Zusammenfassung
Hintergrund: Zur palliativen Behandlung metastasierter kolorektaler und Magenkarzinome werden
zunehmend 5-Fluorouracil-24-h-Hochdosischemotherapie-Schemata (HD-5-FU) eingesetzt.
Hierbei werden gehäuft persistierende Durchfälle und abdominelle Schmerzen
beobachtet. Als Ursache wird eine 5-FU-assoziierte Kolitisform angenommen, die
bisher nicht ausreichend charakterisiert ist. Hier werden 6 Fälle einer 5-Fluorouracil-induzierten
Kolitis dokumentiert und auf eine mögliche Beteiligung des Dünndarms anhand von
endoskopischen und histologischen Untersuchungen des Dünn- und Dickdarms untersucht.
Fallsammlung: 2 Männer und 4 Frauen zwischen 49 und 62 Jahren erhielten im Rahmen metastasierter
Kolon- (n = 2) Magen- (n = 3)- bzw. Gallengangskarzinome (n = 1) eine palliative
wöchentliche Chemotherapie mit 5-Fluorouracil (2600 mg/m2/24 h)/Folinsäure (500 mg/m2/2 h). Zwischen der 1. und 5. Applikation der Chemotherapie stellten sich die
Patienten mit z. T. heftigsten wässrigen Durchfällen (bis zu 20-mal/Tag) außerplanmäßig
vor (WHO-Klassifikation Stadium Grad III). Die Stuhlkulturen waren bei allen
Patienten negativ einschließlich des fehlenden Nachweises von Clostridium difficile
und seinen Toxinen A und B. Die bei der Koloskopie erhobenen Befunde reichten
von unauffälliger Schleimhaut (n = 2) bis zu kolitischen Veränderungen mit hochrotem
Ödem, verstärkten Fibrinausschwitzungen sowie Mikroulzerationen (n = 4). Bei
4 Patienten war zusätzlich zum Kolon auch der obere Dünndarm mit endoskopisch
imponierendem Erythem (n = 1) oder schmierigen Belägen und Ulzerationen (n = 3).
befallen. In der histologischen Aufarbeitung zeigte sich eine unterschiedlich
ausgeprägte apoptotische Destruktion der Krypten, bei Dünndarmbefall partiell
Zottenatrophie und minimale apikale Erosionen. Unter der Therapie mit Antibiotika
(Vancomycin [n = 2] , Metronidazol [n = 3]) Glukokortikoiden (n = 5) und/oder
dem Hefepräparat Saccaromyces cerevisiae (n = 3) waren 5 Patienten innerhalb von
8-10 Tagen beschwerdefrei. Eine Patientin verstarb an den Folgen der Enterokolitis.
Schlussfolgerung: Diese Fallsammlung zeigt, dass 5-Fluoruracil nicht nur eine histologisch nachweisbare
Kolitis induzieren, sondern auch das gesamte Intestinum erfassen kann. Die oft
schweren, persistierenden Verlaufsformen stellen eine seltene, aber ernst zu nehmende
Komplikation dar. Die Genese der Kolitis (medikamententoxisch und/oder bakteriell)
mit dem Ziel einer gezielten Therapie und/oder Prophylaxe muss weiter untersucht
werden.
5-fluorouracil-induced colitis-A review based upon consideration of 6 cases
Background: At increasing use of high-dose 5-fluorouracil-based chemotherapy for metastatic
colorectal and gastric cancer complicated drug-induced colitis is being observed
more frequently. From May 1998 to November 2000 we observed 6 cases of 5-fluorouracil-induced
colitis, in which we looked for involvement of small intestine. We report summing
up on the 6 cases including both endoscopic and histological findings in both
sites of the gut.
Case reports: In 2 men and 4 women (age 49-78 years) with advanced colon (n = 2), gastric
(n = 3 ) and gallbladder (n = 1) cancer a palliative weekly high-dose infusional
5-fluorouracil (2,6 g/m2/24 h) and folinic acid (500 mg/m2/2 h) chemotherapy was performed. Few days after 1-5 chemotherapy courses the
patients were admitted to our hospital with abdominal pain and partly severe watery
diarrhea (up to 20 times evacuations/per day). The stool cultures were negative
and there were no proof both of clostridium difficile and his toxin A and B. In
4 patients colonoscopy showed different grades of colitis up to diffuse erythema
and microlesions, 2 patients had no visible lesions. In 4 patients endoscopy of
the upper GI-tract showed a severe inflammation (n = 1) and a fibrinopurulent
exsudate, severe edema and isolated ulcerations (n = 3) of jejunum after gastrectomy
or duodenum with intact stomach. In the histological assessment different grades
of 5-FU-induced colitis without (n = 2) or with (n = 4) involvement of the
upper small intestine destruction of the superficial mucosa and crypts (epitheliumapoptosis)
were found. 5 patients were treated by antibiotics (vancomycin n = 2 , metronidazole
n = 3), glucocorticoids (n = 5) and Saccaromyces cerevisiae (n = 3). After
8-10 days the patients were complete free of symptoms. One patient died due to
the enterocolitis.
Conclusions: The present cases demonstrate that high-dose 5-fluorouracil-based chemotherapy
not only induces a colitis but also may involve the upper small intestine tract.
Consequently, it represents an increasing and serious adverse event of high-dose
chemotherapy. The etiology of the enterocolitis (drug- or bacterial-induced) needs
further investigations in order to find a causal therapy and/or prophylaxis.
Schlüsselwörter
5-Fluorouracil - 5-FU - Hochdosischemotherapien - Kolitis
Key words
Literatur
- 1
Silva J, Fekety R, Werk C. et al .
Inciting and etiologic agents of Colitis.
Rev Infect Dis.
1984;
6
214-221
(suppl.1)
- 2
Dosik G M, Luna M, Valdivisio M. et al .
Necrotizing colitis in patients with cancer chemotherapy.
Am J Med.
1979;
67
646-656
- 3
Cudomore M, Silva J, Fekety R.
Clostridium difficile associated with cancer chemotherapy.
Arch Intern Med.
1982;
142
333-335
- 4
Kamthan A G, Bruckner H W, Hirschmann S Z. et al .
Clostridium difficile diarrhea induced by cancer chemotherapy.
Arch Intern Med.
1992;
152
1715-1717
- 5
Trevesani F, Simoncini M, Alampi G, Bernardi M.
Colitis associated to chemotherapy with 5-Fluorouracil.
Hepatogastroenterology.
1997;
44
710-712
- 6
Kronawitter U, Kemeny N E, Blumgart L.
Neutropenic enterocoloitis in a patient with colorectal carcinoma. Unusual course
after treatment with 5-Fluorouracil and leucovorin - A case report.
Cancer.
1997;
80
656-660
- 7
Iveson T J, Chan A.
Pseudomembranous colitis complicating chemotherapy.
Lancet.
1992;
339
192-193
- 8
Yang X Y.
Colitis due to chemotherapeutic agent.
Chung Hua Fu Chan Ko Tsa Chih.
1990;
25
272-274(article in Chinese)
- 9
Baker J L, Gosland M P, Herrington J D, Record K E.
Cytomegalovirus colitis after 5-Fluorouracil and interferon-alpha therapy.
Pharmacotherapy.
1994;
14
246-249
- 10
Van den Brande J, Schrijvers D, Colpaert C, Vermorken J B.
Cytomegalovirus colitis after administration of docetaxel-5-fluorouracil-cisplatin
chemotherapy for locally advanced hypopharyngeal cancer.
Ann Oncol.
1999;
10
1369-1372
- 11
Schoeber C H, Bokemeyer M, Stahl M. et al .
The role of schedule dependency of 5-Fluorouracil/leucovorin combinations in
advanced colorectal cancer.
Semin Oncol.
1992;
19
131-135
- 12
Tuchmann M, Stoeckeler J S, Kiang D T. et al .
Familial pyrimidinemia and pyrimidurea associated with severe fluorouracil toxicity.
N Engl J Med.
1985;
313
245-249
- 13
Harris B E, Carpenter J T, Diasio R B.
Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase
deficiency.
Cancer.
1991;
68
499-501
- 14
Van Kuilenburg A BP, Vreken P, Abeling N GGM. et al .
Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency.
Hum Genet.
1999;
104
1-9
- 15
Fata F, Ron I G, Kemeny N. et al .
5-Fluorouracil-induced small bowel toxicity in patients with colorectal
carcinoma.
Cancer.
1999;
86
1129-1134
- 16
Ardalan B, Chua L, Tian E M. et al .
A phase II study of weekly 24-hour infusion with high-dose fluorouracil with
leucovorin in colorectal carcinoma.
J Clin Oncol.
1991;
9
625-630
- 17
Moertel C, Flemming T, Macdonald J. et al .
Levamisole and Fluorouracil for adjuvant therapy of resected colon carcinoma.
N Engl J Med.
1990;
322
352-358
- 18
Lev R, Sweeney K G.
Neutropenic enterocolitis. Two unusual cases with review of the literature.
Arch Pathol Lab Med.
1993;
117
524-7
- 19
Wolmark N, Rockette H, Mamounas E. et al .
Clinical trial to assess the relative efficacy of fluorouracil and leucovorin,
fluorouracil and levamisol, and fluorouracil, leucovorin, and levamisol in patients
with dukes’ B and C carcinoma of the colon: Results from national surgical adjuvant
breast and bowel project c-04.
J Clin Oncol.
1999;
17
3553-3559
- 20
Wein A, Riedel C, Bruckl W, Kastl S. et al .
Weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) with folinic acid (FA)
in adjuvant therapy of colon cancer.
Z Gastroenterol.
2001;
39
153-156
- 21
Ragnhammar P, Hafstrom L, Nygren P. et al .
A systematic overview of chemotherapy effects in colorectal cancer.
Acta Oncol.
2001;
40
282-308
- 22
Porschen R, Bermann A, Loffler T. et al .
Fluorouracil plus leucovorin as effective adjuvant chemotherapy in curatively
resected stage III colon cancer: Results of the trial adjCCA-01.
J Clin Oncol.
2001;
19
1787-1794
- 23
O’Conell M J, Maillirad A, Kahn J. et al .
Controlled trial of fluorouracil and low-dose leucovorin given for 6 months
as postoperative adjuvant therapy for colon cancer.
J Clin Oncol.
1997;
15
246-250
- 24
Goldberg R M, Hatfield A K, Kahn M. et al .
Prospectively randomized North Central Cancer Treatment Group trial of intensive-course
fluorouracil combined the I-isomer of intravenous leucovorin, oral leucovorin,
or intravenous leucovorin for the treatment of advanced colorectal cancer.
J Clin Oncol.
1997;
15
3320-3329
- 25 Germ J L. Fluorinated pyrimidines. Chatsner BA, Collins JM Cancer chemotherapy
principles and practice Philadelphia; J. B. Lippincott Co 1990: 197-200
- 26
Fainstein V, Bodey G P, Fekety R.
Relapsing pseudomembranous colitis associated with cancer chemotherapy.
J Infect Dis.
1981;
143
865
- 27 Haskell C M. Drugs used in cancer chemotherapy. Haskell CM Cancer treatment
Philadelphia; W. B. Saunders Company 1990: 44-102
- 28
Lee F D.
Importance of apoptosis in the histopathology of drug related lesions in the
large intestine.
J Clin Pathol.
1993;
46
118-122
- 29
Zidan J, Haim N, Beny A. et al .
Octreotide in the treatment of severe chemotherapy-induced diarrhea.
Ann Oncol.
2001;
12
227
(2(??))
- 30
Cascinu S, Fedeli A, Fedeli S L, Catalano G.
Octreotide versus loperamide in the treatment of fluorouracil-induced diarrhea:
A randomized trial.
J Clin Oncol.
1993;
11
148-151
Korrespondenzadresse
Dr. med. Ahmed Madisch
Abteilung für Gastroenterologie
Allgemeines Krankenhaus Celle
Siemensplatz 4
29223 Celle
eMail: gastroenterologie@akh-celle.de