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Transcript of Andrés Cervantes Stefano Cascinu Clinica di Oncologia Medica Universit à Politecnica delle Marche...
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Andrés CervantesAndrés Cervantes
Stefano Cascinu Clinica di Oncologia Medica Università Politecnica delle Marche Ancona
Adjuvant or neoadjuvant therapy?
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Changing incidence of gastric cancers in Western populations
Distal esophagus
Proximal stomach
Distal stomach
GE junction
Blot
0
YearYear1950 1960 1970 1980 1990 1997
Stomach
•More aggressive disease
•Locally advanced
•Early hematogenous spread
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Stomach Cancer - Presentation
• Location at Presentation
US Italy
(1980) (2000)
Upper third: 37% 12% 30%
Middle third: 20% 70% 50%
Lower third: 30% 15% 10%
Diffuse: 12% 3% 10%
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Il tipo istologico
• Intestinale in calo
• Diffuso in aumento
• Giovani donne; T. di Krukenberg:– Follow up mirato– Chirurgia come migliore approccio nelle
pazienti senza carcinosi peritoneale
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Krukenberg tumours: the treatment
• Surgical management and outcome of metachronous Krukenberg tumors from gastric cancer. Cheong JH et al, J Surg Oncol 2004
Metastasectomy may improve the overall and progression free survival
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La prognosi nel carcinoma gastrico radicalmente resecato
50%50%
70%70%
80%80%
Anni 80 Anni 2000
80%80%
50%50%
20%20%
5%5% 5%5%
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Come migliorare la prognosi dei pazienti radicalmente operati
• Chemioterapia postoperatoria
• Chemio-radioterapia postoperatoria
• Chemioterapia perioperatoria
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La terapia adiuvante nel carcinoma gastrico: le linee guida
– Stati Uniti: CT/RT
– Europa controllo
– Italia chemioterapia
– Giappone S-1
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ADJUVANT CHEMOTHERAPY
Meta-analyses Studies (n) Patients (n) Odds ratio (CI)
Hermans 93 11 2096 0.88 (0.78-1.08)
Earle 99 13 1990 0.80 (0.66-0.97)
Mari 00 21 3658 0.82 (0.75-0.89)
Janunger 02 21 3962 0.84 (0.74-0.96)
Panzini 02 18 3118 0.72 (0.62-0.84)
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% 5 years OS5052
HR=0.95, 95% CI=0.70-1.29
Cascinu S, JNCI 2007Cascinu S, JNCI 2007
De Vita F, Ann Oncol 2007De Vita F, Ann Oncol 2007
Adjuvant chemotherapy: new trialsAdjuvant chemotherapy: new trials
Di Costanzo F, JNCI 2008
Di Costanzo F, JNCI 2008
FOLLOW-UP
0.0
1.0
0.8
0.6
0.4
0.2Overa
ll s
urv
ival
1 2 3 4 60 5
Patients at risk
HR: 0.90 [95% CI 0.64-1.26]
Totals128130
Events7067 2 (log-rank): 0.4462 (p=0.504)
3932
Follow-upChemotherapy
128130
109114
86100
7275
5755
4943
Years from randomisation
Follow-upChemotherapy
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TrialTrialControl Control
arm 5 year arm 5 year OSOS
Experimental Experimental arm 5 year arm 5 year
OSOS
GOIM 9602GOIM 9602 2020 3535
ITMOITMO 3030 4545
FFCD 8801FFCD 8801 4040 5555
GISCADGISCAD 2020 3535
GOIRCGOIRC 3030 5050
15-20%15-20%
Increase in 5 year
OS
Increase in 5 year
OS
4%4%
Survivalbenefit from
meta-analysis
Survivalbenefit from
meta-analysis
Post-op CT: statistical endpointsPost-op CT: statistical endpoints
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86% 87%
42%
42%
61%
25%
62%61%
0
50
100
ITMO FFCD8801
GISCAD GOIM MAGIC MAGIC FFCD9703
FFCD9703
86% 87%
42%
42%
61%
25%
62%61%
0
50
100
ITMO FFCD8801
GISCAD GOIM MAGIC MAGIC FFCD9703
FFCD9703
POST-OP
PRE-OP
POST-OP
PRE-OP
Adjuvant chemotherapy: Rate of pts completing post-CT according to the planned dose and timingAdjuvant chemotherapy: Rate of pts completing post-CT according to the planned dose and timing
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0.600.40 0.80 0.90 1.00 1.10 1.20 1.30 1.400.700.50Surgery
alone betterAny
chemotherapy betterHazard ratio
Overall effortHR: 0.83 (95% CI 0.76-0.91)P<0.0001
16 RCT3710 pts
16 RCT3710 pts
Absolute benefit at 5 years: 6.3%
Absolute benefit at 5 years: 6.3%
Buyse ME, 2009
Adjuvant CT: meta-analysis on individual data. Global Advanced/Adjuvant Stomach Tumor Research International Collaboration (Gastric Project)
Adjuvant CT: meta-analysis on individual data. Global Advanced/Adjuvant Stomach Tumor Research International Collaboration (Gastric Project)
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s1 Attenzione a polimorfismi enzimatici:
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Chemioterapia adiuvanteun ruolo nella pratica clinica?
• 5-fluorouracile: nei pazienti ad alto rischio (pT3 N0; istotipo diffuso o scarsamente differenziato; linfonodi positivi N1)
• 5-fluorouracile/cisplatino (+/- antraciclina): nei pazienti ad altissimo rischio (N2-3), sostanzialmente metastatici.
(ovviamente dipende da eta’ e condizioni generali)
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Come migliorare la prognosi dei pazienti radicalmente operati
• Chemioterapia postoperatoria
• Chemio-radioterapia postoperatoria
• Chemioterapia perioperatoria
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Disease-free survivalDisease-free survival
CRT of resected GC: a 10 year follow-up of the INT0116
trial
CRT of resected GC: a 10 year follow-up of the INT0116
trialOverall survivalOverall survival
SWOG 9008/INT 0016SWOG 9008/INT 0016
OSOS Hazard Hazard ratioratio 95% CI95% CI P-valueP-value Median Median
obsobsMedian Median
RXRX
NEJM NEJM ‘‘0101 1.321.32 (1.06-1.64)(1.06-1.64) .005.005 27 mos27 mos 36 mos36 mos
UpdateUpdate 1.311.31 (1.09-1.59)(1.09-1.59) .005.005 27 mos27 mos 35 mos35 mos
DFSDFS
NEJM NEJM ‘‘0101 1.521.52 (1.23-1.86)(1.23-1.86) <.001<.001 19 mos19 mos 30 mos30 mos
UpdateUpdate 1.521.52 (1.25-1.83)(1.25-1.83) <.001<.001 19 mos19 mos 27 mos27 mos
Macdonald JS, 2009Macdonald JS, 2009
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CRT of resected GC: a 10 year follow-up of the INT0116 trial
CRT of resected GC: a 10 year follow-up of the INT0116 trial
Macdonald JS, 2009Macdonald JS, 2009
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Chemioradioterapia adiuvantequale ruolo nella pratica clinica?
• Nei pazienti con R1
• Nei pazienti che hanno ricevuto una linfoadenectomia insufficiente
<15 linfonodi se N negativi e T3
(soprattutto se invasione vascolare)
<25 linfonodi se N positivi (ovviamente dipende da eta’ e condizioni generali)
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Come migliorare la prognosi dei pazienti radicalmente operati
• Chemioterapia postoperatoria
• Chemio-radioterapia postoperatoria
• Chemioterapia perioperatoria
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MAGIC-Trial MAGIC-Trial
St. II + IIIGastric +Junction +Esophagus
N = 503
1994-2002
St. II + IIIGastric +Junction +Esophagus
N = 503
1994-2002
RANDOM
Chemotherapy:ECF x 3 Resection ECF x 3Chemotherapy:ECF x 3 Resection ECF x 3
Surgery aloneSurgery alone
Primary endpoint: 5-y-survival
Cunningham D et al. N Engl J Med 2006;355:11-20
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FFCD 9703 FFCD 9703
St. II + IIIGastric +JunctionN = 224
1995-2003
St. II + IIIGastric +JunctionN = 224
1995-2003
RANDOM
Chemotherapy:CF x 2 Resection CF x 4Chemotherapy:CF x 2 Resection CF x 4
Surgery aloneSurgery alone
Primary endpoint: Survival20% 35% after 5 years, =5%, =20%
Ychou et al.
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Pre-operative CT: the EORTC 40954 trial
144 patients
resectable adenoca. of the stomach R
Surgery
PLF x 1 cycle
Surgery
PLF x 1 cycle
144 patients randomized /360 in 4 years
Study prematurely closed because of poor accrual
Surgery
RestagingIf NO PD/tox/WHO 2
N= 72
N= 72
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NeoadjuvantArm
Surgery arm
p
R0 resection 59 (81.9%) 48 (66.7%) 0.036
N0 node 27 (38.6%) 13 (19.1%) 0.018
Preoperative CT: the EORTC 40954 trial
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EORTC 40954: DFS and OS
(years)
0 1 2 3 4 5 6 7
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment44 72 44 34 28 16 11 4
40 72 56 41 31 24 13 5
S
CS
Overall Logrank test: p=0.200
(years)
0 1 2 3 4 5 6 7
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment35 72 58 48 34 20 11 4
32 72 61 49 41 29 15 6
S
CS
Overall Logrank test: p=0.466
DFS OS
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I punti critici
• I tumori della giunzione esofago-gastrica
• La sopravvivenza nei due studi
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Treatment Effect by Primary Site
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2007
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Chemotherapy is more active against proximal than distal gastric carcinoma
• 270 pazienti con carcinoma gastrico avanzato:
Risposte Sopravv. su primitivo (giorni)
Terzo superiore 91 (33.7%) 51/87 (58.6%) 318
Distale 179 (66.3%) 59/168 (35%) 251
Higuchi, Ajani Oncology 2004
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I punti critici
• I tumori della giunzione esofago-gastrica
• La sopravvivenza nei due studi
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IL PROBLEMA DELLA SOPRAVVIVENZA NEI DUE STUDI
5y DFS 5y OS
• Magic 20% 23%
• Studio francese 21% 24%
Ricordate gli studi italiani: 5y OS 50% !!!
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• Attenzione:
Due popolazioni completamente differenti:– Postoperatoria pazienti resecati R0– Preoperatoria pazienti con malattia non
resecabile
IL PROBLEMA DELLA SOPRAVVIVENZA NEI DUE STUDI
D2 in oltre 60% dei casi
19 LN asportati in media
D2 nel 40% dei casi
N° LN non riportati
MAGIC
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Chemoradiotherapy
Can radiotherapy add something to chemotherapy?
We have no randomised trials to support its use in combination with chemotherapy, but……
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Terapia integrata nel cancro gastrico
• La terapia intraperitoneale
• La chemioipertermia intraperitoneale
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Le nuove frontiere
• I fattori predittivi di risposta– La PET– La genomica/proteomica– La farmacogenomica
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Nel carcinoma gastrico: modificazioni metaboliche dopo 4 settimane
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