Neoadjuvante Therapie des resektablen Ösophaguskarzinoms

Zusammenfassung

Hintergrund: Die chirurgische Therapie des lokalisierten Ösophaguskarzinoms stellt nach wie vor das einzige kurative Therapieverfahren dar. Häufig sind bei Patienten mit lokal fortgeschrittenen Tumoren bereits intraabdominelle paraaortale Lymphknotenmetastasen nachweisbar und/oder es besteht eine beträchtliche Komorbidität, so dass nur wenige operiert werden können. Diese Tatsache hat dazu geführt, perioperative Therapiemodalitäten zu prüfen, wobei ein allgemein akzeptierter multimodaler Therapiestandard derzeit für kein Tumorstadium existiert. Methodik: Mittels einer computerunterstützten (MEDLINE, ASCO Proceedings) sowie manuellen Suche wurden randomisierte klinische Studien und Metaanalysen, welche eine präoperative Therapie plus anschließender Operation bei Patienten mit resektablen Ösophaguskarzinom untersuchten, identifiziert. Ergebnisse: Dreiundzwanzig randomisierte kontrollierte Studien und fünf Metaanalysen wurden identifiziert. Probleme in der Interpretation vor allem älterer Studien ergeben sich unter anderem durch das Fehlen moderner bildgebender Untersuchungsmethoden, wodurch keine exakte Festlegung des Tumorstadiums möglich war, durch die Inklusion von Patienten mit unterschiedlichen Tumorstadien (potenziell resektabel/lokal fortgeschritten) sowie unterschiedliche histologische Entitäten (Plattenepithelkarzinom/Adenokarzinom), durch den Einsatz unterschiedlicher Operationstechniken und durch das Vorliegen kleiner Patientenzahlen. Es gab keine Unterschiede bezüglich der Mortalität für folgende perioperative Therapiemodalitäten: präoperative Radiotherapie versus postoperative Radiotherapie, prä- und postoperative Radiotherapie versus postoperative Radiotherapie (prä- und postoperative Radiotherapie zeigte eine höhere Sterblichkeitsrate), präoperative Radiotherapie versus Operation, präoperative Chemotherapie versus Operation, prä- und postoperative Chemotherapie versus Operation. Bezüglich der 3-Jahres-Mortalität ergaben sich für folgende Therapiemodalitäten statistisch signifikante Unterschiede: präoperative Radiochemotherapie versus Operation (präoperative Therapie überlegen), präoperative Chemotherapie versus präoperative Radiotherapie (präoperative Radiotherapie überlegen). Schlussfolgerung: Aus der vorliegenden Literatur kann keine eindeutige Standardempfehlung zur multimodalen Therapie bei resektablen Ösophaguskarzinomen abgeleitet werden. Somit kann heutzutage eine neoadjuvante Therapie dieser Erkrankung ausschließlich an Zentren mit maximaler chirurgischer Expertise und im Rahmen interdisziplinär erarbeiteter Studienprotokolle gerechtfertigt werden.

Abstract

Background: Surgical excision remains the only therapeutic approach with curative potential in patients with localized esophageal cancer. Due to the presence of lymph node metastases upon diagnosis in a large percentage of patients with locally advanced tumors and/or the presence of considerable co-morbidity, only a limited number of patients are amenable to surgery. These facts have prompted us to evaluate approaches including perioperative therapy modalities. Methods: By means of a computer-supported search (MEDLINE, ASCO Proceedings) as well as a manual literature search, randomized clinical trials and meta-analyses evaluating preoperative therapy plus surgery in patients with resectable esophageal cancer were identified. Results: Twenty-three randomized clinical studies and five meta-analyses were identified. Interpretation - especially of the older studies - however, is hampered by the lack of a stringent application of modern examination techniques allowing for exact specification of tumor stage (resectable/locally advanced) as well as the inclusion of patients with different histological entities (squamous cell/adenocarcinoma), different surgical techniques and the low number of patients. There were no significant differences for the following perioperative therapy modalities regarding tumor-related mortality: preoperative radiotherapy versus postoperative radiotherapy, preoperative and postoperative radiotherapy versus postoperative radiotherapy (higher mortality in preoperative and postoperative radiotherapy arm), preoperative radiotherapy versus surgery, preoperative chemotherapy versus surgery, preoperative and postoperative chemotherapy versus surgery. In terms of 3-year mortality, statistically significant differences could be found for the following therapy modalities: preoperative radiochemotherapy versus surgery (preoperative therapy superior), preoperative chemotherapy versus preoperative radiotherapy (preoperative radiotherapy superior). Conclusion: Judging from these data, no clear recommendation for a standard multimodality approach outside clinical studies can be given for patients with resectable esophageal cancer. Neoadjuvant therapy, therefore, can only be recommended in centers with a maximum surgical expertise and in the context of multidisciplinary study protocols.

Ösophaguskarzinom - präoperative Therapie - neoadjuvante Therapie - Chemotherapie - Radiotherapie - Radiochemotherapie

Esophageal cancer - preoperative therapy - neoadjuvant therapy - chemotherapy - radiotherapy - radiochemotherapy

Literatur

• 1 Wittekind C, Tannapfel A. Pathologische Morphologie und Prognosefaktoren. Meyer HJ, Buhr HJ, Wilke H Management des Ösophagus- und Magenkarzinoms Berlin, Heidelberg; Springer-Verlag 2004: 82-92
• 2 Lordick F, Stein H J, Peschel C. et al . Neoadjuvant therapy for oesophageal cancer.  Br J Surg. 2004;  91 540-551
• 3 Kelsen D P, Ginsberg R, Pajak T F. et al . Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer.  N Engl J Med. 1998;  339 1979-1984
• 4 Medical R esearch Council Oesophageal Cancer Working Party. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomized controlled trial.  Lancet. 2002;  359 1727-1733
• 5 Fok M, McShane J, Law S YK. et al . Prospective randomised study in the treatment of oesophageal carcinoma.  Asian J Surg. 1994;  17 223-229
• 6 Launois B, Delarue D, Campion J P. et al . Preoperative radiotherapy for carcinoma of the esophagus.  Surg Gynecol Obstet. 1981;  153 690-692
• 7 Gignoux M, Roussel A, Paillot B. et al . The value of preoperative radiotherapy in esophageal cancer: results of a study of the E.O.R.T.C.  World J Surg. 1987;  11 426-432
• 8 Wang M, Gu X Z, Yin W. et al . Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of esophageal carcinoma: report on 206 patients.  Int J Radiat Oncol Biol Phys. 1989;  16 325-327
• 9 Nygaard K, Hagen S, Hansen H S. et al . Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer.  World J Surg. 1992;  16 1104-1109
• 10 Arnott S J, Duncan W, Kerr G R. et al . Low dose preoperative radiotherapy for carcinoma of the oesophagus: results of a randomized clinical trial.  Radiother Oncol. 1992;  24 108-113
• 11 Arnott S J, Duncan W, Gignoux M. et al . Preoperative radiotherapy for esophageal carcinoma.  Cochrane Database Syst Rev. 2000;  (4) CD001799
• 12 Iizuka T, Ide H, Kakegawa T. et al . Preoperative radioactive therapy for esophageal carcinoma. Randomized evaluation trial in eight institutions.  Chest. 1988;  93 1054-1058
• 13 Schlag P M. Randomized trial of preoperative chemotherapy for squamous cell cancer of the esophagus. The Chirurgische Arbeitsgemeinschaft fuer Onkologie der Deutschen Gesellschaft fuer Chirurgie Study Group.  Arch Surg. 1992;  127 1446-1450
• 14 Maipang T, Vasinanukorn P, Petpichetchian C. et al . Induction chemotherapy in the treatment of patients with carcinoma of the esophagus.  J Surg Oncol. 1994;  56 191-197
• 15 Law S, Fok M, Chow S. et al . Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a prospective randomized trial.  J Thorac Cardiovasc Surg. 1997;  114 210-217
• 16 Kok T C, van Lanschot J, Siersema P D. et al . Neoadjuvant chemotherapy in operable esophageal squamous cell cancer: final report of a phase III multicenter randomized controlled trial [abstract].  Proc Annu Meet Am Soc Clin Oncol. 1997;  16 277 a
• 17 Ancona Z F, Yang Z Y, Liang J. et al . Value of radiotherapy after radical surgery for esophageal carcinoma: a report of 495 patients.  Ann Thorac Surg. 2003;  75 (2) 331-336
• 18 Bhansali M S, Vaidya J S, Bhatt R G. et al . Chemotherapy for carcinoma of the esophagus: a comparison of evidence from meta-analyses of randomized trials and of historical control studies.  Ann Oncol. 1996;  7 355-359
• 19 Urschel J D, Vasan H, Blewett C J. A meta-analysis of randomized controlled trials that compared neoadjuvant chemotherapy and surgery to surgery alone for resectable esophageal cancer.  Am J Surg. 2002;  183 (3) 274-279
• 20 Malthaner R, Fenlon D. Preoperative chemotherapy for resectable thoracic esophageal cancer (Cochrane Methodology Review). The Cochrane Library Chichester, UK; John Wiley & Sons Ltd 2003 (4): 174
• 21 Roth J A, Pass H I, Flanagan M M. et al . Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus.  J Thorac Cardiovasc Surg. 1988;  96 242-248
• 22 Kelsen D P, Minsky B, Smith M. et al . Preoperative therapy for esophageal cancer: a randomized comparison of chemotherapy versus radiation therapy.  J Clin Oncol. 1990;  8 1352-1361
• 23 Le P rise E, Etienne P L, Meunier B. et al . A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus.  Cancer. 1994;  73 1779-1784
• 24 Apinop C, Puttisak P, Preecha N. A prospective study of combined therapy in esophageal cancer.  Hepatology Gastroenterol. 1994;  41 391-393
• 25 Walsh T N, Noonan N, Hollywood D. et al . A comparison of multimodal therapy and surgery for esophageal adenocarcinoma.  N Engl J Med. 1996;  335 462-467
• 26 Bosset J F, Gignoux M, Triboulet J P. et al . Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus.  N Engl J Med. 1997;  337 161-167
• 27 Walsh T N, McDonell C O, Mulligan E D. et al . Multimodal therapy versus surgery alone for squamous cell carcinoma of the esophagus: a prospective randomized trial.  Gastroenterology. 2000;  118 A1008 (abstract)
• 28 Urba S G, Orringer M B, Turrisi A. et al . Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma.  J Clin Oncol. 2001;  19 305-313
• 29 Burmeister B H, Smithers B M, Gebski V. et al . Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial.  Lancer Oncol. 2005;  6 (9) 659-668
• 30 Lee J L, Park S I, Kim S B. et al . A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma.  Ann Oncol. 2004;  15 (6) 947-954
• 31 Fiorica F, Cammà C, Venturi A. et al . Preoperative radiotherapy and chemotherapy in patients with esophageal carcinoma: a meta-analysis.  Int J Radiat Oncol Biol Phys. 2002;  54 (2) 220
• 32 Urschel J D, Vasan H. A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer.  Am J Surg. 2003;  185 538-543
• 33 Andersen A P, Berdal P, Edsmyr F. et al . Irradiation, chemotherapy and surgery in esophageal cancer: a randomized clinical study. The first Scandinavian trial in esophageal cancer.  Radiother Oncol. 1984;  2 179-188