Onkologische Chirurgie Struktur und Entwicklung an einer Universitätsklinik

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1 Campus Großhadern Chirurgische Klinik und Poliklinik CAMPUS GROSSHADERN CAMPUS INNENSTADT LOREM IPSUM SETUR ALARME Onkologische Chirurgie Struktur und Entwicklung an einer Universitätsklinik C. J. Bruns Chirurgische Klinik und Poliklinik, Klinikum Großhadern LMU München

2 Additiver Effekt von Gemcitabine, Cisplatin und Hyperthermie

3 Hyperthermie-System BSD-2000 System: SIGMA-60 (4 Antennas, W,90 MHz) Radiofrequency Temperatures: C Estimated perfusion: 20 ml/100g/min Site of recurrent disease: Retroperitoneum: 35-85% Peritoneum: 20-55% Liver: 40-70% Lungs: 10-30% SIGMA-Eye (12 Antennas, 100 MHz, W)

4 2 nd -line Treatment in Gemcitabine-Refractory Pancreatic Cancer REGIONAL HYPERTHERMIA in pancreatic cancer A phase II trial adding an upper abdominal heating technology (RHT) to gemcitabine and cisplatin as secondline chemotherapy Trial Title: Gemcitabine plus cisplatin chemotherapy with the addition of regional hyperthermia as secondline treatment in gemcitabine-refractory patients with locally advanced or metastatic pancreatic cancer For patients with: A phase II open clinical trial EudraCT-Nummer: Failure after: Adjuvant gemcitabine-based treatment OR 1 st -line gemcitabine-based treatment N = 32 patients Gemcitabine + Cisplatin + RHT

5 Patient characteristics Toxicität nach GEM+Cis+RHT (NCI CTCAE version 4.0)

6 Gemcitabine und Cisplatin kombiniert mit regionaler Hyperthermie beim Gemcitabinerefraktären, fortgeschrittenen Pankreaskarzinom PFS 4,3 months [CI 1,2-7,4] OS 12,9 months [CI 9,9-15,9]

7 Statistik Hypothese: Studiendesign: mit 80% power einen Anstieg im medianen disease free survival (DFS) von 14 auf 19 Monate (HR 0.73) zu detektieren. Gruppengröße: 168 Patienten pro Behandlungsarm Interimanalyse nach 92, 182 und 274 Ereignissen basierend auf einem Gruppen-sequentiellem Design Intent to treat Analyse (ITT) Primärer Endpunkt: Sekundärer Endpunkt: Rekrutierung: Follow-up: Disease free survival Overall survival Quality of Life Toxizität 3 Jahre 2 Jahre Randomisierung: Ratio 1:1 Internet basierte Randomisierung (Randoulette)

8 Clinical response rate entsprechend RECIST-Kriterien nach Gem+Cis mit RHT * Clinical response was evaluable in 16 out of 23 patients

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10 CAMPUS GROSSHADERN MEDIZINSCHE KLINIK UND POLIKLINIK III HEAT Hyperthermia European Adjuvant Trial A phase III, randomized, open multicenter clinical trial of adjuvant gemcitabine chemotherapy versus intensified therapy with gemcitabine, cisplatin and regional hyperthermia for patients with R0/R1 resected pancreatic cancer Trial of the: ESHO (European Society for Hyperthermic Oncology) AIO (Arbeitsgemeinschaft Internistische Onkologie) For patients with: Complete (R0) or marginal (R1) resected pancreatic cancer Any ductal adenocarcinoma Age 18 years ECOG 0-2 N = 336 Randomization 1:1 Gemcitabine Standard Gemcitabine 1000 mg/m 2 : days 1, 8 and 15, q4w Primary Endpoint: Disease-free Survival Gemcitabine + Cisplatin + RHT Gemcitabine 1000 mg/m 2 : days 1 and 15, q4w Cisplatin 25 mg/m 2 : days 2, 3* and 16, 17*, q4w Regional Hyperthermia (RHT) 60 min, 42 C: days 2, 3* and 16, 17*, q4w Follow up: 3-monthly Secondary Endpoints: Overall Survival, Toxicity, Quality of Life Trial Office: ; heat@med.uni-muenchen.de Dr. Katharina Lechner * as an exception: RHT and cisplatin can be applied day 4 instead of 3 and day 18 instead of 17 MEDIZINISCHE KLINIK UND POLIKLINIK III, CAMPUS GROßHADERN N = 18 patients

11 Hyperthermia European Adjuvant Trial (HEAT) Prospective randomized phase III clinical trial CAMPUS GROSSHADERN MEDIZINSCHE KLINIK UND POLIKLINIK III EudraCTNumber: AIO-Nr: AIO-PAK-0111 ClinicalTrials.gov Indentifier: NCT Resectable Pancreatic Cancer Staging Signed informed consent Surgical Resection R0/R1 (± N; M0) Randomization Stratification R0/1 and N+/- and surgical center Start: 4-8 weeks postop. Arm G (n= 168): gemcitabine 1000 mg/m 2 days 1, 8 and 15 total number of courses: 6 total dose of gemcitabine: 18 g/m 2 Staging: every 3 months Arm G + Cis + RHT (n= 168): gemcitabine 1000 mg/m 2 days 1 and 15 cisplatin 25mg/m 2 with regional hyperthermia days 2, 3 and 16, 17 total number of courses: 6 Total dose of gemcitabine: 12 g/m 2 Dr. Katharina Lechner DFS: 14 months Follow up (3 monthly) Primary end point: DFS DFS: 19 months MEDIZINISCHE KLINIK UND POLIKLINIK III, CAMPUS GROßHADERN

12 HEAT- Hyperthermia European Adjuvant Trial CAMPUS GROSSHADERN MEDIZINSCHE KLINIK UND POLIKLINIK III Recruitment 04/ patients screened and excluded prior to the Amendments 18 patients on study 14 randomized 1 inoperable 1 insufficient renal function 1 benign histology 1 peritoneal carcinomatosis 2 waiting for randomization 9 patients refuse 8 liver metastases 1 peritoneal carcinomatosis 7 reduced ECOG/advanced age 15 no ductal adenocarcinoma 11 benign histology 5 inoperable 1 pancytopenia 1 nephrectomy Dr. Katharina Lechner 1 lung metastases MEDIZINISCHE KLINIK UND POLIKLINIK III, CAMPUS GROßHADERN

13 Hyperthermia European Adjuvant Trial (HEAT) Nr. Zentrum Vertrag Initiation 1 LMU München Chirurgie, Onkologie, Hyperthermie = Sponsor Rotkreuzklinikum München Chirurgie Hämato-Onkologische Schwerpunktpraxis, Prof. Salat Städtisches Klinikum München- Bogenhausen Onkologie, Hyperthermie Chirurgie, Gastroenterologie TU München Gastroenterologie Amper Kliniken AG, Klinikum Dachau Chirurgie, Onkologie Klinik Bad Trissl GmbH Onkologie, Hyperthermie BRK Schlossbergklinik Oberstaufen Onkologie, Hyperthermie Universitätsklinikum Erlangen Hyperthermie Universitätsklinikum Tübingen Chirurgie Onkologie Hyperthermie Universitätsklinikum Düsseldorf Chirurgie Onkologie Hyperthermie

14 HEAT Translational Medicine Program CAMPUS GROSSHADERN MEDIZINSCHE KLINIK UND POLIKLINIK III Topics and Participating Centers Stress response Hsp 60, 70, 90, Th1- and Th2-cytokines, Glucose metabolism GTT, Insulin level,. Clinical cooperation group hyperthermia Tumor microenvironment CD45RO Tcells, Treg, NK-cells,. Parraffin-embedded tissue Pharmacodynamic studies hent1, CDA, XPD, ERCC1, DCK, RRM1, Dept. of internal medicine (Oncology) Heparinized blood samples and serum Histopathomorphology KRAS, BRCA2, PTEN,.. Neoangiogenesis mtor, p70s6k, VEGF. Dept. of Pathology Dept. Of Surgery HSP27 as predictive factor Dept. of internal medicine (Gastroenterology) Dr. Katharina Lechner Pages-F JCO 27(35): , 2009; Schäfer-C J Cell Mol Med. j , 2011; Multhoff-G Int J Hyperthermia 25(3): ; Li-D Molecular Carcinogenesis 51:64-74, 2012 MEDIZINISCHE KLINIK UND POLIKLINIK III, CAMPUS GROßHADERN

15 Hyperthermia European Adjuvant Trial (HEAT) Protokollkommittee Protokoll Review Board Onkologie, LMU München Prof. R. Issels Prof. V. Heinemann Dr. Ph. Aubele Chirurgie, LMU München Prof. K.-W. Jauch Prof. C. J. Bruns Onkologie: Prof. M. Lutz, Caritas Klinikum Saarbrücken St. Theresia Prof. D. F. Lordick, Universitätsklinikum Leipzig Hyperthermie: Prof. S. Hegewisch-Becker, Onkol. Hämatol. Schwerpunktpraxis Eppendorf Gastroenterologie, LMU München Prof. F. Kolligs