Effect of preoperative concurrent chemoradiotherapy on survival of patients with resectable esophageal or esophagogastric junction cancer: Results from a multicenter randomized phase III study. A. van der Gaast, P. van Hagen, M. Hulshof, M.I. van Berge Henegouwen, G.A. Nieuwenhuijzen, J.T. Plukker, J.J. Bonenkamp, E.W. Steyerberg, H.W. Tilanus. CROSS study group

Erasmus Medisch Centrum, Rotterdam Academisch Medisch Centrum, Amsterdam Catharina Ziekenhuis, Eindhoven UMC St. Radboudt, Nijmegen Universitair Medisch Centrum Groningen VU Medisch Centrum, Amsterdam Rijnstate Ziekenhuis, Arnhem CROSS study 2

Background  The incidence of esophageal (adenocarcinomas) cancer increases  Despite careful preoperative staging in 20% - 30% an irradical resection is performed  A radical resection is a strong prognostic factor  Preoperative chemoradiotherapy may increase the number of radical resection and therefore the prognosis of these patients CROSS study 3

Objectives Primary endpoints  To compare median survival rates between patients treated for resectable esophageal adenocarcinoma or squamous cell carcinoma  To compare quality of life before, during and after treatment Secondary endpoints  To compare pathological responses  To compare progression free survival  To compare the number of R0 resections  To compare treatment toxicity  To compare costs CROSS study 4

Eligibility criteria Major Inclusion criteria:  Esophageal SCC or AC (cT1N1, T2-3Nx, M0)  Adequate hematologic, renal, hepatic and pulmonary functions  WHO 0, 1 or 2  Written informed consent Major exclusion criteria:  T1N0 or M+  Tumor length > 8 cm  Weight loss > 10% CROSS study 5

Statification and statistical considerations  Stratification parameters  WHO performance  N- stage  Tumor type  Hospital  Sample size calculation  16 versus 22 months median survival  175 patients per treatment-arm CROSS study 6

Accrual CROSS study 7

Chemoradiotherapy treatment regimen  Chemoradiotherapy regimen:  Paclitaxel 50mg/m 2 + Carboplatin AUC=2 on days 1, 8, 15, 22 and 29  Concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy  Surgery within 6 weeks after completion of chemoradiotherapy (THE/TTE) CROSS study 8

Baseline characteristics (1) Surgery aloneCRT + Surgery Performance (WHO) Median0 (0-1) cN-stage cN166%67% Sex Male81%75% Histology AC139 (74%)129 (74%) SCC44 (23%)40 (23%) Other5 (3%)6 (3%) CROSS study 9

Baseline characteristics (2) Surgery aloneCRT + Surgery Age (y) Median60 (36-73)60 (37-79) Dysphagia score Median1 (0-4) Tumor length (cm) Median4 (1-10)4 (1-13) Tumor location proximal43 mid1827 distal GEJ2123 CROSS study 10

Baseline uTN-stage Number of patients TN-Stage CROSS study 11

Delivery of treatment  Number of courses:  1 course = 175 pts  2 courses = 172 pts  3 courses = 172 pts  4 courses = 167 pts  5 courses = 163 pts  Number of operated patients:  CRT arm: 166/175 (95%)  Surgery arm: 184/188 (98%) % CROSS study 12

Toxicity of treatment (chemoradiotherapy)  Major toxicities (grade 3-5 CTC 3.0)  Hematologic: n=12 (6.8%)  Grade 3: n=12  Grade 4: n=0  Grade 5: n=0  Non-hematologic: n=28 (16%)  Grade 3: n=26  Grade 4: n=1  Grade 5: n=1 CROSS study 13

Resection rate and resection margins Resection rate of all randomised patients Surgery aloneCRT + surgery 162/188 (86%)157/175 (90%) Resection margins Surgery aloneCRT + surgery R0110 (67%)145 (92.3%) p<0.002 R1 52 (33%) 12 (7.6%) R0 = no tumor within 1 mm of the resection margins CROSS study 14

Pathology after CRT Pathologic complete response rate 32% in primary tumors (in 145 revised resection specimens of 158 in total) Number of patients Tumor Regression Grade TGR1: No vital cells (pCR) TGR2: <10% vital cells TGR3: 10-50% vital cells TGR4: >50% vital cells CROSS study 15

Morbidity and Mortality (postoperative) Surgery aloneCRT + Surgery Pulmonary complications 66% 69% Cardiac complications 24% 23% Chylothorax 8% 11% Mediastinitis 6% 4% Anastomotic leakage 25% 22% In-hospital mortality 7 (3.8%) 6 (3.4%) CROSS study 16

Follow-up and survival  Median follow-up 32 months Surgery alone CRT + Surgery  1 year survival rate 70% 82%  2 year survival rate 52% 67%  3 year survival rate 48% 59%  Median survival 26 months 49 months CROSS study 17

No’s at risk Surgery alone CRT + surgery HR % CI ( ) P=0.012 Overall survival HR % CI ( ) CRTx Surgery CROSS study 18

HR’s (95% CI) for death according to baseline variables Favors preoperative CRTFavors surgery alone CROSS study 0.67 (0.49 – 0.91) 0.49 (0.27 – 0.90) 0.72 (0.50 – 1.04) 0.62 (0.44 – 0.87) 0.92 (0.45 – 1.89) 0.82 (0.58 – 1.16) 0.34 (0.17 – 0.68) 0.67 (0.49 – 0.94) 0.67 (0.32 – 1.41) 19

CONCLUSION Neoadjuvant chemoradiotherapy with weekly administrations of carboplatin and paclitaxel and concurrent radiotherapy followed by surgery improves survival compared to surgery alone In this study we observed no increase in postoperative complications or postoperative mortality with preoperative chemoradiotherapy CROSS study 20

ACKNOWLEDGEMENTS We want to thank all our patients and families CROSS study 21