Leucovorin colorectal cancer

The clinical trial that resulted in FDA approval of bevacizumab (February 2004) was a randomized, double-blind, phase III study in which bevacizumab was administered in combination with bolus-IFL (irinotecan, 5FU, leucovorin) chemotherapy as first-line therapy for previously untreated metastatic colorectal cancer [3]. Median survival was increased from 15.6 months in the bolus-IFL + placebo arm to 20.3 months in the bolus-IFL + bevacizumab arm. 

Goldberg RM, Sargent DJ, Morton RF, et al. A randomized, controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004 22 23-30. 

Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New Engl J Med 2004 350 2335-2342. 

Saltz LB, Cox JV, Blanke C et al. Irino-tecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000 343 905-914. 

Leichman CG, Lenz HJ, Leichman L et al. Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluoro-uracil and weekly leucovorin. J Clin Oncol 1997 15 3223-3229. 

Fluorouracil (5-FU) is the most widely used chemotherapeutic agent for colorectal cancer. Leucovorin (folinic acid) is usually added to 5-FU as a biochemical modulator to improve response rates. 

Giacchetti, S. et al. Phase III multicenter randomized trial of oxaUplatm added to chronomod-ulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer,. Clin. Oncol, 18, 136-147, 2000. 

Colorectal cancer is the third most common cancer and the second leading cause of cancer-related deaths in the United States. (77). The incidence is approx. 40 per 100,000 in men and 25-30 per 100,000 in women (78). For those with stage 111 disease with presumed micrometastatic disease, adjuvant chemotherapy is used, typically 5-fluorouracil (5-FU) and leucovorin for 6-8 mo, with a 30% reduction in disease recurrence and 22-32% reduction in mortality (79,80). 

Oxaliplatin is a newer platinum-based agent. It is most frequently administered in combination with fluorouracil and leucovorin for the treatment of colorectal cancer. Oxaliplatin has less ototoxicity and nephrotoxicity than cisplatin and carboplatin. 

Until the year 2000, the only systemic therapy for metastatic CRC was a bolus or infusional 5-FU regimen, mostly in combination with leucovorin (5-FU/LV), achieving a median survival of 12 month (20). However, over the last 6 years many new agents have been developed and approved by the Federal Drug and Food Administration (FDA) for the treatment of mCRC (7). A summary of the current guidelines for treating colorectal cancer is shown in Table 1. 

Jemal A, Siegel R, Ward E et al. Cancer statistics, 2006. CA Cancer J Clin 2006 56 106-130. 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. 

Thirion P, Michiels S, Pignon JP et al. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer an updated meta-analysis. J Clin Oncol 2004 22 3766-3775. 

Van Cutsem E, Twelves C, Cassidy J et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer results of a large phase III study. J Clin Onco/2001 19 4097 106. 

Ichikawa W, Nihei Z, Uetake Ft et al. UFT plus leucovorin for metastatic colorectal cancer Japanese experience. Oncology (Williston Park) 2000 14 41 3. 

Tsalic M, Bar-Sela G, Beny A et al. Severe toxicity related to the 5-fluorouracil/leucovorin combination (the Mayo Clinic regimen) a prospective study in colorectal cancer patients. Am J Clin Oncol. 2003 Feb 26 103-106. 

Irinotecan is a prodrug that is converted mainly in the liver by the carboxylesterase enzyme to the SN-38 metabolite, which is 1000-fold more potent as an inhibitor of topoisomerase I than the parent compound. In contrast to topotecan, irinotecan and SN-38 are mainly eliminated in bile and feces, and dose reduction is required in the setting of liver dysfunction. Irinotecan was originally approved as second-line monotherapy in patients with metastatic colorectal cancer who had failed fluorouracil-based therapy. It is now approved as first-line therapy when used in combination with 5-FU and leucovorin. Myelosuppression and diarrhea are the two most common adverse events. There are two forms of diarrhea an early form that occurs within 24 hours after administration and is thought to be a cholinergic event effectively treated with atropine, and a late form that usually occurs 2-10 days after treatment. The late diarrhea can be severe, leading to significant electrolyte imbalance and dehydration in some cases. 

Oxaliplatin is a third generation diaminocyclohexane platinum analog. Its mechanism of action is identical to that of cisplatin and carboplatin. However, it is not cross-resistant to cancer cells that are resistant to cisplatin or carboplatin on the basis of mismatch repair defects. This agent was recently approved for use as second-line therapy in metastatic colorectal cancer following treatment with the combination of fluorouracil-leucovorin and irinotecan, and it is now widely used as first-line therapy of this disease as well. Neurotoxicity is dose-limiting and characterized by a peripheral sensory neuropathy, often triggered or worsened upon exposure to cold. While this neurotoxicity is cumulative, it tends to be reversible—in contrast to cisplatin-induced neurotoxicity. 

Methods for Evaluating Effects of an Irinotecan + 5-Fluorouracil/Leucovorin (IFL) Regimen in an Orthotopic Metastatic Colorectal Cancer Model Utilizing In Vivo Bioluminescence Imaging... 

Key words HT-29, metastatic colorectal cancer, irinotecan, 5-FU, leucovorin, bioluminescence... 

Kabbinavar F Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003 21 60-65. 

Levi, F., Zidani, R., Vannetzel, J.M., Per-point, B., Focan, C., Faggiuolo, R., Chollet, P., Garufi, C., Itzhaki, M., Dogliotti L. 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. 

Two Phase III clinical studies of orally administered capecitabine in over 1,200 patients with untreated metastatic colorectal cancer demonstrated at least equal efficacy and improved tolerability versus the Mayo Clinic regimen of intravenous 5-fluorouracil/leucovorin administration. The overall response rate for patients taking capecitabine orally was 21%, versus 14% for the intravenous 5-FU/leucovorin regimen. A median 53-month follow-up revealed a three-year disease-free survival rate of 66% for capecitabine versus 63% for 5-FU/leucovorin patients. International Phase II trials also demonstrated therapeutic benefits of capecitabine monotherapy for women with metastatic breast cancer that was either resistant to both paclitaxel and anthracycline therapy. Orally administered at the twice-daily 1,250 mg/m2 regimen (cycles of two weeks of therapy followed by a week of rest), the tumor response rate was in the range of 20-25%. In addition, combination of capecitabine with a taxane yielded a unique survival benefit compared to the previous standard of taxane monotherapy for anthracycline-resistant breast cancer.13,14... 

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