Chirurgisches Management der perforationsbedingten Peritonitis im Zusammenhang mit einer Bevacizumab-Therapie

Zusammenfassung

Hintergrund: Bevacizumab (Avastin®, Fa. Roche, Genentech) ist der erste Angiogeneseinhibitor, der für die routinemäßige klinische Behandlung maligner Tumoren zugelassen wurde. Das Nebenwirkungsprofil des Antikörpers (Ak) unterscheidet sich von jenem der traditionellen Chemotherapie. Eine zwar seltene, aber schwerwiegende Avastin®-spezifische Komplikation ist die gastrointestinale (GI) Perforation. Sie geht mit einer hohen Morbidität und Letalität einher. Das Ziel der vorliegenden Arbeit bestand darin, anhand eigener und publizierter Erfahrungen befundbezogene Besonderheiten dieser außergewöhnlichen Pathogenese einer perforationsbedingten Peritonitis einschließlich therapeutischem „Outcome“ darzustellen. Methodik: Es wurden die Daten von Patienten mit einer bevacizumabinduzierten perforationsbedingten Peritonitis seit klinischer Einführung i) aus der eigenen Patientenklientel prospektiv erfasst, ii) Literaturangaben gegenübergestellt (historische Vergleichsgruppe) und iii) hinsichtlich der Ergebnisse des chirurgischen Managements (Zielparameter: Raten von Anastomoseninsuffizienzen / Wundheilungsstörungen, Morbidität, Letalität) ausgewertet. Ergebnisse: Über einen 4-Jahres-Zeitraum vom 1.2.2004–31.1.2008 wurden insgesamt 15 Patienten ermittelt, wovon 4 aus der berichtenden Klinik stammten (Durchschnittsalter: 57 Jahre; Frauen / Männer = 2 : 2). Die durchschnittliche Behandlungsdauer bis zum Auftreten der Komplikation betrug im Mittel 70 Tage (Spanne: 8–150 Tage). 13 Patienten wurden operiert, 2 Patienten verstarben ohne operative Versorgung jeweils an den Folgen der Peritonitis. Die Letalität betrug 33,3 % (n = 5 / 15), die Gesamtmorbidität 73,3 % (n = 11 / 15). In allen Fällen, in denen primär eine Anastomose angelegt wurde (n = 4), trat im Verlauf eine Anastomoseninsuffizienz auf (100 %). Die Rate der Wundheilungsstörungen betrug 38,5 % (n = 5 / 13). Schlussfolgerungen: Die Peritonitis nach GI-Perforation infolge einer Bevacizumab-Therapie stellt eine seltene Ak-assoziierte, aber ernst zu nehmende, da lebensbedrohliche Komplikation dar. Die im Zusammenhang mit der Neoangiogeneseinhibition gestörte Wundheilung bedingt Abweichungen im Management gastrointestinaler Perforationsereignisse im Vergleich zur etablierten chirurgischen Standardversorgung. Insbesondere ist zu empfehlen, auf Anastomosen oder Übernähungen zu verzichten und stattdessen, vergleichbar mit der Situation der Immunsuppression, großzügig die Indikation zur Stomaanlage zu stellen.

Abstract

Introduction: Bevacizumab (Avastin®, Fa. Roche, Genentech) is the first anti-angiogenic agent to be approved for the routine clinical treatment of cancer. Its toxicity profile is different to that of standard chemotherapeutic substances. Despite the rarity of gastrointestinal (GI) perforation in patients treated with bevacizumab, this serious adverse event results in significant morbidity and mortality. It was the aim of this study, based on exemplary cases of the reporting clinic as well as on published experiences, to characterise the specific clinical findings, the extraordinary pathogenesis, and the therapeutic outcome of such cases of peritonitis caused by perforation after antibody treatment. Methods: Data of all patients with perforation-caused peritonitis due to bevacizumab therapy since its clinical inauguration were sought in i) the database of the reporting clinic (case series), ii) in the published literature for comparison (historical comparative group) and iii) analysed with regard to results of the surgical management (evaluated parameters: rate of anastomotic insufficiency / disturbances of wound healing, morbidity, mortality). Results: Over a time period of 4 years (from 2 / 1 / 2004 to 1 / 31 / 2008), overall 15 patients were found in this study, among whom 4 patients came from the reporting clinic (mean age, 57 years; males : females = 2 : 2). The mean duration of antibody (Ab) treatment until occurrence of the complication was 70 days (range: 8–150 days). Thirteen patients underwent surgical intervention, 2 patients died due to severe peritonitis without any operation. The overall morbidity was 73.3 % (n = 11 / 15), the mortality was 33.3 % (n = 5 / 15). All patients with an anastomosis developed an anastomotic insufficiency (100 %). Wound healing complications occurred in 38.5 % of the subjects (n = 5 / 13). Conclusions: Peritonitis after GI perforation due to bevacizumab-based Ab treatment needs to be considered as a rare but serious and life-threatening complication. Impairment of wound healing because of the inhibition of angiogenesis is the reason for a different management of GI perforation under these conditions compared with the standard surgical treatment of peritonitis of other causes. In particular, it is recommended to avoid primary anastomosis and to prefer application of an intestinal stoma.

Schlüsselwörter

Bevacizumab - gastrointestinale (GI) Perforation - Peritonitis - chirurgisches Management

Key words

bevacizumab - gastrointestinal (GI) perforation - peritonitis - surgical management

Literatur

• 1 Abbrederis K, Kremer M, Schumacher C. Ischämische Anastomosenperforation im Bereich einer Ileotransversostomie unter Therapie mit Bevacizumab.  Chirurg. 2007;  ,  [online publ]
• 2 August D A, Serrano D, Poplin E. “Spontaneous” delayed colon and rectal anastomotic complications associated with bevacizumab therapy.  J Surg Oncol. 2008;  97 180-185
• 3 Badgwell B D, Camp E R, Feig B et al. Management of bevacizumab-associated bowel perforation: A case series and review to the literature.  Ann Oncol. 2008;  19 577-582
• 4 Cannistra S A, Matulonis U A, Penson R T et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer.  J Clin Oncol. 2007;  25 5180-5186
• 5 Chau I, Cunningham D. Adjuvant therapy in colon cancer – what, when and how?.  Ann Oncol. 2006;  17 1347-1359 ,  Published online 8 March 2006
• 6 Chen H X, Mooney M, Boron M et al. Phase II multicenter trial of bevacizumab plus flourouracil and leucovorin in patients with advanced refractory colorectal cancer: An NCI treatment referral center trial TRC-0301.  J Clin Oncol. 2006;  24 3354-3360
• 7 Cohen M H, Gootenberg J, Keegan P et al. FDA drug approval summary: Bevacizumab (Avastin®) plus carbolatin and paclitaxel as first-line treatment of advanced / metastatic recurrent nonsquamous non-small cell lung cancer.  Oncologist. 2007;  12 713-718
• 8 Cohen M H, Gootenberg J, Keegan P et al. FDA drug approval summary: Bevacizumab plus FOLFOX 4 as second-line treatment of colorectal cancer.  Oncologist. 2007;  12 356-361
• 9 D'Angelica M, Kornprat P, Gonen M et al. Lack of evidence for increased operative morbidity after hepatectomy with perioperative use of bevacizumab: A matched case study.  Ann Surg Oncol. 2007;  14 759-765
• 10 Díaz-Rubio E, Schmoll H J. The future development of bevacizumab in colorectal cancer.  Oncol. 2005;  69 suppl. 3 34-45
• 11 Gordon M S, Cunningham D. Managing patients treated with bevacizumab combination therapy.  Oncol. 2005;  69 suppl. 3 25-33
• 12 Gordon M S, Margolin K, Talpaz M et al. Phase I safety and pharmacokinetic study of recombinant human antivascular endothelial growth factor in patients with advanced cancer.  J Clin Oncol. 2001;  19 843-850
• 13 Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.  N Engl J Med. 2004;  350 2335-2342
• 14 Hurwitz H, Kabbinavar F. Bevacizumab combined with standard fluoropyrimidine-based chemotherapy regimes to treat colorectal cancer.  Oncol. 2005;  69 suppl. 3 17-24
• 15 Hurwitz H, Saini S. Bevacizumab in the treatment of metastatic colorectal cancer: safety profile and management of adverse effects.  Semin Oncol. 2006;  33 (5 suppl. 3) 26-34
• 16 Kamba T, McDonald D M. Mechanisms of adverse effects of anti-VEGF therapy for cancer.  Br J Cancer. 2007;  96 1788-1795
• 17 Kindler H L, Friberg G, Singh D A et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer.  J Clin Oncol. 2005;  23 8033-8040
• 18 Krämer I, Lipp H P. Bevacizumab, a humanized anti-angionetic monoclonal antibody for the treatment of colorectal cancer.  J Clin Pharm Ther. 2007;  32 1-14
• 19 Lordick F, Geinitz H, Theisen J et al. Increased risk of ischemic bowel complications during treatment with bevacizumab after pelvic irradiation: report of three cases.  Int J Radiat Oncol Biol Phys. 2006;  64 1295-1298
• 20 Lordick F, Siewert J R. Bevacizumab-(Avastin®) bedingte chirurgische Komplikationen. Kommentar zum Beitrag Abbrederis K et al.  Chirurg. 2007;  ,  [online publ]
• 21 Prat A, Casado E, Cortés J. New approaches in angiogenic targeting for colorectal cancer.  World J Gastroenterol. 2007;  13 5857-5866
• 22 Presta L G, Chen H, O'Connor S J et al. Humanisation of an anti-vascular endothelial groth factor monoclonal antibody for the therapy of solid tumors and other disorders.  Cancer Res. 1997;  57 4593-4599
• 23 Saif M S, Elfiky A, Salem R R. Gastrointestinal perforation due to bevacizumab in colorectal cancer.  Ann Surg Oncol. 2007;  14 1860-1869
• 24 Saif M S, Mehra R. Incidence and management of bevacizumab-related toxicities in colorectal cancer.  Expert Opin Drug Saf. 2006;  5 553-566
• 25 Scappaticci F A, Fehrenbacher L, Cartwrith T et al. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab.  J Surg Oncol. 2005;  91 173-180
• 26 Shah M A, Ramanathan R K, Ilson D H et al. Multicenter phase II study of irinothecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma.  J Clin Oncol. 2006;  24 5201-5206
• 27 Shih T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies.  Clin Ther. 2006;  28 1779-1802
• 28 Simkins F, Belinson J L, Rose P G. Avoiding Bevacizumab related gastrointestinal toxicity for recurrent ovarian cancer by careful patient screening.  Gynecol Oncol. 2007;  107 118-123 ,  Epub 2007 Jul 23
• 29 Sugrue M, Kozloff M, Hainsworth J et al. Risk factors for gastrointestinal perforations in patients with metastatic colorectal cancer receiving bevacizumab plus chemotherapy.  J Clin Oncol 2006 ASCO Annual Meeting Proceedings Part I. 2006;  24 No. 18S (June 20 Supplement) 3535
• 30 Thornton A D, Ravn P, Winslet M et al. Angiogenesis inhibition with bevacizumab and the surgical management of colorectal cancer.  Br J Surg. 2006;  93 1456-1463
• 31 Genentech September 2007.  www.gene.com/gene/common/inc/pi/avastin.jsp#warnings
• 32 Wright J D, Hagemann A, Rader J S et al. Bevacizumab combination therapy in recurrent platinium-refracory, epithelial ovarian carcinoma: A retrospective analysis.  Cancer. 2006;  107 83-89