5-Fluorouracil with irinotecan

C. Levy-Piedbois, I. Durand-Zaleski, H. Juhel, C. Schmitt, A. Bellanger, P. Piedbois, Cost-effectiveness of second-line treatment with irinotecan or infusional 5-fluorouracil in metastatic colorectal cancer, Ann. Oncol. 11 (2000) 157-161. 

Colorectal cancer (CRC) is the third most common cause of cancer-related death in women and men in the United States (4). Although surgical resection is the primary therapy for CRC, prognosis remains poor and not all patients are candidates for surgery. The current therapeutic options for patients with metastatic CRC (mCRC) are 5-fluorouracil (5-FU) based therapy regimens in combination with irinotecan (CPT-11) or oxaliplatin (5,6). 

I Irinotecan. Two important trials have delineated an appropriate standard of care for patients who experience disease progression with fluorouracil therapy for metastatic colorectal cancer. The results of these trials demonstrate a survival benefit associated with irinotecan, which was approved by the FDA in 1996, as second-line therapy for recurrent or progressive disease following fluorouracil. In phase n studies of previously treated patients with metastatic colorectal cancer, objective response rates of 13% to 27% have been observed. ... 

Miscellaneous Salvage Chemotherapy. Similar to initial treatment of metastatic colon cancer, capecitabine is being investigated as a replacement for infusional fluorouracil in salvage regimens in combination with irinotecan or oxaliplatin. Initial results from small trials suggest that this will be a safe and effective way to treat refractory disease. 

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. 

Azrak et al. (2004) Nude mice Maximum tolerable dose <30% cure with irinotecan 0% cure with 5-fluorouracil 60-100% cure with combination of both agents... 

Note that application in the particular indications is usually restricted either to patients expressing the target (e.g. trastuzumab, cetuximab, lapatinib, imatinib) and/or after failure of prior therapies (e.g. cetuximab, erlotinib, lapatinib, sutinib, dasatinib). Furthermore, for cancer treatment most tyrosine kinase inhibitors are applied in combination with conventional chemotherapeutic drugs, such as fluorouracil, taxanes, platin-based regimens, anthracylines and irinotecan or radiotherapy. 

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

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). 

Cunningham, D. et al.. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. The Lancet, 352, 1413-1418, 1998. 

Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouraeil eompared with fluorouracil alone as first-line treatment for metastatic colorectal cancer a multieentre randomised trial. Lancet 2000 355 1041-1047. 

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. 

Bevacizumab, a humanized IgG and cetuximab, a chimeric IgGx, are currently marketed in the US for treatment of metastatic colorectal cancer [92, 93]. Bevacizumab neutralizes the biological activity of vascular endothelial growth factor (VEGF), while cetuximab binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). Bevacizumab, in combination with IV 5-fluorouracil (5-FU) -based chemotherapy, is indicated for first-line treatment of metastatic colorectal cancer, whereas cetuximab is used in patients refractory to or intolerant to irinotecan-based chemotherapy. The clinical pharmacokinetics of cetuximab are discussed in detail in Chapter 14. 

It was significantly effective when used in combination with fluorouracil-based chemotherapy and led to the improvement of overall response rates, time to progression, and survival of patients with metastatic colon cancer (55,57,58). Bevacizumab and irinotecan, fluorouracil, leucov-orin (IFL) chemotherapy regimen showed an increase in median survival by 4.7 months, in progression free survival by 4.36 months, and in overall response rates (complete and partial responses) by 10.2% when compared with IFL plus placebo. 

About 76% of patients given irinotecan complained of weakness. Grade 3 and 4 weakness has been described in 12-15% with weekly or thrice-weekly administration and during the administration of combination regimens containing fluorouracil. 

If irinotecan is combined with 5-fluorouracil and calcium folinate, an infusion regimen of fluorouracil rather than bolus administration is associated with a lower incidence of severe toxicity (leukopenia and life-threatening sepsis) (157). 

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. 

---