locally advanced ge junction cancer: perioperative ...€¦ · •pt1 tumors 15% vs. 25% (p=0.001)...
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Locally Advanced GE Junction Cancer: Perioperative chemotherapy
Salah-Eddin Al-Batran, MDNorthwest Hospital
UCT - University Cancer Center Frankfurt
MAGIC and FFCD: peri-op Chemo improves outcome vs. surgery alone
D. Cunningham et al., N Engl J Med 2006 (355): 11-20
Overall SurvivalN=503
Perioperative Chemotherapy with ECF5y-OS 23% vs. 36%
Overall SurvivalN=224
Perioperative Chemotherapy with CF5y-OS 24% vs. 38%
Ychou M. J Clin Oncol. 2011 May 1;29(13):1715-21
No difference in complication ratesNo difference in periop hospital stay time
MAGIC FFCD
Study/ primary N Design R0 ITT Extrapolated 5-year OS
MAGICStomach, 74%GEJ, 11%OES, 15%
n=503
perioperative 3+3 cycles ECF vs. surgery alone
68% vs. 66%5-year OS: 36% vs. 23%
FFCD/ACCODStomach, 25%GEJ, 64%OES, 11%
n=224
perioperative 3+3 cycles CFvs.surgery alone
84% vs. 74%5-year OS:38% vs. 24%
MAGIC vs. FFCD
D. Cunningham et al., N Engl J Med 2006 (355): 11-20Ychou M. J Clin Oncol. 2011 May 1;29(13):1715-21
FLOT4-AIO Study Design
Primary endpoint OS; HR 0.76; 2-sided log rank test a 5% significance level; median OS ECF/ECX 25 months
Al-Batran et al, Lancet 2019
56% GEJ 44% Gastric80% of patients cT3/480% of patients cN1
FLOT4 Trial: FLOT improved complete resection rates, downsizing/-staging, and survival vs. ECF
• R0 resection rate 78% vs. 85% (p=0.016)• pT1 tumors 15% vs. 25% (p=0.001)
Disease-free survival Overall survival
3-year OS-rate with FLOT vs. ECF: 57% vs. 48%Median OS with FLOT vs. ECF: 50 months vs. 35 months
∆ 15 months in median OS
Al-Batran et al, Lancet 2019
FLOT4: consistent results among all subgroups
Al-Batran et al, Lancet 2019
R
Operation
Chemoradiation + Operation
ØPaclitaxel 50mg/m2 + Carboplatin AUC2 d1,8,15,22,29ØRadiotherapie 23x1.8 Gy (41 Gy )
OES, 73%GEJ, 24%cN1, 65%
CROSS Trial
N=366 (23% SCC, 75% AC)
Neoadjuvant chemoradiation for esophageal and GEJ cancer
van Hagen P, et al. N Engl J Med 2012;366:2074–84
CROSS: Subgroups
van Hagen P, et al. N Engl J Med 2012;366:2074–84
How did patients with GEJ in these trials?
HRs for OS in the GEJ subgroups in peri-op chemo trials were favorable
Study HR overall HR GEJ
MAGIC 0.75 0.49
FFCD/ACORD 0.67 0.57
FLOT vs. MAGIC 0.77 0.76
GEJ tumors benefits form perioperative chemotherapy In studies vs. surgery alone, the effect is even pronounced
Subgroup Analysis for overall survival
Al-Batran et al, Lancet 2019
Homann et al. IJC, 2011: pCR acc. to Becker (TRG1a) 17.4% after 4x FLOT• 30.8% in intestinal type histology vs. 0% in diffuse type tumors • 30.4% in tumors located in the GEJ vs. 4.3% in tumors located in the stomach
Schulz et al. IJC, 2014: pCR acc. to Becker (TRG1a) 17.2% after 6x FLOT
• 25% in intestinal type histology vs. 5.3% in diffuse/mixed type tumors
Al-Batran et al. Lancet Oncology, 2017: pCR acc. to Beker (TRG1a) 16% after 4x FLOT
• 23% in intestinal type histology vs. 2.2% in diffuse/mixed type tumors
GEJ tumors are more responsive to chemotherapy Path response rates with FLOT range in the 25% range
Landmark studies including of neoadjuvant/perioperative treatment of localised esophageal and GEJ cancer
Trial Arms N Survival rate % HR (95% CI)
OE02 SurgeryCF x2 + surgery
802 5y:17% vs. 23%
0.84; P=0.03
MAGICSurgeryECF (3 pre-op + post-op.) + surgery
503 5y:23% vs. 36%
0.75; p=0.009
FFCDSurgeryCF (3 pre-op and post op.) + surgery
224 5y:24% vs. 38%
0.69; p=0.02
FLOT4-AIOECF/X – surgery –ECF/XFLOT – surgery – FLOT
716 3y48% vs. 57%
0.77 p=0.012
CALGB 9781SurgeryCF+ RT (50.4Gy) + surgery
56 5y:16% vs. 39%
Na; p=0.002
CROSSSurgeryCarbo-Pac + 41.1Gy + surgery
366 5y:34% vs. 47%
0.66; p=0.003
Adopted and modified acc. to Smyth et al. Nat Rev Dis Primers 2017
Parameters FLOT CROSS
Margin-free resection 85% 82%
Important Subgroups
Signet cell 0.74 not known
ECOG/WHO PS 1 0.73 0.9
Older adults (>70y) 0.72 not known
Quality of Surgery (median no. of LN removed)
25/24 18/15
FLOT vs. CROSS
Parameters FLOT CROSS
Size (GEJ) 716 (398) 366 (275)
HR (GEJ/Adenocarcinoma) 0.76 vs. MAGIC 0.74 vs. surgery alone
HR (Barrett) 0.61 vs. MAGIC not known
FLOTCROSS
T4, 0%cN1, 65%
T4, 8%cN1, 78%
Toxicity and convenience
• More acute tox: gr. 3/4 neutropenia, diarrhea
• Chronis tox: PNP!• But: more convenient:
less visits (8 visits w FLOT vs. 23 visits w CROSS); immediate start, no need for nutritional tubes
• More chronic tox: strictures, pneumonitis, cardiac and second malignancies
• Surgical mortality increased in many studies
Chemotherapy (FLOT) Chemoradiation (CROSS)
The history of RT + Chemo vs. Chemo in the adjuvant setting
• Decades of debate • Meta-analysis showed superiority• Individual Phase III trials:
– ARTIST (JCO 2011, 2015)– CRITICS (Lancet Oncol 2018)– ARTIST2 (ASCO 2019)
Negative
Why?..because gastroesophageal cancer is a systemic disease
Conclusions
• Large and consistent data sets of prospective randomized trials provide definite proof of the efficacy of peri-op chemo– peri-op chemo works best in GEJ tumors– pCR rates with FLOT are comparable to
chemoradiation (with more systemic effects)– R0-resection rates are similar despite more
advanced tumors in FLOT4 studies (85% vs. 82%)– FLOT is better than ECF but CROSS is not
Conclusions
• The best therapy option for patients with >=cT2 or N1 GEJ cancer is peri-op FLOT + surgery incl. 2-field lymphadenectomy
• Future trials should determine which groups may benefit form adding radiation to peri-op FLOT chemotherapy– E.g. induction chemo followed by chemoradiation
for large tumors T3/T4 or bulky N
Thank you