Können neue Substanzen endlich die Prognose verbessern? - Interdisziplinäre Behandlung des Pankreaskarzinoms

Zusammenfassung

Trotz großer therapeutischer Bemühungen ist die Prognose von Patienten mit Pankreskarzinom noch immer als sehr schlecht einzuschätzen, da lokale Infiltrationen oder eine Fernmetastasierung frühzeitig auftreten können. Zudem fehlen Frühsymptome, was die Diagnose lokaler Stadien erschwert. Als einzige kurative Therapieoption gilt die chirurgische Entfernung des Tumors (R0-Resektion), die jedoch nur in wenigen Fällen möglich ist. Eine neoadjuvante (präoperative) Radio-Chemotherapie kann bei einem Teil der Patienten jedoch ein Downstaging, eine lokale Tumorremission und in Einzelfällen sogar eine komplette Remission erreichen. Dies wiederum hat eine verbesserte Resektabilität und somit eine verbesserte lokale Kontrolle zur Folge. Noch kann eine postoperative adjuvante Therapie nach kurativer Resektion (R0-Resektion) - wie auch die neoadjuvante Therapie - allerdings nicht als Behandlungsstandard gelten. Nach einer palliativen R1-Resektion kann aufgrund des hohen lokalen und systemischen Rezidivrisikos eine postoperative Therapie empfohlen werden. Dagegen gilt bei primär inoperablen, nichtmetastasierten Pankreaskarzinomen eine Radiochemotherapie oder eine alleinige systemische Chemotherapie als Standard. Sie ermöglichen zumindest bei einem Teil der Patienten ein Downstaging und im günstigen Fall eine sekundäre Resektabilität. Angesichts neuer Medikamente und effektiverer Kombinationstherapien kann das Pankreaskarzinom nicht mehr als chemotherapieresistent bezeichnet werden. Patienten mit primär metastasiertem Krankheitsbild sollten daher - sofern es der Allgemeinzustand erlaubt - einer systemischen Gemcitabin-Chemotherapie zugeführt werden.

Summary

Despite great therapeutic efforts the prognosis of pancreatic cancer patients remains dismal which is explained by early local tumor spread and rapid systemic metastasis. Since specific symptoms are missing in early disease, most patients are diagnosed with advanced tumors. Complete surgical resection of the pancreatic tumor (R0), known as the only curative therapeutic option, can therefore be performed in only a few patients. Neoadjuvant (preoperative) chemoradiotherapy may induce tumor downstaging which in selected cases may allow resectability and thereby improve local control. The benefit from postoperative treatment after complete tumor resection (R0) is presently evaluated in several randomised trials. Since clear results are missing so far, postoperative adjuvant treatment is not a standard of therapy. After incomplete (R1) resections, postoperative treatment can be recommended due to a high risk of local and systemic relapse. Since the benefit of chemotherapy versus chemoradiotherapy remains to be established also in this setting, there is a clear need to treat patients in controlled clinical trials. Patients with locally advanced non-metastatic pancreatic cancer should, however, receive chemotherapy or chemoradiotherapy with gemcitabine as a standard of care.

Key Words

pancreatic cancer - chemoradiotherapy - gemcitabine

Literatur

• 1 Abe M, Shibamoto Y, Nishimura Y. Intraoperative radiotherapy for pancreatic cancer in Japan: Multi-institutional and Kyoto University experiences.  In: Schildberg FW, Willich N, Krämling H-J (eds). Intraoperative radiation therapy.  Essen: Verlag Die blaue Eule. 1993;  278-281
• 2 Bruckner HW, Kalnicki S, Dalton J. Combined modality therapy increasing local control of pancreatic cancer.  Cancer Invest. 1993;  11 241-246
• 3 Brunner TB, Grabenbauer GG, Baum U. et al. . Adjuvant and neoadjuvant radiochemotherapy in ductal pancreatic carcinoma.  Strahlenther Onkol. 2000;  176 265-273
• 4 Burris HA, Moore MJ, 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
• 5 Carducci MA, Abrams RA, Yeo CJ. et al. . Early evaluation of abdominal/hepatic irradiation and 5-fluorouracil/leucovorin infusion after pancreaticoduodenectomy.  Int J Radiat Oncol Biol Phys. 1996;  35 143-150
• 6 Carmichael J, Fink U, Russell RC. et al. . Phase II study of Gemcitabine in patients with advanced pancreatic cancer.  Br J Cancer. 1996;  73 101-105
• 7 Casper ES, Green MR, Kelsen DP. et al. . Phase II trial of Gemcitabine (2,2'-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas.  Invest New Drugs. 1994;  12 29-34
• 8 Cullinan S, Moertel CG, Wieand HS. et al. . A phase III trial on the therapy of advanced pancreatic carcinoma. Evaluations of the Mallinson regimen and combined 5-fluorouracil, doxorubicin, and cisplatin.  Cancer. 1990;  65 2207-2212
• 9 Gastrointestinal Tumor Study Group . Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer.  Cancer. 1987;  59 2006-2010
• 10 Gastrointestinal Tumor Study Group . Radiation therapy combined with adriamycin or 5-fluorouracil for the treatment of locally unresectable pancreatic carcinoma.  Cancer. 1985;  56 2563-2568
• 11 Gastrointestinal Tumor Study Group . Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose radiation alone, moderate dose radiation and high dose radiation + 5-FU.  Cancer. 1981;  48 1705
• 12 Gastrointestinal Tumor Study Group . Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone.  J Natl Cancer Inst. 1988;  80 751-755
• 13 Heinemann V, Wilke H, Possinger K. et al. . Gemcitabine and cisplatin in the treatment of advanced and metastatic pancreatic cancer. Final results of a phase II study.  Proc Am Soc Clin Oncol. 1999;  18 1052
• 14 Hoffman JP, Lipsitz S, Pisansky T. et al. . Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group Study.  J Clin Oncol. 1998;  16 317-323
• 15 Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection.  Arch Surg. Published erratum appears in Arch. 1986;  121 899-903
• 16 Kamthan AG, Morris JC, Dalton J. et al. . Combined modality therapy for stage II and stage III pancreatic carcinoma.  J Clin Oncol. 1997;  15 2920-2927
• 17 Kelly DM, Benjamin IS. Pancreatic carcinoma.  Ann Oncol. 1995;  6 19-28
• 18 Klaassen DJ, MacIntyre JM, Catton GE. et al. . Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil - an Eastern Cooperative Oncology Group study.  J Clin Oncol. 1985;  3 373-378
• 19 Klinkenbijl JH, Jeekel J. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastro-intestinal tract cancer cooperative group.  Ann Surg. 1999;  230 776-784
• 20 Lawrence TS, Chang EY, Hahn TM. et al. . Radiosensitization of pancreatic cancer cells by 2',2'-difluoro-2'-deoxycytidine.  Int J Radiat Oncol Biol Phys. 1996;  34 867-872
• 21 Leitlinien der Deutschen Krebsgesellschaft . Exokrines Pankreaskarzinom. In: Kurzgefasste interdisziplinäre Leitlinie 2002 - Diagnostik und Therapie maligner Erkrankungen (3. Auflage).  München - Bern - Wien - New York: W. Zuckschwerdt Verlag. 2002; 
• 22 McGinn CJ, Shewach DS, Lawrence TS. Radiosensitizing nucleosides.  J Natl Cancer Inst. 1996;  88 1193-1203
• 23 Moertel CG, Childs DS, Reitemeier RJ. et al. . Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer.  Lancet. 1969;  2 865-867
• 24 Mose S, Karapetian M, Jüling-Pohlit L. et al. . Verstärkung der radiotherapeutischen Wirkung auf HeLa-Zellen durch Gemcitabine.  Strahlenther Onkol. 1999;  175 78-83
• 25 Neoptolemos JP, Dunn JA, Moffitt DD. et al. . ESPAC-1 interim results: A european, randomised study to assess the roles of adjuvant chemotherapy (5FU + folinic acid) and adjuvant chemoradiation (40 GY + 5 FU) in resectable pancreatic cancer.  Lancet. 2001;  358 1576-585
• 26 Neoptolemos JP, Stocken DD. et al. . Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial.  Ann Surg. 2002;  234 758-768
• 27 Ozaki H, Kinoshira T, Kosuge T. et al. . Effectiveness of multimodality treatment for resectable pancreatic cancer.  Int J Pancreatol. 1990;  7
• 28 Rau HG, Wichmann MW, Wilkowski R. et al. . Chirurgische Therapie des lokal fortgeschrittenen und primär inoperablen Pankreaskarzinoms nach neoadjuvanter präoperativer Radiochemotherapie.  Chirurg. 2002;  132-137
• 29 Rothenberg ML, Moore MJ, Cripps MC. et al. . A phase II trial of Gemcitabine in patients with 5-FU-refractory pancreas cancer.  Ann Oncol. 1996;  7 347-353
• 30 Shewach DS, Hahn TM, Chang E. et al. . Metabolism of 2',2'-difluoro-2'-deoxycytidine and radiation sensitization of human colon carcinoma cells.  Cancer Res. 1994;  54 3218-3223
• 31 Sindelar WF, Kinsella TJ. Studies of intraoperative radiotherapy in carcinoma of the pancreas.  Ann Oncol. 1999;  10 226-230
• 32 Spitz FR, Abbruzzese JL, Lee JE. et al. . Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas.  J Clin Oncol. 1997;  15 928-937
• 33 Tepper J, Nardi G, Sutt H. Carcinoma of the pancreas: review of MGH experience from 1963 to 1973. Analysis of surgical failure and implications for radiation therapy.  Cancer. 1976;  37 1519-1524
• 34 van Heerden JA, ReMine WH, Weiland LH. et al. . Total pancreatectomy for ductal adenocarcinoma of the pancreas. Mayo Clinic experience.  Am J Surg. 1981;  142 308-311
• 35 Westerdahl J, Andren-Sandberg A, Ihse I. Recurrence of exocrine pancreatic cancer - local or hepatic?.  Hepatogastroenterology. 1993;  40 384-387
• 36 Wilkowski R, Heinemann V, Rau HG. Locally advanced pancreatic carcinoma - Radiochemotherapy prolongs survival.  MMW Fortschr Med. 2000;  142 31-32
• 37 Wilkowski R, Heinemann V, Stoffregen C. Gemcitabine (Gemzar) and radiotherapy - is it feasible?.  Front Radiat Ther Oncol. 2002;  37 78-83
• 38 Wilkowski R, Thoma M, Heinemann V. et al. . Radiochemotherapy with gemcitabine and cisplatin in pancreatic cancer - feasible and effective.  Strahlenther Onkol. 2003;  179 78-86
• 39 Wilkowski R, Thoma M, Dühmke E. et al. . Concurrent chemoradiotherapy with Gemcitabine and Cisplatin after incomplete (R1-)resection of locally advanced pancreatic carcinoma.  ASCO (in Vorbereitung). 2003; 
• 40 Yeo CJ, Abrams RA, Grochow LB. et al. . Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience.  Ann Surg. 1997;  255 621-636
• 41 Yeung RS, Weese JL, Hoffman JP. et al. . Neoadjuvant chemoradiation in pancreatic and duodenal carcinoma. A Phase II Study.  Cancer. 1993;  72 2124-2133

1 european study group for pancreatic cancer

2 5-Fluorouracil, Doxorubicin, Mitomycin C

3 Streptozotocin, Mitomycin C, 5-Fluorouracil

4 5-Fluorouracil, Cyclophosphamid, Methotrexat und Vincristin

Anschrift für die Verfasser