5-Fluorouracil with oxaliplatin

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

Levi F, Zidani R, Misset JL. Randomized multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. Lancet 1997 350 681-686. 

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. 

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. 

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. 

Kuebler JP, de Gramont A. Recent experience with oxaliplatin or irinote-can combined with 5-fluorouracil and leucovorin in the treatment of colorectal cancer. Semin Oncol 2003 30(4 Suppl 15) 40-46. 

Raymond E, Louvet, C, Tournigand C, et al. Premetrexed disodium combined with oxaliplatin, SN38, or 5-fluorouracil, based on the quantitation of drug interactions in human HT29 colon cancer cells. Int J Oncol 2002 21 361-367. 

Van Hazel G, Price D, Bower G et al (2005) Selective internal radiation therapy (SIRT) plus systemic chemotherapy with Oxaliplatin, 5-Fluorouracil and Leucovorin A phase I dose escalation study. Proceedings of the ASCO GI Cancers Symposium 133... 

Gastrointestinal Oral mucositis is a dose-limiting adverse reaction to fluorouracil. It affects 40% of patients overall and is grade 3/4 in about 15% [83 , 84 ]. Prophylactic use of a chlorhexidine mouthwash or topical cooling with crushed ice can reduce the severity of symptoms [85 ]. Diarrhea is also common and affects up to 40-50% of patients, particularly with bolus regimens with leucovorin and in combination therapy with oxaliplatin [86 ]. In one phase... 

Giacchetti S, Itzhaki M, Gruia G, et al (1990) Long-term survival of patients with unresectable colorectal cancer liver metastases following infusion al chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 10 663-669... 

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. 

Chemotherapeutic agents that have significant cancer response when combined with hyperthermia (up to 43°C) include doxorubicin, melphalan, mitomycin C (MMC), mitoxantrone, gemcitabine, etoposide, and especially the platinum-based agents carboplatin and oxaliplatin (Mohamed et al., 2003 Sugarbaker et al., 2005). Agents that do not work well with hyperthermia include irinotecan, paclitaxel, docetaxel, 5-fluorouracil, and floxuridine (Mohamed et al., 2003 Sugarbaker et al., 2005). 

Oxaliplatin (trans-L-diaminocyclohexane oxalate platinum II) was selected for development based on preclinical antitumor activity in murine leukemia lines and in colon cancer models (151,152). The clinical development of oxaliplatin has been primarily in colorectal cancer alone and in combination with 5-fluorouracil. 

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. 

T. Leong, D. Lim-Joon, J. Mackay, D. Rischin, Oxaliplatin combined with infusional 5-fluorouracil and concomitant radiotherapy in inoperable and metastatic rectal cancer A phase I trial, Br. J. Cancer 92(4) (2005) 655-661. 

Colorectal cancer (CRC) is the third most common cause of cancer-related death in women and men in the United States. The current therapeutic options for patients with metastatic CRC (mCRC) are 5-fluorouracil (5-FU) based chemotherapy regimens with the addition of irinotecan (CPT-11) or oxaliplatin. It still remains a challenge for oncologists to evaluate the reasons for a wide variation in response and toxicity among patients undergoing systemic 5-FU based chemotherapy. Pharmacogenomics... 

Grothey A, Sargent D, Goldberg RM et al. Survival of patients with advaneed eoloreetal eaneer improves with the availability of fluorouracil-leucovorin, irinoteean, and oxaliplatin in the eourse of treatment. J C// Oncol 2004 22 1209-1214. 

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. 

Metzger, G., Massari, C., Etienne, M.C., Comisso, M., Brienza, S., Touitou, Y., Milano, G., Bastian, G., Misset, J.L., Levi, F. Spontaneous or imposed circadian changes in plasma concentrations of 5-fluorouracil coadministered with folinic acid and oxaliplatin relationship with mucosal toxicity in patients with cancer. Clin. Pharmacol. Ther. 1994, 56 190-201. 

Prophylactic administration of antiemetics is essential in any patient receiving FOLFOX chemotherapy. The combination of oxaliplatin and 5-fluorouracil results in a moderate level of emetogenicity and requires the administration of 5HT3-receptor antagonists and corticosteroid treatment, generally with a dopamine antagonist such as metoclopramide or domperidone. Severe manifestations may have to be managed by delay and/or dose modification of the patient s next cycle of chemotherapy. 

Hepatic and renal function. Patients with advanced cancer may have impaired liver function due to the presence of liver metastases. In this case drug doses may need to be adjusted. In the case of the FOLFOX regimen, 5-fluorouracil dose may need to be reduced if the impairment is moderate or severe. Mrs KT s baseline liver function tests indicate a normal liver function, but these parameters should be monitored carefully throughout treatment. Reduced renal function may also necessitate a decrease in drug dosage. In the case of the FOLFOX regimen, oxaliplatin is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min). 

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