Michael Stahl on behalf of the German Oesophageal Cancer Study Group PreOperative Chemotherapy or Radiochemotherapy in Esophago- gastric Adenocarcinoma Trial POET

German Oesophageal Cancer Study Group (GOeCSG) Kliniken Essen-Mitte University Clinic of Marburg University Clinic of Tuebingen University Clinic of Dresden Alfried Krupp Krankenhaus Essen University Clinic of Duesseldorf University Clinic of Essen Städt. Klinikum Krefeld University Clinic of Bonn Krankenhaus St. Georg, Leipzig Kaiserswerther Diakonie Düsseldorf Marienhospital Düsseldorf Klinikum Nürnberg Nord Klinikum Kassel Klinikum Oldenburg Katholische Kliniken im Kreis Kleve Knappschaft-Krankenhaus Bottrop Phillippus-Stift Essen Asklepios-Kliniken Bad Oldesloh

Eligibility Criteria Adenocarcinoma of the esophago-gastric junction (type I – III according to the Siewert classification) Locally advanced stage uT3-T4 NX M0 (CT and EUS mandatory, diagnostic laparoscopy to detect peritoneal carcinosis, no PET) POET GOeCSG

Rationale Preoperative CTX will be a standard of care Additional radiotherapy may increase rate of R0-resection, rate of pN0, and rate of major histologic response (phase II trial of the group) This may increase the number of long term survivors POET GOeCSG

Statistics Additional radiotherapy will increase 3-year survival from 25% to 35% 177 evaluable patients per arm needed (alpha level 5%, power 80%) Stratification was done for center, type of AC, uT-stage, weight loss, and gender POET GOeCSG

Endpoints Primary endpoint - Overall survival Secondary endpoints - Rate of R0-Resection - Rate of PCR - Postoperative Mortality - Local tumor control POET GOeCSG

Recruitment Opened to accrualDecember 2000 Planned interim analysis October 2005 Closed due to poor accrualDecember pts. randomized after stratification 119 pts. eligible and evaluated Arm A (CTX + S) 59 pts. Arm B (CTX + CRTX + S)60 pts. POET GOeCSG

Treatment Arm A Week Arm B POET GOeCSG PLF I PLF III (3 weeks) 15 x 2 Gy in 3 weeks PE (1 week) Surgery PLF: Cisplatin 50mg/m2, 1h, d 1,15,29. Leukovorin/5-FU 500mg/m2 2h / 2g/m2 24h, d 1,8,15,22,29,36 PE: Cisplatin 50 mg/m2, 1h, d 2+8. Etoposide 80 mg/m2, 1h, d 3-5 PLF II 6 7 PLF IPLF II

Typical Radiation Field in EGJ-Cancer Type I POET GOeCSG

Patient Characteristics Arm AArm B (N=59) (N=60) (N=59) (N=60) uT3 / T454 / 555 / 5 AEG I / II-III32 / 2733 / 27 Weight loss 10% 43 / 1644 /16 Male / female54 / 554 / 6 WHO PS0 / 138 / 17 # 33 / 24 # Age (years) * POET GOeCSG * Mann-Whitney p = # unknown in 7 pts.

Compliance to Treatment Arm A Arm B Started treatment(n) Completed part 1 73% 70% Completed part 2 66% 70% Underwent surgery 88% 83% POET GOeCSG

Results at Surgery Arm A Arm B (n=59)(n=60) (n=59)(n=60) Patients with S88.1%81.7% R0-Resection69.5%71.7% R1/R213.6% 3.3% Exploration(n) 3 4 peritoneal mets 3 peritoneal mets 2 peritoneal mets 3 unresect. 1 hepatic mets 1 POET GOeCSG

Pathohistologic Results Arm A Arm B p Arm A Arm B p (n=49)(n=45) (n=49)(n=45) T0N0M0 2.0% 15.6%0.03 T1-4N0M0 34.7% 48.9% T0-4N0M0 36.7% 64.4%0.01 T0-4N+M0 55.1% 31.1% T1-4N+M1 8.2% 4.4% POET GOeCSG

Mortality after Surgery Arm A Arm B Arm A Arm B (n=52) (n=49) (n=52) (n=49) Hospital mortality2 (3.8%) 5 (10.2%)* Pneumonia1 2 Anastom. leakage1 2 Kardiac shock0 1 POET GOeCSG * Fisher´s exact p = 0.26

Overall Survival Logrank p = 0.07 HR Arm B vs. A 0.67 ( ) Arm B Arm A POET GOeCSG Follow-up 45.6 mo 47.4% 27.7%

Freedom from Local Tumor Progression Logrank p = 0.06 HR Arm B vs. A 0.45 ( ) POET GOeCSG 76.5% 59.0% Arm B Arm A

Survival Arm AArm BDifference 2 year survival43.1%61.9%18.8% 3 year survival27.7%47.4%19.7% ( ) ( ) ( ) ( ) Median survival21.1 mo33.1 mo12 mo Median follow-up 45.2 mo46.2 mo 1 mo POET GOeCSG

POET - Conclusions There is a strong trend for improved survival by adding radiotherapy to preoperative chemotherapy Statistical significance was not reached in our trial due to low number of patients randomized These results are in line with other published phase II-III trials investigating perioperative chemoradiation in EG-junction cancer POET GOeCSG