Adjuvante und palliative Therapie des Pankreaskarzinoms – Update

Kernaussagen

Kurative, adjuvante und additive Therapie

• Eine kurative Therapie bei Patienten mit Pankreaskarzinom ist nur nach radikaler Resektion (meist pyloruserhaltende Whipple-Operation) möglich, wobei ein Langzeitüberleben nur bei ca. 1 – 3 % der Patienten erreicht werden kann.

• Nach potenziell kurativer Resektion sind der Resektionsstatus, das Grading, die Tumorgröße und der Nodalstatus entscheidende Prognoseparameter.

• Eine adjuvante, aber auch eine additive Chemotherapie mit Gemcitabin ist sinnvoll.

Neoadjuvante Therapie

• Eine neoadjuvante Radiochemotherapie mit modernen Bestrahlungsregimen ist noch nicht etabliert. Möglicherweise kann bei einem Teil der Patienten durch eine präoperative Radiochemotherapie die Prognose verbessert werden, wenn durch diese Therapie eine Operabilität zu erreichen ist.

• Eine Induktionschemotherapie hilft eventuell dabei, Patienten zu identifizieren, die von einer neoadjuvanten Radiochemotherapie profitieren.

Palliative Therapie

• Jede Therapie eines lokal fortgeschrittenen oder metastasierten Pankreaskarzinoms erfolgt in palliativer Absicht.

• Trotz einzelner Studien, in denen eine geringe Überlegenheit einer Kombinationstherapie gezeigt werden konnte, bleibt Gemcitabin derzeit die palliative Standardchemotherapie. Das mittlere Überleben von Patienten mit metastasiertem Pankreaskarzinom beträgt bei Durchführung einer palliativen Chemotherapie etwas mehr als 6 Monate.

• Durch Addition von „Biologicals” wie dem EGFR-Inhibitor Erlotinib kann nur bei Auftreten einer signifikanten Hautreaktion eine klinisch relevante Verbesserung des Überlebens erreicht werden.

• Zweitlinientherapien nach Progress unter einer Erstlinientherapie sind wahrscheinlich wirksam, hier bieten sich Kombinationen aus Fluoropyrimidinen und Oxaliplatin an. Konzepte zur Zweitlinientherapie beim Pankreaskarzinom sollten weiter in Studien geprüft werden.

Literatur

• 1 Adler G, Seufferlein T, Bischoff S C. et al . [S3-Guidelines „Exocrine pancreatic cancer” 2007].  Z Gastroenterol. 2007;  45 487-523
• 2 Jemal A, Siegel R, Ward E. et al . Cancer statistics, 2009.  CA Cancer J Clin. 2009;  59 225-249
• 3 Larsson S C, Permert J, Hakansson N. et al . Overall obesity, abdominal adiposity, diabetes and cigarette smoking in relation to the risk of pancreatic cancer in two Swedish population-based cohorts.  Br J Cancer. 2005;  93 1310-1315
• 4 Luo J, Ye W, Zendehdel K. et al . Oral use of Swedish moist snuff (snus) and risk for cancer of the mouth, lung, and pancreas in male construction workers: a retrospective cohort study.  Lancet. 2007;  369 2015-2020
• 5 Wolpin B M, Chan A T, Hartge P. et al . AB0 Blood Group and the Risk of Pancreatic Cancer.  J Natl Cancer Inst. 2009;  101 424-431
• 6 Amundadottir L, Kraft P, Stolzenberg-Solomon R Z. et al . Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer.  Nat Genet. 2009;  41 986-990
• 7 Hartwig W MD, Hackert T MD, Hinz U M. et al . Multivisceral Resection for Pancreatic Malignancies: Risk-Analysis and Long-Term Outcome.  Ann Surg. 2009;  250 81-87
• 8 Berger A C, Garcia  Jr M, Hoffman J P. et al . Postresection CA 19-9 predicts overall survival in patients with pancreatic cancer treated with adjuvant chemoradiation: a prospective validation by RTOG 9704.  J Clin Oncol. 2008;  26 5918-5922
• 9 David M, Lepage C, Jouve J L. et al . Management and prognosis of pancreatic cancer over a 30-year period.  Br J Cancer. 2009;  101 215-218
• 10 Oettle H, Post S, Neuhaus P. et al . Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial.  JAMA. 2007;  297 267-277
• 11 Gudjonsson B. Cancer of the pancreas. 50 years of surgery.  Cancer. 1987;  60 2284-2303
• 12 Carpelan-Holmstrom M, Nordling S, Pukkala E. et al . Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish Cancer Registry.  Gut. 2005;  54 385-387
• 13 Moertel C G, Frytak S, Hahn R G. et al . Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group.  Cancer. 1981;  48 1705-1710
• 14 Wilkowski R, Thoma M, Schauer R. et al . Effect of chemoradiotherapy with gemcitabine and cisplatin on locoregional control in patients with primary inoperable pancreatic cancer.  World J Surg. 2004;  28 1011-1018
• 15 Chauffert B, Mornex F, Bonnetain F. et al . Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000–01 FFCD/SFRO study.  Ann Oncol. 2008;  19 1592-1599
• 16 Sultana A, Smith C T, Cunningham D. et al . Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer.  J Clin Oncol. 2007;  25 2607-2615
• 17 Huguet F, Andre T, Hammel P. et al . Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies.  J Clin Oncol. 2007;  25 326-331
• 18 Krishnan S, Rana V, Janjan N A. et al . Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy.  Cancer. 2007;  110 47-55
• 19 Evans D B, Varadhachary G R, Crane C H. et al . Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head.  J Clin Oncol. 2008;  26 3496-3502
• 20 Hennig R, Tempia-Caliera A A, Hartel M. et al . Staging laparoscopy and its indications in pancreatic cancer patients.  Dig Surg. 2002;  19 484-488
• 21 Pisters P W, Lee J E, Vauthey J N. et al . Laparoscopy in the staging of pancreatic cancer.  Br J Surg. 2001;  88 325-337
• 22 Kalser M H, Ellenberg S S. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection.  Arch Surg. 1985;  120 899-903
• 23 Klinkenbijl J H, Jeekel J, Sahmoud T. et al . Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group.  Ann Surg. 1999;  230 776-782; discussion 782 – 774
• 24 Neoptolemos J P, Dunn J A, Stocken D D. et al . Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial.  Lancet. 2001;  358 1576-1585
• 25 Neoptolemos J P, Stocken D D, Friess H. et al . A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer.  N Engl J Med. 2004;  350 1200-1210
• 26 Picozzi V J, Kozarek R A, Traverso L W. Interferon-based adjuvant chemoradiation therapy after pancreaticoduodenectomy for pancreatic adenocarcinoma.  Am J Surg. 2003;  185 476-480
• 27 Picozzi V, Abrams R, Traverso L. et al . ACOSOG Z05031: Report on a multicenter, phase II trial for adjuvant therapy of resected pancreatic cancer using cisplatin, 5-FU, and alpha-interferon. In: 2008 ASCO Annual Meeting.  J Clin Oncol. 2008;  26 Abstract 4505
• 28 Regine W F, Winter K A, Abrams R A. et al . Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial.  JAMA. 2008;  299 1019-1026
• 29 Neoptolemos J, Buechler M, Stocken D. et al . ESPAC-3(v2): A multicenter, international, open-label, randomized, controlled phase III trial of adjuvant 5-fluorouracil/folinic acid (5-FU/FA) versus gemcitabine (GEM) in patients with resected pancreatic ductal adenocarcinoma. In: 2009 ASCO Annual Meeting.  J Clin Oncol. 2009;  27 Abstract LBA4505
• 30 Esposito I, Kleeff J, Bergmann F. et al . Most pancreatic cancer resections are R1 resections.  Ann Surg Oncol. 2008;  15 1651-1660
• 31 Chabot J A, Tsai W Y, Fine R L. et al . Pancreatic Proteolytic Enzyme Therapy Compared With Gemcitabine-Based Chemotherapy for the Treatment of Pancreatic Cancer.  J Clin Oncol. 2009;  27 [Epub ahead of print]
• 32 Glimelius B, Hoffman K, Sjoden P O. et al . Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer.  Ann Oncol. 1996;  7 593-600
• 33 Lutz M P, Koniger M, Muche R. et al . A phase II study of weekly 24-h infusion of high-dose 5-fluorouracil in advanced pancreatic cancer.  Z Gastroenterol. 1999;  37 993-997
• 34 Burris H A 3rd, Moore M J, Andersen J. et al . Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial.  J Clin Oncol. 1997;  15 2403-2413
• 35 Tempero M, Plunkett W, Ruiz Van Haperen V. et al . Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma.  J Clin Oncol. 2003;  21 3402-3408
• 36 Louvet C, Labianca R, Hammel P. et al . Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial.  J Clin Oncol. 2005;  23 3509-3516
• 37 Poplin E, Feng Y, Berlin J. et al . Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group.  J Clin Oncol. 2009;  27 3778-3785
• 38 Heinemann V, Quietzsch D, Gieseler F. et al . Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer.  J Clin Oncol. 2006;  24 3946-3952
• 39 Heinemann V, Labianca R, Hinke A. et al . Increased survival using platinum analog combined with gemcitabine as compared to single-agent gemcitabine in advanced pancreatic cancer: pooled analysis of two randomized trials, the GERCOR/GISCAD intergroup study and a German multicenter study.  Ann Oncol. 2007;  18 1652-1659
• 40 Cunningham D, Chau I, Stocken D. et al .Phase III randomised comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer. In: ECCO 13 – the European Cancer Conference Paris. European Journal of Cancer Supplements. 2005: 4
• 41 Berlin J D, Catalano P, Thomas J P. et al . Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297.  J Clin Oncol. 2002;  20 3270-3275
• 42 Herrmann R, Bodoky G, Ruhstaller T. et al . Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group.  J Clin Oncol. 2007;  25 2212-2217
• 43 Riess H, Helm A, Niedergethmann M. et al .A Randomised, Prospective, Multicenter, Phase III Trial of Gemcitabine, 5-Fluorouracil (5-FU), Folinic Acid vs. Gemcitabine alone in Patients with Advanced Pancreatic Cancer. In: 2005 ASCO Annual Meeting Journal of Clinical Oncology; 2005 ASCO Annual Meeting Proceedings;. 2005: Abstract 4009
• 44 Van Cutsem E, van de Velde H, Karasek P. et al . Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer.  J Clin Oncol. 2004;  22 1430-1438
• 45 Bramhall S R, Schulz J, Nemunaitis J. et al . A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer.  Br J Cancer. 2002;  87 161-167
• 46 Moore M J, Goldstein D, Hamm J. et al . Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group.  J Clin Oncol. 2007;  25 1960-1966
• 47 Philip P, Benedetti J, Fenoglio-Preiser C. et al .Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study. In: 2007 ASCO Annual Meeting: Journal of Clinical Oncology; 2007 ASCO Annual Meeting Proceedings. 2007: Abstract LBA4509
• 48 Kindler H, Niedzwiecki D, Hollis D. et al .A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis of Cancer and Leukemia Group B (CALGB). In: 2007 ASCO Annual Meeting Journal of Clinical Oncology; 2007 ASCO Annual Meeting Proceedings. 2007: Abstract 4508
• 49 Van Cutsem E, Vervenne W L, Bennouna J. et al . Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.  J Clin Oncol. 2009;  27 2231-2237
• 50 Verslype C, Vervenne W, Bennouna J. et al .Rash as a marker for the efficacy of gemcitabine plus erlotinib-based therapy in pancreatic cancer: Results from the AViTA Study. In: 2009 ASCO Annual Meeting Journal of Clinical Oncology; 2009 ASCO Annual Meeting Proceedings;. 2009: Abstract 4532
• 51 Boeck S, Heinemann V. Second-Line Therapy in Gemcitabine-Pretreated Patients with Advanced Pancreatic Cancer.  J Clin Oncol. 2008;  26 1178-1179
• 52 Pelzer U, Stieler J, Roll L. et al . Second-line therapy in refractory pancreatic cancer. Results of a phase II study.  Onkologie. 2009;  32 99-102
• 53 Oettle H, Pelzer U, Stieler J. et al .Oxaliplatin/folinic acid/5-fluorouracil [24 h] (OFF) plus best supportive care versus best supportive care alone (BSC) in second-line therapy of gemcitabine-refractory advanced pancreatic cancer (CONKO 003). In: 2005 ASCO Annual Meeting Journal of Clinical Oncology; 2005 ASCO Annual Meeting Proceedings. 2005: Abstract 4031
• 54 Boeck S, Weigang-Kohler K, Fuchs M. et al . Second-line chemotherapy with pemetrexed after gemcitabine failure in patients with advanced pancreatic cancer: a multicenter phase II trial.  Ann Oncol. 2007;  18 745-751
• 55 Sudo K, Yamaguchi T, Ishihara T. et al .Phase II study of S-1 in patients with gemcitabine resistant advanced pancreatic carcinoma. In: 2006 ASCO Annual Meeting Journal of Clinical Oncology; 2006 ASCO Annual Meeting Proceedings; 2006: Abstract 14 070. 
• 56 Kulke M H, Blaszkowsky L S, Ryan D P. et al . Capecitabine Plus Erlotinib in Gemcitabine-Refractory Advanced Pancreatic Cancer.  J Clin Oncol. 2007;  25 4787-4792
• 57 Wolpin B M, Hezel A F, Abrams T. et al . Oral mTOR Inhibitor Everolimus in Patients with Gemcitabine-Refractory Metastatic Pancreatic Cancer.  J Clin Oncol. 2009;  27 193-198
• 58 Loehrer P, Powell M, Cardenes H. et al .A randomized phase III study of gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with localized, unresectable pancreatic cancer: E4201. In: 2008 ASCO Annual Meeting Journal of Clinical Oncology; 2008 ASCO Annual Meeting Proceedings; 2008: Abstract 4506. 
• 59 Rocha Lima C M, Green M R, Rotche R. et al . Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate.  J Clin Oncol. 2004;  22 3776-3783
• 60 Oettle H, Richards D, Ramanathan R K. et al . A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer.  Ann Oncol. 2005;  16 1639-1645
• 61 Abou-Alfa G K, Letourneau R, Harker G. et al . Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer.  J Clin Oncol. 2006;  24 4441-4447
• 62 Van Cutsem E, Aerts R, Haustermans K. et al . Systemic treatment of pancreatic cancer.  Eur J Gastroenterol Hepatol. 2004;  16 265-274