BACKGROUND: Combination of platinum derivatives with paclitaxel is currently the standard front line regimen for patients with epithelial ovarian carcinoma, and represents also an active regimen in patients with metastatic breast or unknown primary carcinomas. Measurement of intestinal permeability represents one of the potential methods of noninvasive laboratory assessment of gastrointestinal mucositis induced by chemotherapy, but little is known about intestinal permeability in patients treated with paclitaxel or platinum. METHODS: Intestinal permeability was assessed in 36 breast and ovarian cancer patients treated with paclitaxel/platinum combination by measuring, using capillary gas chromatography, urinary sucrose, lactulose, xylose and mannitol after oral challenge. The significance of differences during the therapy compared to pre-treatment values was studied by Wilcoxon paired test. The differences between groups of patient were studied by Mann-Whitney U test. Fisher exact test was used to compare the frequency in different subgroups. RESULTS: After administration of the first dose, a significant (p < 0.05) decrease in xylose absorption and increased lactulose/mannitol, sucrose/mannitol, lactulose/xylose and sucrose/xylose ratios were observed, but these parameters returned subsequently to pre-treatment levels. Patients who experienced serious (grade 3 or 4) toxicity had at baseline significantly lower percentages of xylose, mannitol and sucrose, and higher lactulose/mannitol ratio. Nine of 13 (69%) patients with baseline lactulose/mannitol ratio 0.070 or above experienced serious toxicity compared to 4 out of 23 patients (17%) with the ratio below 0.070 (p = 0.002). Post-treatment lactulose, lactulose/mannitol, sucrose/mannitol and lactulose/xylose ratios were significantly increased in patients with serious toxicity. CONCLUSION: A transient significant increase in lactulose/monosaccharide and sucrose/monosaccharide ratios was observed in ovarian and breast cancer patients treated with paclitaxel and platinum. Increased lactulose absorption, lactulose/mannitol, sucrose/mannitol and lactulose/xylose ratios were evident in patients with grade 3 or 4 toxicity, and increased baseline lactulose/mannitol ratio predicted serious toxicity.

Department of Oncology and Radiotherapy Charles University Medical School and Teaching Hospital Sokolská 581 Building 23 500 05 Hradec Králové Czech Republic

Zobrazit více v PubMed

McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, Clarke-Pearson DL, Davidson M. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334:1–6. doi: 10.1056/NEJM199601043340101. PubMed DOI

Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, Stuart G, Kaye S, Vergote I, Blom R, Grimshaw R, Atkinson RJ, Swenerton KD, Trope C, Nardi M, Kaern J, Tumulo S, Timmers P, Roy JA, Lhoas F, Lindvall B, Bacon M, Birt A, Andersen JE, Zee B, Paul J, Baron B, Pecorelli S. Randomized Intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst. 2000;92:699–708. doi: 10.1093/jnci/92.9.699. PubMed DOI

Fountzilas G, Kalofonos HP, Dafni U, Papadimitriou C, Bafaloukos D, Papakostas P, Kalogera-Fountzila A, Gogas H, Aravantinos G, Moulopoulos LA, Economopoulos T, Pectasides D, Maniadakis N, Siafaka V, Briasoulis E, Christodoulou C, Tsavdaridis D, Makrantonakis P, Razis E, Kosmidis P, Skarlos D, Dimopoulos MA. Paclitaxel and epirubicin versus paclitaxel and carboplatin as first-line chemotherapy in patients with advanced breast cancer: a phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol. 2004;15:1517–1526. doi: 10.1093/annonc/mdh395. PubMed DOI

Hainsworth JD, Erland JB, Kalman LA, Schreeder MT, Greco FA. Carcinoma of unknown primary site: treatment with 1-hour paclitaxel, carboplatin, and extended schedule etoposide. J Clin Oncol. 1997;15:2385–2393. PubMed

Rubenstein EB, Peterson DE, Schubert M, Keefe D, McGuire D, Epstein J, Elting LS, Fox PC, Cooksley C, Sonis ST. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer. 2004;100:2026–2046. doi: 10.1002/cncr.20163. PubMed DOI

Sonis ST, Etting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M, Bekele DN, Raber-Durlacher J, Donnely JP, Rubenstein EB. Perspectives on cancer therapy-induced mucosal injury. Cancer. 2004;100:1995–2025. doi: 10.1002/cncr.20162. PubMed DOI

Lorusso D, Ferrandina G, Graggi S, Gadduci A, Pignata S, Tateo S, Biamonte R, Manzione L, Di Vagno G, Ferrau F, Scambia G. Phase III multicenter randomized trial of amifostine as cytoprotectant in first-line chemotherapy in ovarian cancer patients. Ann Oncol. 2003;14:1086–1093. doi: 10.1093/annonc/mdg301. PubMed DOI

Bjarnason I, Macpherson A, Hollander D. Intestinal permeability: an overview. Gastroenterology. 1995;108:1566–1581. doi: 10.1016/0016-5085(95)90708-4. PubMed DOI

Uil JJ, van Elburg RM, van Overbeek FM, Mulder CJJ, van Berge-Henegouwen GP, Heymans HSA. Clinical implications of the sugar absorption test: intestinal permeability test to assess mucosal barrier function. Scand J Gastroenterol. 1997;32:70–78. PubMed

Meddings JB, Sutherland LR, Byles NI, Wallace JL. Sucrose: a novel permeability marker for gastroduodenal disease. Gastroenterology. 1993;104:1619–1626. PubMed

Melichar B, Dvorak J, Hyspler R, Zadak Z. Intestinal permeability in the assessment of intestinal toxicity of cytotoxic agents. Chemotherapy. 2005;51:336–338. doi: 10.1159/000088957. PubMed DOI

Common Terminology Criteria for Adverse Events version 3.0

Melichar B, Urbanek L, Krcmova L, Kalabova H, Svobodova I, Dragounova E, Vesely P, Hyspler R, Solichova D. Urinary neopterin in patients with ovarian cancer. Pteridines. 2006;17:145–153.

Matthews JNS, Altman DG, Campbel MJ, Royston P. Analysis of serial measurements in medical research. Br Med J. 1990;300:230–235. PubMed PMC

Parrilli G, Iaffaioli RV, Capuano G, Budillon G, Bianco AR. Changes in intestinal permeability to lactulose by cytotoxic chemotherapy. Cancer Treat Rep. 1982;66:1435–1436. PubMed

Parrilli G, Iaffaioli RV, Martorano M, Cuomo R, Tafuto S, Zampino MG, Budillon G, Bianco AR. Effects of anthracycline therapy on intestinal absorption in patients with advanced breast cancer. Cancer Res. 1989;49:3689–3691. PubMed

Kohout P, Cerman J, Bratova M, Zadak Z. Small bowel permeability in patients with cytostatic therapy. Nutrition. 1999;15:546–549. doi: 10.1016/S0899-9007(99)00113-6. PubMed DOI

Daniele B, Secondulfo M, De Vivo R, Pignata S, De Magistris L, Delrio P, Palaia R, Barletta E, Tambaro R, Carratu R. Effect of chemotherapy with 5-fluorouracil on intestinal permeability and absorption in patients with advanced colorectal cancer. J Clin Gastroenterol. 2001;32:228–230. doi: 10.1097/00004836-200103000-00010. PubMed DOI

Fazeny-Dörner B, Vetl M, Wenzel C, Brodowicz T, Zielinski C, Muhm M, Vogelsang H, Marosi C. Alterations in intestinal permeability following the intensified polydrug-chemotherapy IFADIC (ifosfamide, Adriamycin, dacarbazine) Cancer Chemother Pharmacol. 2002;49:294–298. doi: 10.1007/s00280-001-0414-2. PubMed DOI

Gonzalez-Martin AJ, Calvo E, Bover I, Rubio MJ, Arcusa A, Casado A, Ojeda B, Balana C, Martínez E, Herrero A, Pardo B, Adrover E, Rifa J, Godes MJ, Moyano A, Cervantes A. Randomized phase II trial of carboplatin versus paclitaxel and carboplatin in platinum-sensitive recurrent advanced ovarian carcinoma: a GEICO (Grupo Espanol de Investigacion en Cancer de Ovario) study. Ann Oncol. 2005;16:749–755. doi: 10.1093/annonc/mdi147. PubMed DOI

Havrilesky LJ, Alvarez AA, Sayer RA, Lancaster JM, Soper JT, Berchuck A, Clarke-Pearson DL, Rodriguez GC, Carney ME. Weekly low-dose carboplatin and paclitaxel in the treatment of recurrent ovarian and peritoneal cancer. Gyn Oncol. 2003;88:51–57. doi: 10.1006/gyno.2002.6859. PubMed DOI

Vasey PA, Gordon CJ, Gordon A, Gabra H, Coleman R, Atkinson R, Parkin D, Paul J, Hay A, Kaye SB. Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst. 2004;96:1682–1691. PubMed

Melichar B, Kohout P, Bratova M, Solichova D, Kralickova P, Zadak Z. Intestinal permeability in patients with chemotherapy-induced stomatitis. J Cancer Res Clin Oncol. 2001;127:314–318. doi: 10.1007/s004320000209. PubMed DOI

Bow EJ, Loewen R, Cheang MS, Shore TB, Rubinger M, Schacter B. Cytotoxic therapy-induced D-xylose malabsorption and invasive infection during remission-induction therapy for acute myeloid leukemia in adults. J Clin Oncol. 1997;15:2254–2261. PubMed

Blijlevens NMA, van t Land B, Donnely JP, M Rabet L, De Pauw BF. Measuring mucosal damage induced by cytotoxic therapy. Support Care Cancer. 2004;12:227–233. doi: 10.1007/s00520-003-0572-3. PubMed DOI

DeMeo MT, Mutlu EA, Keshavarzian A, Tobin MC. Intestinal permeation and gastrointestinal disease. J Clin Gastroenterol. 2002;34:385–396. doi: 10.1097/00004836-200204000-00003. PubMed DOI