Leucovorin with irinotecan

Triple -drug therapy consisting of 5-fluorouracil and leucovorin with oxaliplatin or irinotecan improves survival compared with 5-fluorouracil plus leucovorin alone and is... 

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. 

Based on these studies, the addition of irinotecan to fluorouracil plus leucovorin (IFL) has been proved to increase survival when compared to fluorouracil plus leucovorin in the first-line treatment of metastatic colorectal cancer. These data support the current consensus that the three-drug treatment regimen be considered a first-line option for metastatic colorectal cancer. Accordingly, irinotecan received approval from the FDA in 2000 as first-line therapy for metastatic colorectal cancer in combination with fluorouracil and leucovorin. The use of fluorouracil plus leucovorin without irinotecan is appropriate as first-line therapy when a less-toxic regimen is desirable, especially for patients with a poor performance status. 

Based on the results of these trials, irinotecan shonld be considered standard second-line therapy for patients who have failed prior treatment with fluorouracil-based regimens. Either dosage regimen (irinotecan 125 mg/m IV weekly for 4 weeks followed by a 2-week rest period or 300 to 350 mg/m IV every 3 weeks) is acceptable. For the every 3-week regimen, initial administration of irinotecan at the lower dose should be considered for patients who have received significant prior pelvic or abdominal irradiation. Protracted continnons-infusion fluorouracil could be considered for those individuals with disease that no longer responds to bolus IV fluorouracil plus leucovorin or irinotecan. 

Veronese, M.L. et al., A phase II trial of gefitinib with Sfluorouracil, leucovorin, and irinotecan in patients with colorectal cancer, Br. J. Cancer, 92, 1846, 2005. 

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. 

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. 

A 60-year-old woman is being treated for metastatic colon cancer with her first course of irinotecan combined with fluorouracil (5-FU) and leucovorin. One hour after completing the irinotecan infusion, she complains of diaphoresis, crampy abdominal pain, and diarrhea. 

Triple-drug therapy consisting of fluorouracil and leu- covorin with oxaliplatin or irinotecan improves survival compared to fluorouracil plus leucovorin alone, and is considered as standard first-line therapy for metastatic disease. Bevacizumab, in combination with fluorouracil-based chemotherapy, is also indicated for initial treatment of metastatic colorectal cancer. Patients may benefit from more than one regimen duringthe treatment of their disease. 

Intergroup Trial N9741, a comparison of oxaliplatin plus fluorouracil and leucovorin (FOLFOX4) to weekly irinotecan plus IV bolus fluorouracil and leucovorin (IFL), and a combination of irinotecan plus oxaliplatin (IROX) in 795 patients with previously untreated metastatic colorectal cancer showed superior efficacy with... 

Kouroussis C, Souglakos J, Mavroudis D, et al. Oxaliplatin with high-dose leucovorin and infusional 5-fluorouracil in irinotecan-pretreated patients with advanced colorectal cancer. Am J CUn Oncol 2002 25 627-631. 

Weihrauch, M.R., S. Ansen, E. Jurkiewicz, C. Geisen, Z. Xia, K.S. Anderson, E. Gracien, M. Schmidt, B. Wittig, V. Diehl, J. Wolf H. Bohlen, and L.M. Nadler (submitted) Phase I/II combined immuno-/chemotherapy with CEA derived HLA-A2 restricted CAP-1 peptide and irinotecan, 5-fluorouracil and leucovorin in patients with primary metastatic colorectal cancer. 

Higher response rates are seen when 5-FU is used in combination with other agents, such as cyclophosphamide and methotrexate (breast cancer), cisplatin (head and neck cancer), and with oxaliplatin or irinotecan in colon cancer. The combination of 5-FU and oxaliplatin or irinotecan has become the standard first-line treatment for patients with metastatic colorectal cancer. The use of 5-FU in combination regimens has improved survival in the adjuvant treatment for breast cancer, and with oxaliplatin and leucovorin, for colorectal cancer. 5-FU also... 

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