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

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

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

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

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.

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.

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.

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.

MAGIC - Survival

Cunningham D et al. N Engl J Med 2006;355:11-20

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

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%

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

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

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