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