Download PDF
Z Gastroenterol 2001; 39(12): 1033-1047
DOI: 10.1055/s-2001-19029
Übersichten
© Karl Demeter Verlag im Georg Thieme Verlag Stuttgart · New York

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
Further Information

Publication History

6.4.2001

21.5.2001

Publication Date:
17 December 2001 (online)

Also available at
    Permissions and Reprints

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

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
    Google Scholar
  • 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
    Google Scholar
  • 3 Schmoll H J, Büchele T, Grothey A, Dempke W. Where do we stand with 5-FU?.  Semin Oncol. 1999;  26 589-605
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 20 Rosenberg B. Fundamental studies with cisplatin.  Cancer. 1985;  55 2303-2316
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 32 Schmidt W, Chaney S G. Role of carrier ligand in platinum resistance of human carcinoma cell lines.  Cancer Res. 1993;  53 799-805
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 39 Graham M A, Gamelin E, Misset J -L. et al . Clinical pharmacokinetics of oxaliplatin.  Proc Am Assoc Cancer Res. 1998;  39 159a
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 47 Mathé G, Kidani Y, Noji M. et al . Antitumor activity of l-OHP in mice.  Cancer Lett. 1985;  27 135-143
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 58 Kern W, Braess J, Böttger B. et al . Oxaliplatin pharmacokinetics during a four-hour infusion.  Clin Cancer Res. 1999;  5 761-765
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 62 Sandor V. Chronotherapy with 5-fluorouracil, oxaliplatin, and folinic acid in colorectal cancer.  Lancet. 1997;  350 1325-1326
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 96 Borner M M. Neoadjuvant chemotherapy for unresectable liver metastases of colorectal cancer - to good to be true?.  Ann Oncol. 1999;  10 623-626
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 110 Extra J M, Marty M, Brienza S, Misset J L. Pharmacokinetics and safety profile of oxaliplatin.  Semin Oncol. 1998;  25 13-22
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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)
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 117 Baur M, Kienzer H -R, Rath T, Dittrich C. Extravasation of oxaliplatin (Eloxatin) - clinical course.  Onkologie. 2000;  23 468-471
    Google Scholar
  • 118 Tournigand C, Maindrault-Goebel, Louvet A, de Gramont A, Krulik M. Severe anaphylactic reactions to Oxaliplatin.  Eur J Cancer. 1998;  34 1297-1298
    Google Scholar
  • 119 Médioni J, Coulon M A, Morere J F. et al . Anaphylaxis after oxaliplatin.  Ann Oncol. 1998;  10 610
    Google Scholar
  • 120 Larzillière I, Brandissou S, Breton P. et al . Anaphylactic reaction to oxaliplatin: A case report (letter).  Am J Gastroenterol. 1999;  94 3387-3388
    Google Scholar
  • 121 Büchele T, Grothey A, Schmoll H J. Neue Perspektiven mit neuen Zytostatika in der Behandlung des kolorektalen Karzinoms.  Onkologie. 2000;  6 410-119
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar

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

      >