Original Article

Compassionate-use Oxaliplatin with Bolus 5-Fluorouracil/Leucovorin in Heavily Pretreated Patients with Advanced Colorectal Cancer

Authors: Renato V. LaRocca, MD, Shawn D. Glisson, MD, Jeffrey B. Hargis, MD, Rodney E. Kosfeld, MD, Karen E. Leaton, RN,OCN, Rebecca M. Hicks, Falguni Amin-Zimmerman, MD

Abstract

Objectives: The efficacy of a concomitant oxaliplatin/bolus 5-fluorouracil/leucovorin regimen in 123 heavily pretreated patients with advanced colorectal cancer was evaluated. Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2 and radiographically progressive cancer which failed to respond to between two and five prior treatment modalities were consented and enrolled.


Methods: Patients received oxaliplatin on day 1 of weeks 1, 3, and 5 of an 8-week cycle. 5-fluorouracil/leucovorin was administered on day 1 of weeks 1 through 6.


Results: Grade 3 to 4 toxicities were as follows: diarrhea 30%; vomiting 11%; hematologic <3%; peripheral neuropathy 2.5%. Of the 101 patients evaluable for response, 7% achieved a partial response (median duration 4.25 mo), 1 patient achieved a minor response (7 mo), and 31% had stable disease (median duration 6.08 mo). The median time to progression was 3.6 months.


Conclusion: This regimen in heavily pretreated patients with disseminated colorectal cancer is of modest benefit, often at the expense of considerable gastrointestinal toxicity. It appears that the use of oxaliplatin/bolus 5-fluorouracil/leucovorin is more toxic than oxaliplatin/infusional 5-fluorouracil and possibly less effective.


Key Points


* Oxaliplatin and bolus 5-FU/leucovorin does exhibit modest benefit in heavily pretreated patients with colorectal cancer.


* Oxaliplatin and bolus 5-FU/leucovorin causes considerable toxicity, primarily gastrointestinal, in the heavily pretreated colorectal cancer patient.


* It appears that the use of a biweekly oxaliplatin with weekly bolus 5-FU/leucovorin regimen in the management of advanced colorectal cancer is considerably more toxic than oxaliplatin/infusional 5-FU regimens, and quite possibly less effective.

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References

1. American Cancer Society. Cancer facts and figures, 2001. Atlanta, ACS, 2001 (publication no. 5008.01).
 
2. Bleiberg H, and de Gramont A. Oxaliplatin plus 5-FU: clinical experience in patients with advanced colorectal cancer. Semin Oncol 1998;25:32–39.
 
3. Rustum YM, Cao S, Zhang Z. Rationale for treatment design: biochemical modulation of 5-Fluorouracil by leucovorin. Cancer J Sci Am 1998;4:12–18.
 
4. Saltz L, Douillard J, Pirotta N, et al. Irinotecan plus Fluorouracil/Leucovorin for metastatic colorectal cancer: a new survival standard. Oncologist 2001;6:81–91.
 
5. Cvitkovic E. A historical perspective on oxaliplatin: rethinking the role of platinum compounds and learning from near misses. Semin Oncol 1998;25:Suppl 5:1–3.
 
6. Khayat D, Gil-Delgado M, Antoine E, et al. The role of irinotecan and oxaliplatin in the treatment of advanced colorectal cancer. Oncology 2001;April:415–434.
 
7. Raymond E, Faivre S, Woynarowski J, et al. Oxaliplatin: mechanism of action and antineoplastic activity. Seminars in Oncology 1998;25:Suppl 5:4–12.
 
8. Raymond E, Chaney SG, Taama A, et al. Oxaliplatin: a review of preclinical and clinical studies. Ann Oncol 1998;9:1053–1071.
 
9. 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;52:1855–1865.
 
10. Hills CA, Kelland LR, Abel G, et al. Biological properties of ten human ovarian cell lines: calibrationin vitro against four platinum complexes. Br J Cancer 1989;59:527–534.
 
11. Behrens SC, Hamilton TC, Masuda H, et al. Characterization of a cis-diamminedichloroplatinum(II)-resistant human ovarian cancer cell line and its use in evaluation of platinum analogues. Cancer Res1987;47:414–418.
 
12. Teicher BA, Holden SA, Herman TS, et al. Characteristics of five human tumor cell lines and sublines resistant to cis-diamminedichloroplatinum(II). Intern J Cancer 1991;47:252–260.
 
13. Balconi G, Pang Y, Broggini M, et al. Cis-dichlorodiammineplatinum induced DNA interstrand cross-links in primary cultures of human ovarian cancer. Br J Cancer 1971;64:288–292.
 
14. Richon VM, Schulte N, Eastman A. Multiple mechanisms of resistance to cis-diamminedichloroplatinum(II) in murine leukemia L1210 cells. Cancer Res 1987;47:2056–2061.
 
15. Brienza S, Bensmaine M, Soulie P, et al. Oxaliplatin added to 5-FU-based therapy in the treatment of 5-FU-pretreated patients with advanced colorectal carcinoma (ACRC): results from the European compassionate-use program. Ann Oncol 1999;10:1311–1316.
 
16. Martoni A, Mini E, Pinto C, et al. Oxaliplatin and protracted continuous 5-FU infusion in patients with pretreated advanced colorectal carcinoma. Ann Oncol 2001;12:519–524.
 
17. Maindrault-Goebel F, Louvet C, Andre T, et al. Oxaliplatin added to the simplified bimonthly leucovorin and 5-Fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). Eur J Cancer 1999;35:1338–1342.
 
18. Mathe G, Kidani Y, Eriguchi M, et al. Antitumor activity of a new platinum complex: an experimental and clinical appraisal and preliminary comparison with cisplatinum and carboplatinum. Biomed Pharmacother 1989;43:237–250.
 
19. Tashiro T, Kawada Y, Sakurai Y, et al. Antitumor activity of a new platinum complex, oxalato (trans-1–1,2-diaminocyclohexane)platinum (II): new experimental data. Biomed Pharmacother 1989;43:251–260.
 
20. WHO handbook for reporting results of cancer treatment. Geneva (Switzerland), World Health Organization Offset Publication, 1979, p 48.
 
21. Cancer Therapy Evaluation Program Common Toxicity Criteria, Version 2.0 DCTC, NCI, NIH, DHHS. March 1998.
 
22. Levi F, Perpoint B, Focan 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 Cancer1993;29A:1280–1284.
 
23. Diaz-Rubio E, Sastre J, Zaniboni A, et al. Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: a phase II multicentric study. Ann Oncol 1998;9:105–108.
 
24. Manchover D, Diaz-Rubio E, de Gramont A, et al. Two consecutive phase II trials in advanced colorectal carcinoma patients who were resistant to previous treatment with fluoropyrimidines. Ann Oncol 1996;1:95–98.
 
25. Andre T, Bensmaine MA, 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.
 
26. Levi F, Zidani R, Misset JL. Randomized multicenter trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. Lancet 1997;350:681–686.
 
27. Giacchetti S, Perpoint B, Zidani R, et al. Phase III multicenter randomised trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000;18:136–147.
 
28. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluoruracil, with or without oxaliplatin, as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938–2947.
 
29. Levi FA, Zidani R, Vannetzel JM, et al. Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy by oxaliplatin, fluorouracil and folinic acid (leucovorin) in patients with colorectal metastasis: a randomized multiinstitutional trial. J Natl Cancer Inst 1994;21:1608–1617.
 
30. Lokich JJ, Ahlren JD, Gullo JJ, et al. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program study. J Clin Oncol 1989;7:425–432.
 
31. Meta-analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998;16:301–308.
 
32. Hochster HS, Chachoua A, Speyer J, et al. First-line activity of oxaliplatin with weekly bolus 5-FU and low dose leucovorin in advanced colorectal cancer. Proc Am Soc Clin Oncol 2001;abstract 548.