NEJM 2008 Al Batran SE, JCO 2008
    18. 18. Oral fluoropyrimidines can replace 5-FU: Capecitabine Okines, Ann Oncol 2009 HR 0.87 (p=0.027)
    19. 19. 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…
    20. 20. …Toxicity Van Cutsem E, JCO 2006 Hematologic and nonhematologic toxicities
    21. 21. Alternative Docetaxel-containing regimen Tebutt NC, Br J Cancer 2010
    22. 22. 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) 165244 Risk Ratio M-H, Fixed, 95% CI 20.5 0.7 1 1.5 Favours DCFFavours Control Forest plot of overall response rate
    23. 23. Overall Response Rate of triplet CT Data from randomized trials EOX Overall Response Rate ECX ECF DCF 48% 46% 45% 35%
    24. 24. Time (months) 294 290 277 266 246 223 209 185 173 143 147 117 113 90 90 64 71 47 56 32 43 24 30 16 21 14 13 7 12 6 6 5 4 0 1 0 0 0 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 167 182 HR 0.74 95% CI 0.60, 0.91 p value 0.0046 Median OS 13.8 11.1 ToGA primary end point: OS Bang, Lancet 2010 Targeting HER-2 ToGA Trial: OS
    25. 25. 1.0 0.8 0.6 0.4 0.2 0.0 363432302826242220181614121086420 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  4.2 0.1 0.3 0.5 0.7 0.9 Months 11 3 218 198 4 0 5 3 12 4 20 11 228 218 196 170 170 141 142 112 122 96 100 75 84 53 65 39 51 28 1 0 0 0 39 20 28 13 No. at risk Probability of survival Exploratory analysis Targeting HER-2 ToGA Trial: OS in pts with IHC 2+/FISH+ or IHC 3+ disease(exploratory analysis) Bang, Lancet 2010
    26. 26. Second-line CT is effective in aGC COUGAR-02
    27. 27. 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
    28. 28. 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
    29. 29. Which pts should receive CT? PS 2 pts present a very poor outcome Shitara K,Gastr Cancer Res 2009 OS TTP
    30. 30. Chau I, JCO 2004 PS2 Liver mets Peritoneal mets Alkaline Phosphatase Overall survival by prognostic index Which pts should receive CT? Different risk groups
    31. 31. Does CT improve/impair QoL? QoL and efficacy outcomes in phase III trials Al Batran SE Cancer,2010
    32. 32. How we will make any progress in the treatment of advanced GC ? 5-FU monotherapy EOX Median overall survival in advanced gastric cancer 5-FU + LV + Oxaliplatin (FLO) Capecitabine + Cisplatin (XP) SP Docetaxel + Cisplatin + 5FU 11.2 mo 10.7 mo 10.5 mo 9.2 mo 7.0 mo 8.6 mo 13 moX/FP+ T HER2 + 16 moHER2 IHC 3+ or IHC 2+/FISH +X/FP+ T Best supportive care 4.0 mo
    33. 33. Shah MA, Clin Canc Res 2011 69 26 345 115 36 18 365 166 115 64 488 221 7247 8110 up down 75 20 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
    34. 34. Targets in advanced GC MET FGFR2 EGFR HER2 PI3K/mTOR VEGF
    35. 35. 1stL Study Target N 1st EP CT scheme mOS (m) ORR TOGA HER2 594 OS CX CX + Trastu 11.1 13.8 (16.0) 34.5% 47.3% LOGIC HER2 497 OS CAPEOX CAPEOX + Lapatinib 10.5 12.2 40% 53% AVAGAST VEGF 774 OS CX CX + Beva 10.1 12.1 37% 46% REAL-3 EGFR 553 (76%) OS EOC mEOC-Pani 11.3 8.8 42% 46% EXPAND EGFR 904 PFS CX CX-Cetuximab 10.7 9.4 29% 30% AMG102 MET 118 PFS (phase II) ECX ECX-Rilotu 8.9 11.1 2ndL GRANITE mTOR 656 PFS Placebo Everolimuns 4.34 5.39 2.1% 4.5% REGARD VEGFR-2 355 OS Placebo Ramucirumab 3.8 5.2 2.6% 3.4% RAINBOW VEGFR-2 665 OS Paclitaxel +/- Ramucirumab 7.36 9.63 16% 28% RAINBOW TOGA AMG102 REGARD Target therapy in GC: results
    36. 36. No patient selection based on PI3K/mTOR status Targeting PI3K/mTOR GRANITE-1 Trial: OS Ohtsu A, JCO 2013
    37. 37. 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
    38. 38. 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
    39. 39. 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)
    40. 40. 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
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