Perioperative chemotherapy: individualized therapy or same treatment for all? Prof. Dr. med. Salah-Eddin Al-Batran Institute of Clinical Cancer Research Krankenhaus Nordwest UCT - University Cancer Center Frankfurt
Gastric Cancer: survival according to stage (UICC classification 7. edition) Survival by pt stage Survival by pn stage UICC, Union for International Cancer Control. Reim D, et al. J Clin Oncol 2013;31:263 71.
Neoadjuvant or perioperative therapy: goals? Induce clinical and pathological remission Increase complete resection (R0) eliminate minimal residual disease decrease local and systemic relapse Note: tumors may behave different depending on location OE vs. GEJ vs. gastric Histology type intestinal vs. diffuse
Resection status and pathological response Survival after perioperative ECX+/- Bev by resection status by Mandard TRG 1.00 0.75 R0 vs. others p<0.001 R0 1.00 0.75 TRG1/2 vs. others p<0.001 TRG1/2 0.50 0.50 TRG3 0.25 R1 0.25 TRG4/5 0.00 0 12 24 36 48 60 0.00 0 12 24 36 48 60 72 84 R0 R1 Not available 1-2 3 1 0 0 4-5 No resection No resection N=1063 N=908 TGR, tumor regression status Cunningham et al. ESMO/ECCO 2015
Histopathological Remission No neoadjuvant Chemo Becker 1a after 4xFLOT
Perioperative or neoadjuvant therapy: selected trials Site of tumour N/histology Design R0 ITT 5-year OS, % MAGIC Stomach, 74% GEJ, 11% OES, 15% FFCD/ACCOD GEJ, 64% Stomach, 25% OES, 11% EORTC 40954 GEJ 51% Stomach 49% CROSS OES, 76% GEJ, 24% N=503 ADC N=224 ADC N=144 ADC N=366 ADC/SCC Perioperative CT (3+3x ECF) Vs. surgery alone Perioperative CT (up to 3+3x CF) Vs. surgery alone Neoadjuvant CT (2x CLF) Vs. surgery alone Neoadjuvant CRT (Carbo/Pac) vs. surgery alone 66 68% (NS) 74 84% (p<.05) 67 82% (p<.05) 59 82% (p<.05) 36 vs. 23 Δ13 38 vs. 24 Δ14-47 vs. 34 Δ13 ADC, adenocarcinoma; Carbo, carboplatin; C, cisplatin; CT, chemotherapy; E, epirubicin; F, fluorouracil; GEJ, gastroesophageal junction; OES, oesophagus; OS, overall survival; Pac, paclitaxel; CRT, chemoradiotherapy; SCC, squamous cell carcinoma. Cunningham D, et al. N Engl J Med 2006;355:11 20; Ychou M, et al. J Clin Oncol 2011;29:1715 21; Schuhmacher, et al. J Clin Oncol 2010;28:5210-8; van Hagen P, et al. N Engl J Med 2012;366:2074 84.
FFCD/ACCORD: subgroup analysis HR total 0.67 HR GEJ 0.57 Ychou M, et al. J Clin Oncol 2011;29:1715 21
MAGIC: subgroup analysis HR total 0.75 HR GEJ 0.49 HR ca. 0.69 0.75 Cunningham D, et al. N Engl J Med 2006;355:11 20
CROSS: subgroup analysis HR total 0.66 HR adeno 0.73 Only 24% of patients had GEJ cancer van Hagen P, et al. N Engl J Med 2012;366:2074 84.
Treatment for our patient? Two or three drugs Based on FFCD and MAGIC: perioperative chemotherapy is a reasonable treatment for our patient What is the optimal regimen? No head to head comparison of FFCD vs. MAGIC Comparison of CFx2 with ECXx4 as a neoadjuvant treatment of esophageal and GEJ cancer (EO05) Preliminary data on head to head comparison of ECFx3+3 vs. FLOTx4+4 (FLOT4)
UK MRC OE05 trial: CF vs. ECX in adenocarcinoma of the oesophagus and EGJ Histologically confirmed adenocarcinoma lower oesophagus and GOJ (Type I and II) MDT - resectable following EUS and CT R 2 cycles CF Surgery Surgery (excluded T1/2 N0) 4 cycles ECX CF: Two 3-weekly cycles of cisplatin (80mg/m 2 D1) and 5FU (1g/m 2 D 1-4) ECX: Four 3-weekly cycles of epirubicin (50mg/m 2 D1), cisplatin (60mg/m 2 D1) and capecitabine (1250mg/m 2 daily) Cunningham et al ASCO 2015
EO05: results Path response Mandard TRG pcr CF ECX PP 3% 11% ITT 1.9% 7.2% Grade 3/4 toxicity CF ECX G3/4 30% 47% (p<0.05) Progression-free survival Overall survival 1.00 CF ECX 1.00 CF ECX Proportion progression free 0.75 0.50 0.25 0.00 P=0.06 0 1 2 3 4 5 6 7 8 Time from randomisation (Years) At risk CF 451 292 188 141 103 66 45 20 13 ECX 446 309 198 149 115 91 70 45 23 Proportion surviving 0.75 0.50 0.25 0.00 P=0.86 0 1 2 3 4 5 6 7 8 Time from randomisation (Years) At risk CF 451 345 227 167 121 71 46 21 13 ECX 446 343 229 172 124 91 70 45 23 Cunningham et al ASCO 2015
Docetaxel as a 3d drug? Rates of complete pathological response in phase II trials docetaxelbased 3-drugs vs. no docetaxel Reference N Regimen pcr or TRG1% Geh 2000 23 Epirubicin/cisplatin/5-FU (ECF) 4.3% Starling 2009 26 Epirubicin/cisplatin/cape (ECX) 5.9% Schuhmacher 2010 72 Cisplatin, 5-FU, leucovorin (PLF) 7.1% Lorenzen 2008 24 Cisplatin/5-FU/docetaxel (mdcf) 17.4% Thuss-Patience 2010 44 Cisplatin/cape/docetaxel (DCX) 15.9% Biffi 2010 32 Cisplatin/5-FU/docetaxel (TCF) 11.7% Homann 2011 46 Oxaliplatin/5-FU/docetaxel (FLOT) 17.4% Schulz 2015 50 Oxaliplatin/5-FU/docetaxel (FLOT) 20% pcr, pathological complete remission; TRG1, Tumor regression grade 1
FLOT4 Study Design Gastric cancer or adenocarcinoma of the gastroesophageal junction type I-III Medically and technically operable stages T2-4, every N, M0 or every T, N+, M0 S T R A T I F I C A T I O N R n=716 4xFLOT - OP - 4xFLOT FLOT: docetaxel 50mg/m2, d1; 5-FU 2600 mg/m², d1; leucovorin 200 mg/m², d1; oxaliplatin 85 mg/m², d1, every two weeks 3xECF(X) - OP - 3xECF(X) ECF(X): Epirubicin 50 mg/m2, d1; cisplatin 60 mg/m², d1; 5-FU 200 mg/m² (or capecitabine 1250 mg/m² p.o. divided into two doses d1-d21), every three weeks Primary endpoint Phase II (n=300): rate of complete pathological remission (pcr) Primary endpoint for phase III (n=714): OS, HR 0.76, power 80%, two sided p<0.05
FLOT4: Pathological Remission with ECF/ECX vs. FLOT Central Evaluation Pathological 1 regression ECF/ECX n(%) N=137 FLOT n(%) N=128 P-Value (2-sided) pcr (TRG1) 8 6% 20 16% 0.015 pcr+psr (TRG1/2) 31 23% 47 37% 0.015 1 ITT group pcr, pathological complete remission; psr, pathological subtotal remission; TRG, tumor regression grade pcr by histology (total population) pcr by histology Does not mean diffuse type does not benefit! CROSS adeno 23% Pauligk et al. ASCO and ESMO/ECCO 2015
Pathological complete plus subtotal remission: FLOT vs. ECF Biomarker? Immune profile?
It appears the docetaxel based triplet adds benefit for patients with intestinal type tumors but not the diffuse type
pcr with CF vs. ECF(X) vs. FLOT Δ 14% % patients with TRG1/pCR 3 17 16 11 7 7 6 2 CF (EO05) ECX (EO05) ECX (FLOT4) FLOT (FLOT4) per protocol group intent to treat group Cunningham et al. ASCO 2015 Pauligk et al. ASCO and ESMO/ECCO 2015
Current Gastroesophageal Cancer Research Program (perioperative therapy) Gastric or GEJ Cancer Resectable Limited metastatic Her2 + Her2 - /PD-L1 - PD-L1 + Phase II/III Phase II/III Phase II/III Phase III PETRARCA (FLOT6) FLOT+/- Trastuzumab Pertuzumab RAMSES (FLOT7) FLOT+/- Ramucirumab FLOT8 FLOT/FOLFOX +/- Atezolizumab Renaissance/ FLOT5 Induction Cx +/- surgery Pre-therapeutic tissue samples Post-therapeutic resection samples Peripheral blood Translational research teams Goals: Increase cure rates Identify genes associated with path complete of subtotal response
GEJ type I-II High risk of R1 Resection Intestinal types FLOT or CROSS (pcr 23%) For large (T3/T4) tumors: include in the RACE study with FLOT + Radiation Stomach cancers Intestinal types FLOT Diffuse types FLOT, ECX, or Platinum/FP doublet (e.g. XP or FOLFOX)
Thank you Prof. Dr. med. Salah-Eddin Al-Batran Krankenhaus Nordwest UCT - University Cancer Center Frankfurt