Stellenwert von Oxaliplatin in der Therapie des fortgeschrittenen   kolorektalen Karzinoms

O. Nehls; R. Porschen; M. Gregor; B. Klump

doi:10.1055/s-2001-19029

Zeitschrift für Gastroenterologie, Inhaltsverzeichnis

Z Gastroenterol 2001; 39(12): 1033-1047
DOI: 10.1055/s-2001-19029

Übersichten

Stellenwert von Oxaliplatin in der Therapie des fortgeschrittenen kolorektalen Karzinoms

The role of oxaliplatin in the therapy for advanced colorectal carcinomaO. Nehls¹ , R. Porschen² , M. Gregor¹ , B. Klump¹

¹Abteilung Innere Medizin I mit den Schwerpunkten Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Tübingen
²Klinik für Innere Medizin mit den Schwerpunkten Gastroenterologie, Hepatologie, Hämatoonkologie, Diabetologie, Zentralkrankenhaus Bremen-Ost

Abstract

Zusammenfassung

In präklinischen Modellen und in zahlreichen Phase-I- bis -III-Untersuchungen wurde die Wirksamkeit des Zytostatikums Oxaliplatin (L-OHP) beim kolorektalen Karzinom nachgewiesen. Bei nicht vorbehandelten Patienten sind die Ansprechraten mit L-OHP plus 5-Fluorouracil und Leukovorin (5-FU/LV) mehr als doppelt so hoch wie mit 5-FU/LV allein und das progressionsfreie Intervall wird signifikant verlängert. Trotzdem ist die Gesamtüberlebenszeit in den Therapiearmen ähnlich, was wahrscheinlich auf das Cross-over-Design dieser Studien zurückzuführen ist. L-OHP plus 5-FU/LV ist zudem häufig wirksam bei 5-FU-resistenten oder 5-FU-refraktären Patienten. Auch in der neoadjuvanten Therapie primär nicht resektabler Leberfiliae beim kolorektalen Karzinom zeigt dieses Zytostatikum in Verbindung mit 5-FU/LV viel versprechende Ergebnisse. Dosislimitierende Toxizität ist eine periphere sensorische Neuropathie, die in der Regel innerhalb weniger Monate nach Absetzen der Substanz reversibel ist. Gastrointestinale Toxizitäten werden als geringfügig eingestuft. Im Vergleich zu den bislang beim kolorektalen Karzinom angewandten Substanzen zeichnet sich L-OHP nicht nur durch ein differentes Wirkspektrum aus, sondern eröffnet wegen Wirkungssynergismus und gering ausgeprägter Hämatotoxizität Kombinationsmöglichkeiten mit zahlreichen Zytostatika. Zusammenfassend sind die therapeutischen Möglichkeiten beim kolorektalen Karzinom durch die Entwicklung von L-OHP wesentlich erweitert worden.

The role of oxaliplatin in the therapy for advanced colorectal carcinoma

Preclinical models and numerous phase I to III trials have demonstrated the efficacy of oxaliplatin (l-OHP) for colorectal carcinoma. In previously untreated patients, response rates with l-OHP plus 5-fluorouracil and leucovorin (5-FU/LV) have been shown to be more than twice as high as compared with 5-FU/LV alone, and progression-free intervals have been significantly increased. Nevertheless, overall-survival was similar in both treatment arms, that was possibly due to the cross-over-design of these studies. Moreover, the combination regimens with l-OHP and 5-FU/LV often have shown activity in 5-FU-resistant or 5-FU- refractory patients. Furthermore, treatment of previously unresectable liver metastases from colorectal carcinoma with l-OHP in combination with 5-FU/LV has provided promising results. Dose-limiting toxicity is a peripheral sensory neuropathy, that was found to be mostly completely reversible within a few months. Gastrointestinal toxicities have been demonstrated to be mild. Compared to other anticancer drugs currently used in the treatment for colorectal carcinoma, l-OHP not only shows a different mechanism of action but displays synergistic anti-tumor activity as well as minimal hematologic toxicity making this agent interesting for combination chemotherapy protocols. In conclusion, the development of l-OHP has essentially increased the therapeutical possibilities of treatment for colorectal carcinoma.

Schlüsselwörter

Chemotherapie - Kolorektales Karzinom - Oxaliplatin - Übersicht

Key words

Chemotherapy - Colorectal Carcinoma - Oxaliplatin - Review

Volltext

Referenzen

Literatur

1 Scheithauer W, Rosen H, Kornek G V, Sebesta C, Depisch D. Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ. 1994; 306 752-755
2 Poon M A, O’Connell M J, Wieand H S. et al . Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol. 1991; 9 1967-1972
3 Schmoll H J, Büchele T, Grothey A, Dempke W. Where do we stand with 5-FU?. Semin Oncol. 1999; 26 589-605
4 Poon M A, O’Connell M J, Moertel G G. et al . Biochemical modulation of fluorouracil: Evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol. 1989; 7 1407-1418
5 The Advanced Colorectal Meta-Analysis Project . Modulation of fluorouracil by leucovorin in patients with advanced CRC: Evidence in terms of response rate. J Clin Oncol. 1992; 10 896-903
6 Weh H J, Zschaber R, Braumann D. et al . A randomized phase III study comparing weekly folinic acid (FA) and high-dose 5-fluorouracil (5-FU) with monthly 5-FU/FA (days 1-5) in untreated patients with metastatic colorectal cancer. Onkologie. 1998; 21 403-407
7 Schmoll H J, Köhne C H, Lorenz M. et al . Weekly 24 h infusion of high-dose (HD) 5-fluorouracil (5-FU24h) with or without folinic acid (FA) vs. bolus 5-FU/FA (NCCTG/Mayo) in advanced colorectal cancer (CRC): A randomized phase III study of the EORTC GITCCG and the AIO. Proc Am Soc Clin Oncol. 2000; 19 A935
8 Conti J A, Kemeny N E, Saltz L B. et al . Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol. 1996; 14 709-715
9 Cunningham D, Pyrhonen S, James R D. Randomised trial of irinotecan plus supportive care versus supportive care alone after 5-fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998; 352 1413-1418
10 Pazdur M, Lassere Y, Rhodes V. et al . Phase II trial of uracil and tegafur plus oral leucovorin: an effective oral regimen in the treatment of metastatic colorectal carcinoma. J Clin Oncol. 1994; 12 2296-2300
11 Cox J V, Paschir R, Thibault A. et al . A phase III trial (SO 15 695) of XelodaTM (Capecitabine) in previously untreated advanced/metastatic colorectal cancer. Proc Am Soc Clin Oncol. 1999; 18 A1016
12 Cunningham D, Zalcberg J R, Rath U. et al . Final results of a randomised trial comparing tomudex (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. Ann Oncol. 1996; 7 961-965
13 Cocconi G, Cunningham D, Van Cutsem E. et al . Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. J Clin Oncol. 1998; 16 2943-2952
14 Rougier P, Ducreux M, Ould K aci M. et al . Randomized phase II study of oxaliplatin alone, 5-fluorouracil (5-FU) alone, and the two drugs combined (OXA-FU) in advanced or metastatic pancreatic adenocarcinoma (APC). Proc Am Soc Clin Oncol. 2000; 19 A1018
15 Louvet C, Andre T, Tigaud J -M. et al . Phase II trial of oxaliplatin in combination with 5-FU and folinic acid (FA) - FOLFOX 6 regimen - as first line treatment for advanced or metastatic gastric cancer (A/MGC) patients. Proc Am Soc Clin Oncol. 2000; 19 A1031
16 Chollet P, Bensmaine M A, Brienza S. et al . Single agent activity of oxaliplatin in heavily pretreated advanced epithelial ovarian cancer. Ann Oncol. 1996; 7 1065-1070
17 Monnet I, Brienza S, Hugret F. et al . Phase II study of oxaliplatin in poor-prognosis non-small cell lung cancer (NSCLC). Eur J Cancer. 1998; 34 1124-1127
18 Garufi C, Nistico C, Brienza S. et al . Oxaliplatin (L-OHP) activity in anthracycline (ANT) resistant metastatic breast cancer (MBC) patients. Proc Am Soc Clin Oncol. 1997; 16 A595
19 Germann N, Brienza S, Rotarski M. et al . Preliminary results on the activity of oxaliplatin (L-OHP) in refractory/recurrent non-Hodgkin’s lymphoma patients. Ann Oncol. 1999; 10 351-354
20 Rosenberg B. Fundamental studies with cisplatin. Cancer. 1985; 55 2303-2316
21 Connors T A, Jones M, Ross W C. et al . New platinum complexes with anti-tumor activity. Chem Biol Interact. 1972; 5 415-424
22 Rixe O, Ortuzar W, Alvarez M. et al . Oxaliplatin, Tetraplatin, Cisplatin and Carboplatin: Spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute’s Anticancer Drug Screen panel. Biochem Pharmacol. 1996; 52 185-1865
23 Kidani Y, Noji M and Tashiro T. Antitumor activity of platinum (II) complexes of 1,2-diamino-cyclohexane isomers. Gann. 1980; 71 637-643
24 Burchenal J H, Kalaher K, O’Toole T, Chisholm J. Lack of cross-resistance between certain platinum coordination compounds in mouse leukemia. Cancer Res. 1977; 37 3455-3457
25 Cvitkovic E. A historical perspective on oxaliplatin: rethinking the role of platinum compounds and learning from near misses. Semin Oncol. 1998; 25 1-3
26 Mathé G, Kidani Y, Triana K. et al . A phase I trial of trans-1-diaminocyclohexane oxalato-platinum (l-OHP). Biomed Pharmacother. 1986; 40 372-376
27 Saris C P, van de Vaart P JM, Rietbroek R C, Blommaert F A. In vitro formation of DNA adducts by cisplatin, lobaplatin and oxaliplatin in calf thymus DNA in solution and in cultured human cells. Carcinogenesis. 1996; 17 2763-2769
28 Fink D, Zheng H, Nebel. et al . In vitro and in vivo resistance to cisplatin in cells that have lost DNA mismatch repair. Cancer Res. 1997; 57 1841-1845
29 Fink D, Nebel S, Aebi S. et al . The role of DNA mismatch repair in platinum drug resistance. Cancer Res. 1996; 56 4881-4886
30 Zwelling L A, Anderson T, Kohn K W. DNA-protein and DNA-interstrand cross-linking by cis- and trans-platinum (II) diamminedichloride in L1210 mouse leukemia cells and relation to cytotoxicity. Cancer Res. 1979; 39 365-369
31 Mamenta E L, Poma E E, Kaufmann E K. et al . Enhanced replicative bypass of platinum-DNA adducts in cisplatin-resistant ovarian carcinoma cell-lines. Cancer Res. 1994; 54 3500-3505
32 Schmidt W, Chaney S G. Role of carrier ligand in platinum resistance of human carcinoma cell lines. Cancer Res. 1993; 53 799-805
33 Wiseman L R, Adkins J C, Plosker G L, Goa K L. Oxaliplatin. A review of its use in the management of metastatic colorectal cancer. Drugs Aging. 1999; 14 459-475
34 Calvert H, Judson I, Vijgh, W J F. Platinum complexes in cancer medicine: Pharmacokinetics and pharmacodynamics in relation to toxicity and and therapeutic activity. Cancer Surv. 1993; 17 189-217
35 Gamelin E, Le B ouil A, Boisdron-Celle M. et al . Cumulative pharmocokinetic study of oxaliplatin, administered every three weeks, combined with 5-fluorouracil in colorectal cancer patients. Clin Cancer Res. 1997; 3 891-899
36 Gamelin E, Allain P, Maillart P. et al . Long-term pharmacokinetic behaviour of platinum after cisplatin administration. Cancer Chemother Pharmacol. 1995; 37 97-102
37 Massari C, Brienza S, Rotarski M. et al . Pharmacokinetics of oxaliplatin in patients with normal versus impaired renal function. Cancer Chemother Pharmacol. 2000; 45 157-164
38 Graham M A, Brienza S, Misset J -L. et al . Pharmacokinetics of oxaliplatin given in repeated doses of 130 mg/m2 by 2-h infusion every three weeks to cancer patients. Sanofi Research Report. 1998; No. VAR3149
39 Graham M A, Gamelin E, Misset J -L. et al . Clinical pharmacokinetics of oxaliplatin. Proc Am Assoc Cancer Res. 1998; 39 159a
40 Allen J, Graham M A, Firth J. et al . Biotransformation and pharmocokinetic analysis of oxaliplatin in patients with advanced gastrointestinal cancer. Proc Am Assoc Cancer Res. 1998; 39 159a
41 Luo F R, Wyrick S D, Chaney S G. Cytotoxicity, cellular uptake, and cellular biotransformations of oxaliplatin in human colon carcinoma cells. Oncol Res. 1998; 10 595-603
42 Misset J L, Brienza S, Taamma A. et al . Pharmacokinetics, urinary and fecal excretion of oxaliplatin in cancer patients (pts). Proc Am Assoc Cancer Res. 1996; 37 A1252
43 Raymond E, Buquet-Fagot C, Djelloul S. et al . Antitumoral activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast, and ovarian cancers. Anticancer Drugs. 1997; 8 876-885
44 Faivre S, Raymond E, Woynarowski J M, Cvitkovic E. Supraadditive effect of 2‘,2‘-difluorodeoxycytidine (gemcitabine) in combination with oxaliplatin in human cancer cell lines. Cancer Chemother Pharmacol. 1999; 44 117-123
45 Zeghari-Squalli N, Raymond E, Cvitkovic E, Goldwasser F. Cellular pharmacology of the combination of the DNA topoisomerase I inhibitor SN-38 and the diaminocyclohexane platinum derivative oxaliplatin. Clin Cancer Res. 1999; 5 1189-1196
46 Erlichmann C, Boerner S, Kaufmann S H. Interactions of oxaliplatin with the topoisomerase I inhibitor topotecan and SN-38. Ann Oncol. 1998; 2 A225
47 Mathé G, Kidani Y, Noji M. et al . Antitumor activity of l-OHP in mice. Cancer Lett. 1985; 27 135-143
48 Tashiro T, Kawada Y, Sakurai Y, Kidani Y. Antitumor activity of a new platinum complex, oxalato (trans-l-1,2-diaminocyclohexane) platinum (II): New experimental data. Biomed Pharmacother. 1989; 43 251-260
49 Diaz-Rubio E, Sastre J, Zaniboni A. Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: A phase II multicentric study. Ann Oncol. 1998; 9 105-108
50 Bécouarn Y, Ychou M, Ducreux M. et al . Phase II trial of Oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. J Clin Oncol. 1998; 16 2739-2744
51 von Roemeling R, Hrushesky W J. Circadian patterning of continuous floxuridine infusion reduces toxicity and allows higher dose intensity in patients with widespread cancer. J Clin Oncol. 1989; 7 1710-1719
52 Moormeier J A, Williams S F, Kaminer L S, Garner M, Bitran J D. High-dose tri-alkylator chemotherapy with autologous stem cell rescue in patients with refractory malignancies. J Natl Cancer Inst. 1990; 82 29-34
53 Hryniuk W M, Figueredo A, Goodyear M. Applications of dose intensity to problems in chemotherapy of breast and colorectal cancer. Semin Oncol. 1987; 14 3-11
54 Smaaland R, Laerum O D, Lote K. et al . DNA synthesis in human bone marrow is circadian stage dependent. Blood. 1991; 77 2603-2611
55 Harris B E, Song R, Soong S J, Diasio R B. Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Cancer Res. 1990; 50 197-201
56 Mormont M C, Boughattas N, Lévi F. Mechanisms of circadian rhythms in the toxicity and the efficacy of anticancer drugs: Relevance for the development of new analogs. Lemmer B (ed) Chronopharmacology: Cellular and Biochemical interactions New York; Marcel Dekker 1989: 395-437
57 Boughattas N A, Lévi F, Fournier C. et al . Circadian rhythm in toxicities and tissue uptake of 1,2-diamminocyclohexane (trans-1) oxalatoplatinum (II) in mice. Cancer Res. 1989; 49 3362-3368
58 Kern W, Braess J, Böttger B. et al . Oxaliplatin pharmacokinetics during a four-hour infusion. Clin Cancer Res. 1999; 5 761-765
59 Lévi F, Zidani R, Vannetzel J -M. et al . Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: A randomized multi-institutional trial. J Natl Cancer Inst. 1994; 86 1608-1617
60 Lévi F, Zidani R, Misset J -L. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. Lancet. 1997; 350 681-686
61 Anonymous. Toxicity of fluorouracil in patients with advanced colorectal cancer: Effect of administration schedule and prognostic factors. J Clin Oncol. 1998; 16 3537-3541
62 Sandor V. Chronotherapy with 5-fluorouracil, oxaliplatin, and folinic acid in colorectal cancer. Lancet. 1997; 350 1325-1326
63 Machover D, Diaz-Rubio E, de Gramont A. et al . Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who where resistant to previous treatment with fluoropyrimidines. Ann Oncol. 1996; 7 95-98
64 Lévi F, Perpoint P, Garufi C. et al . Oxaliplatin activity against metastatic colorectal cancer. A phase II study of 5-day continuous venous infusion at circadian rhythm modulated rate. Eur J Cancer. 1993; 29A 1280-1284
65 Vassilaki M, Desses N, Parassiris V. et al . Two Phase II studies with the combination of oxaliplatin (L-OHP) + 5-fluorouracil (5-FU) + leucovorin (LV) as first-line chemotherapy in patients with metastatic colorectal cancer (MCC). Proc Am Soc Clin Oncol. 2000; 19 A1111
66 Abad A, Navarro M, Sastre J. et al . Biweekly Oxaliplatin plus weekly 48-hour continuous infusion (CI) 5-FU (TTD regimen) in first line treatment of advanced colorectal cancer (ACC). Proc Am Soc Clin Oncol. 2000; 19 A1117
67 Lévi F, Misset J L, Brienza S. et al . A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump. High antitumour effectiveness against metastatic colorectal cancer. Cancer. 1992; 69 893-900
68 Lévi F, Zidani R, Brienza S. et al . A multicenter evaluation of intensified, ambulatory, chronomodulated chemotherapy with oxaliplatin, 5-fluorouracil and leucovorin as initial treatment of patients with metastatic colorectal carcinoma. Cancer. 1999; 85 2532-2540
69 Bertheault-Cvitkovic F, Jami A, Ithzaki M. et al . Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer. J Clin Oncol. 1996; 14 2950-2958
70 Giacchetti S, Perpoint B, Zidani R. et al . Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2000; 18 136-147
71 de Gramont A, Figer A, Seymour M. et al . Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000; 18 2938-2947
72 Giacchetti S, Brienza S, Focan C. et al . Contribution of second line oxaliplatin (OXA)-chronomodulated 5-fluorouracil-folinic acid (CM-5-FU-FA) and surgery to survival in metastatic colorectal cancer patients (MCC PTS). Proc Am Soc Clin Oncol. 1998; 17 A1050
73 Köhne C H, Schöffski P, Wilke H. et al . Effective biomodulation by leucovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion: Results of a randomized trial in patients with advanced colorectal cancer. J Clin Oncol. 1998; 16 418-426
74 Sun Y, Guan Z Z, Jin M L. et al . A multicenter randomized phase II trial of oxaliplatin alone and in combination in patients with advanced colorectal cancer in China. Proc Am Soc Clin Oncol. 1999; 18 A979
75 Comba A Z, Blajman C, Richardet E. et al . Bimonthly oxaliplatin (L-OHP) with (A) or without (B) fluorouracil (5-FU) and leucovorin (LV). Proven evidence of synergism in a phase II: Randomised trial. Proc Am Soc Clin Oncol. 1999; 18 A953
76 de Gramont A, Gastiaburu J, Tournigand C. et al . Oxaliplatin with high-dose folinic acid and 5-fluorouracil 48 hinfusion in pretreated metastatic colorectal cancer. Proc Am Soc Clin Oncol. 1994; 13 220a
77 de Gramont A, Vignoud J, Tournigand C. et al . Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer. 1997; 33 214-219
78 André T, Louvet C, Raymond E. et al . Bimonthly high-dose leucovorin, 5-fluorouracil infusion and oxaliplatin (FOLFOX 3) for metastatic colorectal cancer resistant to the same leucovorin and 5-fluorouracil regimen. Ann Oncol. 1998; 9 1-3
79 André T, Bensmaine M A, Louvet C. et al . Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol. 1999; 17 3560-3568
80 Maindrault-Goebel F, Louvet C, André T. et al . Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX 6). Eur J Cancer. 1999; 35 1338-1342
81 Maindrault-Goebel F, de Gramont A, Louvet C. et al . High-dose oxaliplatin with the simplified 48 hbimonthly leucovorin (LV) and 5-fluorouracil (5-FU) regimen in pretreated metastatic colorectal cancer (FOLFOX). Proc Am Soc Clin Oncol. 1999; 18 A1017
82 Kouroussis C, Mavroudis D, Giannakakis T. et al . Biweekly oxaliplatin (L-OHP) with high-dose leucovorin (LV) and 5-fluorouracil (5-FU) 48-hour continuous infusion in pretreated patients with advanced colorectal cancer (CRC). Proc Am Soc Clin Oncol. 1999; 18 A1111
83 Meyer V, Delva R, Gamelin E. et al . Oxaliplatin (L-OHP) and fluorouracil (5-FU) synergism in advanced colorectal cancer patients (ACRC). Eur J Cancer. 1997; 33 A746
84 Gerard B, Bleiberg H, Michel J. et al . Oxaliplatin combined to 5-fluorouracil and folinic acid (5-FU/FA) as second or third line treatment in patients with advanced colorectal cancer (CRC). Proc Am Soc Clin Oncol. 1997; 16 A1025
85 Janinis J. Fountzilas G, Skarlos DV et al. Second-line chemotherapy with weekly oxaliplatin and high-dose 5-fluorouracil with folinic acid in metastatic colorectal carcinoma: A hellenic Cooperative Oncology Group (HeCOG) phase II feasibility study. Ann Oncol. 2000; 11 163-167
86 Martoni A. Oxaliplatin (OHP) and protracted 5-fluorouracil (5-FU) infusion in pretreated metastatic colorectal cancer (MCRC) patients: a phase II study. Proc Am Soc Clin Oncol. 2000; 19 A1172
87 Kouroussis C, Souglakos J, Giannakanis T. et al . Biweekly oxaliplatin (L-OHP) with high dose leucovorin and 5-fluorouracil (5-FU) in irinotecan pretreated patients with advanced colorectal cancer (ACC). Proc Am Soc Clin Oncol. 2000; 19 A1203
88 Zaniboni A, Merrigi F, Aitini E, Rabbi C, Marzola M. Oxaliplatin (OX) and 5-days 5-fluorouracil ( leucovorin (LV) as salvage treatment for advanced colorectal cancer (ACC). Preliminary results. Proc Am Soc Clin Oncol. 2000; 19 A1195
89 Garufi C, Brienza S, Bensmaine A. et al . Addition of oxaliplatin (L-OHP) to chronomodulated (CM) 5-fluorouracil (5-FU) and folinic acid (FA) for reversal or acquired chemoresistance in patients with advanced colorectal cancer (ACC). Proc Am Soc Clin Oncol. 1995; 14 192a
90 Brienza S, Lévi F, Valori V M. et al . Intensified (every 2 weeks) chronotherapy with 5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (L-OHP) in previously treated patients (pts) with metastatic colorectal cancer. Proc Am Soc Clin Oncol. 1993; 12 197a
91 Bertheault-Cvitkovic, Mefti F, Seitz J. et al . Chronomodulated (CRM) bimonthly 48 hour (Hr) 5-fluorouracil (FU), folinic acid (FA), oxaliplatin (OXA) FOLFOX CRM in 5-FU-refractory (FUR) advanced colorectal cancer (ACRC) patients (pts): phase II study. Proc Am Soc Clin Oncol. 2000; 19 A1242
92 Ardalan B, Chua L, Tian E -M. et al . A phase II sudy of weekly 24-hour infusion with high-dose fluorouracil with leucovorin in colorectal carcinoma. J Clin Oncol. 1991; 9 625-630
93 Kallen K J, Hofmann M AK, Timm A. et al . Weekly oxaliplatin, high-dose infusional 5-fluorouracil and folinic acid as palliative third-line therapy of advanced colorectal carcinoma. Z Gastroenterol. 2000; 38 153-157
94 Bismuth H, Adam R, Lévi F. et al . Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg. 1996; 224 509-520
95 Giacchetti S, Itzhaki M, Gruia G. et al . Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol. 1999; 10 663-669
96 Borner M M. Neoadjuvant chemotherapy for unresectable liver metastases of colorectal cancer - to good to be true?. Ann Oncol. 1999; 10 623-626
97 Scheithauer W, Kornek G V, Raderer M. et al . Combined irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in patients with advanced fluoropyrimidine/ leucovorin-pretreated colorectal cancer. J Clin Oncol. 1999; 17 902-906
98 Wasserman E, Cuvier C, Lokiec F. et al . Combination of Oxaliplatin plus irinotecan in patients with gastrointestinal tumors: Results of two independent phase I studies with pharmacokinetics. J Clin Oncol. 1999; 17 1751-1759
99 Goldwasser F, Gross M, Tigaud J M. et al . CPT-11/Oxaliplatin (L-OHP) combination every two weeks: Final results of a phase I study in advanced digestive malignancies. Proc Am Soc Clin Oncol. 1999; 18 A997
100 Douillard J Y, Michel P, Gamelin E. et al . Raltitrexed (Tomudex) plus oxaliplatin: An active combination for first-line chemotherapy in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol. 2000; 19 A971
101 Scheithauer W, Kornek G, Ulrich-Pur H. et al . Promising therapeutic potential of oxaliplatin ( raltitrexed in patients with advanced colorectal cancer (ACC): Results of a phase I/II trial. Proc Am Soc Clin Oncol. 2000; 19 A997
102 Calvo E, Gonzalez-Cao, Cortes J. et al . Combined iriniotecan, oxaliplatin, 5-FU in patients (pts) with metastatic colorectal cancer (MCC). Proc Am Soc Clin Oncol. 2000; 19 A1008
103 de Gramont A, Bosset J F, Milan C. et al . Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus. J Clin Oncol. 1997; 15 808-815
104 Tournigand C, Louvet C, André T. et al . FOLFIRI followed by FOLFOX or FOLFOX followed by FOLFIRI in metastatic colorectal cancer: Which is the best sequence? Safety and preliminary efficacy results of a randomized phase II study. Proc Am Soc Clin Oncol. 2000; 19 A949
105 Bécouarn Y, Mousseau M, Gamelin E. et al . Final results of CPT-11 and L-OHP (Oxaliplatin) combination versus alternated combination of LV5FU plus CPT-11/ LV5FU plus L-OHP in 5-FU resistant advanced colorectal cancer (ACRC). Proc Am Soc Clin Oncol. 2000; 19 A978
106 Saltz L B, Locker P K, Pirotta N, Elfring G L, Miller L L. Weekly irinotecan (CPT-11), leucovorin (LV), and fluorouracil is superior to daily x5 LV/FU in patients (pts) with previously untreated metastatic colorectal cancer (CRC). Proc Am Soc Clin Oncol. 1999; 18 A898
107 Saltz L B, Douillard J Y, Pirotta N. et al . Combined analysis of two phase III randomized trials comparing irinotecan (C) fluorouracil (F), leucovorin vs F alone as first line therapy of previously untreated metastatic coloorectal cancer (MCRC). Am Soc Clin Oncol. 2000; 19 A938
108 Douillard J Y, Cunningham D, Roth A D. et al . A randomized phase III trial comparing irinotecan (IRI) + 5-FU/folinic acid (FA) to the same schedule of 5-FU/FA in patients (pts) with metastatic colorectal cancer (MCRC) as front line chemotherapy (CT). Proc Am Soc Clin Oncol. 1999; 18 A899
109 Extra J M, Espie M, Calvo F. et al . Phase I study of oxaliplatin in patients with advanced cancer. Cancer Chemother Pharmacol. 1990; 25 299-303
110 Extra J M, Marty M, Brienza S, Misset J L. Pharmacokinetics and safety profile of oxaliplatin. Semin Oncol. 1998; 25 13-22
111 Gilles-Amar V, Garcia M L, Sebille A. et al . Evolution of severe sensory neuropathy with Oxaliplatin combined to the bimonthly 48 h leucovorin (LV) and 5-fluorouracil (5FU) regimens (FOLFOX) in metastatic colorectal cancer. Proc Am Soc Clin Oncol. 1999; 18 A944
112 Brienza S, Vignoud J, Itzhaki M. et al . Oxaliplatin (L-OHP): Global safety in 682 patients (pts). Proc Am Soc Clin Oncol. 1995; 14 A513
113 Adelsberger H, Quasthoff S, Grosskreutz J. et al . Alteration of sodium channel inactivation kinetics on rat sural nerve by the chemotherapeutic agent oxaliplatin. Biol Chem. 1999; 380 132 (special supplement)
114 Lersch C, Eckel F, Assmann G. et al . Prevention of peripheral sensory neuropathy (PSN) by carbamazepine in patients with advanced colorectal cancers treated with oxaliplatin. A pilot study. Gastroenterology. 2000; 118 (Suppl. 2) A2776
115 Mariani G, Garrone O, Granetto C. et al . Oxaliplatin induced neuropathy: Could gabapentin be the answer?. Proc Am Soc Clin Oncol. 2000; 19 A2397
116 Taieb S, Freyer G, Rambaud L, Descos L, Trillet-Lenoir V. Central neurotoxicity induced by oxaliplatin: Report on 4 cases. Proc Am Soc Clin Oncol. 2000; 19 A1234
117 Baur M, Kienzer H -R, Rath T, Dittrich C. Extravasation of oxaliplatin (Eloxatin) - clinical course. Onkologie. 2000; 23 468-471
118 Tournigand C, Maindrault-Goebel, Louvet A, de Gramont A, Krulik M. Severe anaphylactic reactions to Oxaliplatin. Eur J Cancer. 1998; 34 1297-1298
119 Médioni J, Coulon M A, Morere J F. et al . Anaphylaxis after oxaliplatin. Ann Oncol. 1998; 10 610
120 Larzillière I, Brandissou S, Breton P. et al . Anaphylactic reaction to oxaliplatin: A case report (letter). Am J Gastroenterol. 1999; 94 3387-3388
121 Büchele T, Grothey A, Schmoll H J. Neue Perspektiven mit neuen Zytostatika in der Behandlung des kolorektalen Karzinoms. Onkologie. 2000; 6 410-119
122 Nehls O, Klump B, Gregor M, Porschen R. Palliative therapy with oxaliplatin combined with 5-fluorouracil (5-FU) and leucovorin (LV) in advanced, irresectable cholangiocarcinoma (CCC) and gallbladder carcinoma (GBC). Gastroenterology. 2000; 118 (Suppl. 2) A2782
123 Pitt H A, Dooley W C, Yeo C J, Cameron J L. Malignancies of the biliary tree. Curr Probl Surg. 1995; 32 1-90
124 Stillwagon B, Order S E, Haulk T. et al . Variable low dose irradiation (131I-anti-CEA) and integrated low-dose chemotherapy in the treatment of nonresectable primary intrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys. 1991; 21 1601-1605

Anschrift für die Verfasser

Dr. med. O. Nehls

Abteilung Innere Medizin I

Universitätsklinikum Tübingen

Otfried-Müller-Straße 10

72076 Tübingen

eMail: oliver.nehls@uni-tuebingen.de