Regular Article

British Journal of Cancer (2001) 85, 509–517. doi:10.1054/bjoc.2001.1953 www.bjcancer.com
Published online 14 August 2001

Factors predicting efficacy of oxaliplatin in combination with 5-fluorouracil (5-FU) plusminus folinic acid in a compassionate-use cohort of 481 5-FU-resistant advanced colorectal cancer patients

M A Bensmaïne1, M Marty2, A de Gramont3, S Brienza4, F Lévi5, M Ducreux6, E François7, E Gamelin8, H Bleiberg9 and E Cvitkovic1,5

  1. 1Cvitkovic et Associés Consultants, 18–20 rue Pasteur, Kremlin-Bicêtre, 94278
  2. 2Hôpital Saint-Louis, 1 avenue Claude Vellefaux, Paris, 75010
  3. 3Hôpital Saint-Antoine, 184 rue du Fg St Antoine, Paris, 75012
  4. 4Debioclinic, 2 rue du Nouveau Bercy, 94220 Charenton le Pont
  5. 5Hôpital Paul Brousse, 14 avenue Paul Vaillant Couturier, Villejuif Cedex, 94805
  6. 6Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif Cedex, 94805
  7. 7Centre Lacassagne, 33 avenue de Valombrose, Nice Cedex 01, 06050
  8. 8Centre Paul Papin, 2 rue du Moll, Angers Cedex 01, 49033, France
  9. 9Institut Jules Bordet, 1 rue Héger-Bordet, Brussels, 1000, Belgium

Received 8 December 2000; Revised 17 May 2001; Accepted 1 June 2001.

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Abstract

A statistical analysis was performed on the patient data collected from two compassionate-use programmes using oxaliplatin (Eloxatin®) + 5-fluorouracil (5-FU) plusminus folinic acid (FA), to identify predictive factors for oxaliplatin-based salvage treatment in patients with 5-FU-resistant advanced colorectal cancer (ACRC). 481 5-FU-resistant ACRC patients, most with performance status less than or equal to 2, greater than or equal to 3 involved sites, and greater than or equal to 2 prior lines of chemotherapy, received oxaliplatin + 5-FU plusminus FA. Prognostic factors associated with overall response rate (ORR), time to progression (TTP) and overall survival (OS) were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. The ORR was 16% (95% CI: 13–20), the median TTP was 4.2 months (95% CI: 3.4–4.6), and the median OS was 9.6 months (95% CI: 8.6–10.6). The multivariate analysis indicated poor (greater than or equal to 2 WHO) performance status (PS), a large number of prior chemotherapy regimens (greater than or equal to 3), a low baseline haemoglobin level (< 10 g/dl), and a triweekly (vs biweekly) treatment administration schedule as significantly associated (P< 0.05) with a lower ORR. Sex (male), number of organs involved (greater than or equal to3) and alkaline phosphatase (AP) level (greater than or equal to 2 times the upper limit of normal) were associated (P< 0.05) with shorter TTP. Poor PS, a large number of organs involved, and elevated AP were independently and significantly correlated with shorter OS. Our analysis identified a relationship between efficacy results of oxaliplatin + 5-FU plusminus FA treatment in 5-FU-resistant ACRC patients and baseline prognostic factors related to PS, extent of disease and number of prior regimens. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords:

clinical resistance, multivariate analysis, salvage chemotherapy

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References

  1. Advanced Colorectal Cancer Meta-Analysis Project (1992) Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol 10: 896–903 | PubMed | ISI |
  2. André T, Bensmaine A, Louvet C, Francois E, Lucas V, Desseigne F, Beerblock K, Bouché O, Carola E, Merrouche Y, Morvan F, Dupont-André G and De Gramont A (1999) Multicenter Phase II Study of bimonthly High-dose Leucovorin, 5-Fluorouracil Infusion and Oxaliplatin for Metastatic Colorectal cancer resistant to the same leucovorin regimen (FOLFOX 3/4). J Clin Oncol 17: 3560–3568 | PubMed | ISI | ChemPort |
  3. Bécouarn Y, Ychou M, Ducreux M, Borel C, Bertheault-Cvitkovic F, Seitz J, Nasca S, Nguyen T, Paillot B, Raoul J, Duffour J, Fandi A, Dupont-André G and Rougier P (1998) Phase II Trial of Oxaliplatin as First Line Chemotherapy in Metastatic Colorectal Cancer Patients. J Clin Oncol 16: 2739–2744 | PubMed | ISI | ChemPort |
  4. Bécouarn Y, Gamelin E, Coudert B, Négrier S, Pierga JY, Raoul JL, Provencal J, Rixe O, Krisch C, Germau C, Bekradda M, Mignard D and Mousseau M (2001) A randomised multicenter phase II study comparing a combination of 5-fluorouracil (5-FU)/folinic acid (LV5-FV2) and alternating irinotecan and oxaliplatin, with oxaliplatin/irinotecan in 5-FU-pretreated metastatic colorectal cancer patients. J Clin Oncol
  5. Behrens BC, Sickle-Santanello B and Martin E (1989) Protracted venous 5–Fluorouracil infusion and weekly cisplatin in metastatic colorectal cancer. Proc Am Soc Clin Oncol 8: 126
  6. Bertheault-Cvitkovic F, Jami A, Itzhaki M, Depres-Brummer P, Brienza S, Adam R, Kunstlinger F, Bismuth H, Misset JL and Lévi F (1996) Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer. J Clin Oncol 14: 2950–2958 | PubMed | ChemPort |
  7. Boring CC, Squires TS and Tong T (1992) Cancer statistics, 1992. CA Cancer J Clin 42: 19–38 | PubMed | ISI | ChemPort |
  8. Cox DR (1970) The Analysis of binary data London: England
  9. Cox DR (1972) Regression models and life-tables (with discussion). J R Stat Soc 34: 187–220 | ISI |
  10. De Gramont A, Vignoud J, Tournigand C, Louvet C, André T, Varette C, Raymond E, Moreau S, Le Bail N and Krulik M (1997) Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48 hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer 33A: 214–219
  11. De Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, De Braud F, Wilson C, Morvan F and Bonetti A (2000) Leucovorin and Fluorouracil with or without Oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18: 2938–2947 | PubMed | ISI | ChemPort |
  12. Douillard JY, Cunningham D, Roth A, Navarro M, James R, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L and Rougier P (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355: 1041–1047 | Article | PubMed | ISI | ChemPort |
  13. Falcone A, Cianci C, Pfanner E, Bertuccelli I, Muttini MP, Dargenio F, Ricci S and Conte PF (1994) Continuous-infusion 5-Fluorouracil in metastatic colorectal cancer patients pretreated with bolus 5-fluorouracil: clinical evidence of incomplete cross-resistance. Ann Oncol 5: 291 | PubMed | ChemPort |
  14. Garufi C, Brienza S, Bensmaine A, Misset JL, Aschelter A, Pace R, Bertheault-Cvitkovic F, Terzoli E and Lévi F (1995) Addition of oxaliplatin (L-OHP®) to chronomodulated (CM) 5-fluorouracil (5-FU) and folinic acid (FA) for reversal of acquired chemoresistance in patients with advanced colorectal cancer (ACC). Proc Am Soc Clin Oncol 14: 192
  15. Gerard B, Bleiberg H, Michel J, Finet C, Recloux P, Diana D, Dufrane JP, Vandaele D, Hendlisz A, Confente C, Malarme M, Michaux D and Brienza S (1997) Oxaliplatin combined to 5-FU and Folinic Acid (5-FU/FA) as second or third line treatment in patients with advanced colorectal cancer (CRC). Proc Am Soc Clin Oncol 16: 288a
  16. Gerard B, Bleiberg H, Vandaele D, Gil T, Hendlisz A, Di Leo A, Fernez B and Brienza S (1998) Oxaliplatin combined to 5-fluorouracil and folinic acid: an effective salvage therapy in patients with advanced colorectal cancer. Anti-Cancer Drugs 9: 301–305
  17. Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet P, Llory JF, Letourneau Y, Coudert B, Bertheault-Cvitkovic F, Larregain-Fournier D, Le Rol A, Walter S, Adam R, Misset JL and Lévi F (2000) Phase III multicenter randomized trial of Oxaliplatin added to chronomodulated Fluorouracil-Leucovorin as first-line treatment of Metastatic Colorectal Cancer. J Clin Oncol 18: 136–147 | PubMed | ISI | ChemPort |
  18. Goldwasser F, Gross-Goupil M, Tigaud JM, Di Palma M, Marceau-Suissa J, Wasserman E, Yovine A, Misset JL and Cvitkovic E (2000) Dose escalation of CPT-11 in combination with oxaliplatin using an every two weeks schedule: A phase I study in advanced gastrointestinal cancer patients. Ann Oncol 11: 1463–1470 | PubMed | ChemPort |
  19. Graf W, Pahlman L, Bergström R and Glimelius B (1994) The relationship between an objective response to chemotherapy and survival in advanced colorectal cancer. Br J Cancer 70: 559–563
  20. Hill M, Norman A, Cunningham D, Findlay M, Nicolson V, Hill A, Iveson A, Evans C, Joffe J and Nicolson M (1995) Royal Mardsen Phase III Trial of Fluorouracil With or Without Interferon Alfa-2b in Advanced Colorectal Cancer. J Clin Oncol 13: 1297–1302 | PubMed | ISI | ChemPort |
  21. Iyer PR, Moran EM, Kaneshiro CA, Ottenheimer EJ, El Sayad NI, Blitzer JB and Charter RA (1988) Chemotherapy with Cisplatinum (CDDP) and 5FU in Metastatic Colorectal Cancer. Proc Am Soc Clin Oncol 7: 114
  22. Izzo J, Fandi A, Villalobos W, Azli N, Bachouchi M, Levin FM, Benahmed M, Armand J, Rougier P and Cvitkovic E (1994) Low-Dose Protracted Continuous 5-Fluorouracil Infusion in Solid Tumors. Journal of Infusional Chemotherapy 4: 135–139
  23. Lévi F, Misset JL, Brienza S, Adam R, Metzger G, Itzhaki M, Caussanel JP, Kunstlinger F, Lecouturier S, Descorps-Declere A, Jasmin C, Bismuth H and Reinberg A (1992) A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump. Cancer 69: 893–900 | Article | PubMed | ISI | ChemPort |
  24. Lévi F, Perpoint B, Garufi C, Focan C, Chollet P, Depres-Brummer P, Zidani R, Brienza S, Itzhaki M, Iacobelli S, Kunstlinger F, Gastiaburu C and Misset JL (1993) Oxaliplatin activity against metastatic colorectal cancer: a phase II study of 5-day continuous venous infusion at circadian-rhythm modulated rate. Eur J Cancer 29A: 1280–1284
  25. LoRusso P, Pazdur R and Redman SG (1989) Low-dose continuous infusion 5-fluorouracil and cisplatin: Phase II evaluation in advanced colorectal carcinoma. J Clin Oncol 12: 486–490
  26. Machover D, Diaz-Rubio E, De Gramont A, Schilf A, Gastiaburu C, Brienza S, Itzhaki M, Metzger G, N'Daw D, Vignoud J, Abad A, Francois E, Gamelin E, Marty M, Sastre J, Seitz J and Ychou M (1996) Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol 7: 95–98 | PubMed | ISI | ChemPort |
  27. Meyer V, Delva R, Gamelin E, Lamezec B, Maillart P, Danquechin-Dorval E, Lortholary A, Boisdron-Celle M, Maigre M, Brienza S, Cvitkovic E and Larra F (1997) Oxaliplatin (LOHP) and 5-fluorouracil (5-FU) synergism in advanced colorectal cancer patients (ACRC). Eur J Cancer 33: S167
  28. Miller AB, Hoogstraten B, Staquet M and Winkler A (1981) Reporting results of cancer treatment. Cancer 47: 207–214 | Article | PubMed | ISI | ChemPort |
  29. Petrelli NJ, Madejewicz S and Rustum Y (1989) Combination chemotherapy of cisplatin and 5-fluorouracil for advanced colorectal adenocarcinoma. Cancer Chemother Pharmacol 23: 57–60
  30. Raymond E, Chaney S, Taamma A and Cvitkovic E (1998a) Oxaliplatin: a review of preclinical and clinical studies. Ann Oncol 9: 1053–1071 | Article | PubMed | ISI | ChemPort |
  31. Raymond E, Faivre S, Woynarowski J and Chaney S (1998b) Oxaliplatin: mechanism of action and antineoplastic activity. Semin Oncol 25: 4–12 | PubMed | ISI | ChemPort |
  32. Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Awad L, Herait P and Jacques C (1998) Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352: 1407–1412 | Article | PubMed | ISI | ChemPort |
  33. Saltz L, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore M, Maroun JA, Ackland S, Locker P, Pirotta N, Elfring G and Miller LL (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343: 905–914 | Article | PubMed | ISI | ChemPort |
  34. Streit M, Jaehde U, Stremetzne S, Ridwelski K, Kerz H, Strohbach F, Hohenberger P, Zwiebel FM, Hebart H, Bothig R, Kairies M, Zillig D, Schuchmann S, Warnecke S, Thiel E and Kreuser E (1997) Five-Day continuous infusion of 5-Fluorouracil and pulsed folinic acid in patients with metastatic colorectal carcinoma: An effective second-line regimen. Ann Oncol 8: 1163–1165
  35. Tournigand C, Louvet C, Quinaux E, Andre T, Lledo G, Flesch M, Ganem G, Landi B, Colin P, Denet C, Mery-Mignard D, Risse M-L, Buyse M and De Gramont A (2001) FOLFIRI followed by FOLFOX versus FOLFOX followed by FOLFIRI in Metastatic Colorectal Cancer (MCRC): Final results of a Phase III study. Proc Am Soc Clin Oncol 20: 124a
  36. Warr D, McKinney S and Tannock IF (1984) Influence of measurement error on assessment of response to anticancer chemotherapy: proposal for new criteria of tumor response. J Clin Oncol 2: 1040
  37. Wasserman E, Cuvier C, Lokiec F, Goldwasser F, Kalla S, Méry-Mignard D, Ould Kaci M, Bensmaine A, Dupont-André G, Mahjoubi M, Marty M, Misset JL and Cvitkovic E (1999) Combination of Oxaliplatin Plus Irinotecan in Patients With Gastrointestinal Tumors: Results of Two Independent Phase I Studies With Pharmacokinetics. J Clin Oncol 17: 1751–1759 | PubMed | ISI | ChemPort |
  38. Whitehead RP, Fleming T, Macdonald JS, Ahmann FR, Garewal H and Kuebler J (1991) A Phase II study of 5-Fluorouracil plus cisplatin for metastatic colorectal adenocarcinoma: a south-west oncology group (SWOG) study. Invest New Drugs 9: 345–347