Michael Stahlon behalf of the

German Oesophageal Cancer Study Group

PreOperative Chemotherapy or Radiochemotherapy in Esophago-

gastric Adenocarcinoma TrialPOET

German Oesophageal Cancer Study GroupGerman Oesophageal Cancer Study Group(GOeCSG)(GOeCSG)

Kliniken Essen-MitteKliniken Essen-MitteUniversity Clinic of MarburgUniversity Clinic of MarburgUniversity Clinic of TuebingenUniversity Clinic of TuebingenUniversity Clinic of DresdenUniversity Clinic of DresdenAlfried Krupp Krankenhaus EssenAlfried Krupp Krankenhaus EssenUniversity Clinic of DuesseldorfUniversity Clinic of DuesseldorfUniversity Clinic of EssenUniversity Clinic of EssenStädt. Klinikum KrefeldStädt. Klinikum KrefeldUniversity Clinic of BonnUniversity Clinic of BonnKrankenhaus St. Georg, LeipzigKrankenhaus St. Georg, LeipzigKaiserswerther Diakonie DüsseldorfKaiserswerther Diakonie DüsseldorfMarienhospital DüsseldorfMarienhospital DüsseldorfKlinikum Nürnberg NordKlinikum Nürnberg NordKlinikum KasselKlinikum KasselKlinikum OldenburgKlinikum OldenburgKatholische Kliniken im Kreis KleveKatholische Kliniken im Kreis KleveKnappschaft-Krankenhaus BottropKnappschaft-Krankenhaus BottropPhillippus-Stift EssenPhillippus-Stift EssenAsklepios-Kliniken Bad OldeslohAsklepios-Kliniken Bad Oldesloh

Eligibility CriteriaEligibility Criteria

Adenocarcinoma of the esophago-gastric Adenocarcinoma of the esophago-gastric junction (type I – III according to the Siewert junction (type I – III according to the Siewert classification)classification)

Locally advanced stage uT3-T4 NX M0 (CT Locally advanced stage uT3-T4 NX M0 (CT and EUS mandatory, diagnostic laparoscopy and EUS mandatory, diagnostic laparoscopy to detect peritoneal carcinosis, no PET)to detect peritoneal carcinosis, no PET)

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RationaleRationale

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

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StatisticsStatistics

Additional radiotherapy will increase 3-year Additional radiotherapy will increase 3-year survival from 25% to 35% survival from 25% to 35%

177 evaluable patients per arm needed 177 evaluable patients per arm needed (alpha level 5%, power 80%)(alpha level 5%, power 80%)

Stratification was done for center, type of Stratification was done for center, type of AC, uT-stage, weight loss, and genderAC, uT-stage, weight loss, and gender

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EndpointsEndpoints

Primary endpointPrimary endpoint- Overall survivalOverall survival

Secondary endpointsSecondary endpoints- Rate of R0-ResectionRate of R0-Resection- Rate of PCRRate of PCR- Postoperative MortalityPostoperative Mortality- Local tumor controlLocal tumor control

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RecruitmentRecruitment

Opened to accrualOpened to accrual December 2000December 2000Planned interim analysis Planned interim analysis October 2005October 2005Closed due to poor accrualClosed due to poor accrual December 2005December 2005

126 pts. randomized after stratification126 pts. randomized after stratification119 pts. eligible and evaluated119 pts. eligible and evaluatedArm A (CTX + S) Arm A (CTX + S) 59 pts.59 pts.Arm B (CTX + CRTX + S)Arm B (CTX + CRTX + S) 60 pts.60 pts.

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TreatmentTreatment

Arm AArm A

WeekWeek

Arm BArm B

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PLF I PLF III (3 weeks)

15 x 2 Gy in 3 weeks

PE (1 week)

Surgery

Surgery

1 1314 17 20-21

PLF: Cisplatin 50mg/m2, 1h, d 1,15,29. Leukovorin/5-FU 500mg/m2 2h / 2g/m2 24h, d 1,8,15,22,29,36PE: Cisplatin 50 mg/m2, 1h, d 2+8. Etoposide 80 mg/m2, 1h, d 3-5

PLF II

6 7

PLF I PLF II

Typical Radiation Field in Typical Radiation Field in EGJ-Cancer Type IEGJ-Cancer Type I

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Patient CharacteristicsPatient Characteristics

Arm AArm A Arm BArm B (N=59)(N=59) (N=60) (N=60)

uT3 / T4uT3 / T4 54 / 554 / 5 55 / 555 / 5

AEG I / II-IIIAEG I / II-III 32 / 2732 / 27 33 / 2733 / 27

Weight loss </>10%Weight loss </>10% 43 / 1643 / 16 44 /1644 /16

Male / femaleMale / female 54 / 554 / 5 54 / 654 / 6

WHO PSWHO PS 0 / 10 / 1 38 / 1738 / 17 # # 33 / 24 33 / 24 ##

Age (years)Age (years) 56.056.0 60.6 *60.6 *

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* Mann-Whitney p = 0.005# unknown in 7 pts.

Compliance to TreatmentCompliance to Treatment

Arm A Arm A Arm BArm B

Started treatmentStarted treatment (n)(n) 59 59 59 59

Completed part 1 Completed part 1 73% 73% 70% 70%

Completed part 2Completed part 2 66% 66% 70% 70%

Underwent surgeryUnderwent surgery 88% 88% 83% 83%

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Results at SurgeryResults at Surgery

Arm AArm A Arm B Arm B (n=59)(n=59) (n=60)(n=60)

Patients with SPatients with S 88.1%88.1% 81.7%81.7%

R0-ResectionR0-Resection 69.5%69.5% 71.7%71.7%

R1/R2R1/R2 13.6%13.6% 3.3% 3.3%

ExplorationExploration (n)(n) 3 3 4 4

peritoneal mets 2 peritoneal peritoneal mets 3mets 3

unresect. 1unresect. 1 hepatic mets 1 hepatic mets 1

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Pathohistologic Results

Arm AArm A Arm B p Arm B p (n=49)(n=49) (n=45)(n=45)

T0N0M0 T0N0M0 2.0% 2.0% 15.6% 15.6% 0.030.03T1-4N0M0T1-4N0M0 34.7% 34.7% 48.9% 48.9%T0-4N0M0 T0-4N0M0 36.7% 36.7% 64.4% 64.4% 0.010.01T0-4N+M0T0-4N+M0 55.1 55.1%% 31.1% 31.1%T1-4N+M1T1-4N+M1 8.2% 8.2% 4.4% 4.4%

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Mortality after Surgery

Arm AArm A Arm B Arm B (n=52)(n=52) (n=49) (n=49)

Hospital mortalityHospital mortality 2 (3.8%)2 (3.8%) 5 (10.2%)* 5 (10.2%)*

PneumoniaPneumonia 11 2 2

Anastom. leakageAnastom. leakage 11 2 2

Kardiac shockKardiac shock 00 1 1

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* Fisher´s exact p = 0.26

Overall SurvivalOverall Survival

Logrank p = 0.07HR Arm B vs. A0.67 (0.41-1.07)

Arm B

Arm A

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Follow-up 45.6 mo

47.4%

27.7%

Freedom from Local Tumor Freedom from Local Tumor ProgressionProgression

Logrank p = 0.06HR Arm B vs. A0.45 (0.19 -1.05)

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76.5%

59.0%

Arm B

Arm A

SurvivalSurvival

Arm AArm A Arm BArm B DifferenceDifference

2 year survival2 year survival 43.1%43.1% 61.9%61.9% 18.8%18.8%

3 year survival3 year survival 27.7%27.7% 47.4%47.4% 19.7%19.7%

(14.7-42.3) (14.7-42.3) (32.8-60.7)(32.8-60.7)

Median survivalMedian survival 21.1 mo21.1 mo 33.1 mo33.1 mo 12 mo12 mo

Median follow-upMedian follow-up 45.2 mo45.2 mo 46.2 mo46.2 mo 1 mo 1 mo

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POET - ConclusionsPOET - Conclusions

There is a strong trend for improved survival by There is a strong trend for improved survival by adding radiotherapy to preoperative chemotherapyadding radiotherapy to preoperative chemotherapy

Statistical significance was not reached in our trial Statistical significance was not reached in our trial due to low number of patients randomizeddue to low number of patients randomized

These results are in line with other published These results are in line with other published phase II-III trials investigating perioperative phase II-III trials investigating perioperative chemoradiation in EG-junction cancerchemoradiation in EG-junction cancer

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