what is the optimal sequence of therapies for stage ii-iii adenocarcinoma of the proximal stomach?
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What is the optimal sequence of therapies for stage II-III adenocarcinoma of the proximal stomach? Peri -operative chemotherapy . Josep Tabernero, MD PhD Medical Oncology Department Vall d’Hebron University Hospital & Vall d’Hebron Institute of Oncology Barcelona. - PowerPoint PPT PresentationTRANSCRIPT
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What is the optimal sequence of therapies for
stage II-III adenocarcinoma of the proximal stomach?
Peri-operative chemotherapy
Josep Tabernero, MD PhDMedical Oncology Department
Vall d’Hebron University Hospital & Vall d’Hebron Institute of Oncology
Barcelona
Great Debates & Updates in GI MalignanciesNY, March 29th, 2014
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Surv
ival
pro
porti
on
Follow-up (years)
OS, CT + surgery
OS, surgery alone
DFS, CT + surgery
DFS, surgery alone
77% of the recurrences occurred during the first 3 years
Arms 3-yr DFS 5-yr OS
CT + surgery 64% 59%
Surgery alone 58% 52%
GASTRIC meta-analysis on individual data: Survival
Gastric cancer meta-analysis. JAMA 2010;303:1729-37
OS HR = 0.8195% CI = 0.74-0.87p = 0.03
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But adjuvant chemotherapy (radiotherapy) cannot be administered to all patients…
Surgery
- Delayed surgical recovery- Poor food intake- Dumping syndrome- Poor performance status- Treatment refusal
~30 - 50%?
BUT:
50 - 70% may receive adjuvant treatment but tolerance is poor:
- Treatment delays- Dose reductions- Early termination
“in the Real life”
Interest of pre/peri-operative treatment in resectable but infiltrating tumor
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To offer chemotherapy treatment to a larger number of patients
To downsize/downstage the tumor To facilitate the surgery To decrease the risk of local recurrence and distant
metastasis To increase the overall survival To offer a better safety profile and treatment
tolerability To offer a more effective treatment (compliance)
Rationale for peri-operative or pre-operative chemotherapy
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Perioperative or pre-operative chemotherapy
SurgeryPreoperative chemotherapy
Surgery
R
Postoperative chemotherapy
Study Design N
Pre-operative treatment
Surgery Post-operative treatment
MAGIC ECF x 3 cycles (9w) S ECF x 3 cycles (9w) 503 pts
FFCD 9703 FP x 2 cycles (8 w) S FP x 4 cycles 224 pts
EORTC 40954 FP x 2 cycles (8 w) S No CT 144/360 pts
Cunningham D et al. N Engl J Med 2006;355:11-20; Ychou M et al. J Clin Oncol 2011;29:1715-1721; Schuhmacher C et al. J Clin Oncol 2010;28:5210-5218.
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Study Eligibility per protocol Pathology stage in surgery only
MAGIC Stage II or higher T1 & T2 – 37%
FFCD 9703 Suitable for curative resection T1 & T2 – 32%
EORTC 40954
Stage III & IV T1 & T2 – 50%
Stage – Inclusion criteria
Cunningham D et al. N Engl J Med 2006;355:11-20; Ychou M et al. J Clin Oncol 2011;29:1715-1721; Schuhmacher C et al. J Clin Oncol 2010;28:5210-5218.
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Study R0 Resection Pathology Stage
Treated Control Increment / p Treated Control
MAGIC 79% 70% 9%; p=0.03 T1/2: 52%N0/1: 84%
T1/2: 38%N0/1: 76%
FFCD 9703 87% 74% 14%; p=0.04 T1/2: 39%N0: 33%
T1/2: 32%N0: 20%
EORTC 40954 82% 67% 15%; p=0.04 T1/2: 66%N0: 39%
T1/2: 50%N0: 19%
Pathology Results
Cunningham D et al. N Engl J Med 2006;355:11-20; Ychou M et al. J Clin Oncol 2011;29:1715-1721; Schuhmacher C et al. J Clin Oncol 2010;28:5210-5218.
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Study 5-year overall survival Increment HR; p
Treated Control
MAGIC 36% 23% 13% 0.75; 0.009
FFCD 9703 38% 24% 14% 0.69; 0.021
EORTC 40954(2-year OS) 73% 70% 3% 0.84; 0.466
Overall Survival
Cunningham D et al. N Engl J Med 2006;355:11-20; Ychou M et al. J Clin Oncol 2011;29:1715-1721; Schuhmacher C et al. J Clin Oncol 2010;28:5210-5218.
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MAGIC - Survival
Cunningham D et al. N Engl J Med 2006;355:11-20
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Meta-analysis of pre/peri-operative treatment
Ge L et al. World J Gastroenterol 2012;18:7384-7393
Parameter N. Studies OR p Experimental arm
Control arm
OS 7 1.4 0.005 Δ 7.96%
PFS (3-yr) 3 1.62 0.001 37.7% 27.3%
Downstaging (pT1-2) 3 1.77 0.0009 55.8% 41.4%
R0 4 1.38 0.03
Survival
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Comparison between adjuvant and pre/perioperative treatment
Modified from Philippe Rougier
Variable Adjuvant Pre/perioperativePS Poor – variable VariableNutrition Poor VariableDelay to CT Long ShortProgression before surgery
- <10%
Surgeon’s opinion Favorable (reticent)5-yr OS 7-10% (bias) 13%R0 resection - 10%
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Feasible and safe
Compliance: 90% preoperative, 50-70% post-operative
Significantly downstage/downsize the tumor and increase
R0 resections
Does not increase perioperative morbidity and mortality
Significantly improves OS (13% at 5-yr in the largest
studies)
Pre/perioperative treatment – Take home messages
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ECX Repeated every 21 days
for 3 cycles
ECX + Bevacizumab Repeated every 21 days for 3
cycles
Randomised
Surgery5 wk break from last pre-op chemo (8 wk break from last bevacizumab)
ECX + BevacizumabRepeated every 21 days for 3
cycles
ECX Repeated every 21 days
for 3 cycles
Maintenance Bevacizumab Every 21 days for 6 doses
6-10 wk break before post-op chemo
MAGIC – B – STO-03
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Tissuebanking
QoL
Chemoradiation
3x ECC q 3 wks
D1 + surgery
D1 + surgeryPreoperative chemotherapy3x ECC q 3 wks
Preoperative chemotherapy3x ECC q 3 wks
R
“MAGIC”(3xECC) ³15 Lymph nodes 45 Gy/25 fx + Epirubicine /Cisplatin/Capecitabine no splenectomy capecitabine dd
cisplatin 1-5x pw3D -CRT/IMRT
Stratified for:- Centre- Histological type- Localisation of tumour
CRITICS