Irinotecan

Irinotecan is a semisynthetic derivative of camptothecin, a natural alkaloid first extracted from the Camptotheca acuminata tree. Irinotecan is a member of the TOP-I inhibitor class of antineoplastic compounds.14 TOP-I is an enzyme that interacts with DNA and facilitates DNA recombination, replication, and transcription by catalyzing the formation of a transient single-stranded DNA break, thereby allowing the torsionally strained DNA duplex to relax, separate, and reanneal.14,15 Irinotecan is converted in vivo to its active metabolite, SN-38, by a carboxylesterase enzyme in the liver. This metabolite forms a stable, covalent complex with DNA and TOP-I, which then interrupts the breakage–reunion cycle associated with TOP-I activity – a process that eventually leads to cell death.

Second-line Monotherapy

The efficacy of irinotecan as second-line monotherapy in patients with metastatic CRC was established in two randomized Phase III clinical trials conducted in Europe.

Cunningham et al reported that treatment with irinotecan and supportive care resulted in significantly greater overall survival than supportive care alone in patients who progressed while on 5-FU therapy or who progressed within six months after the last 5-FU infusion (one-year survival with irinotecan of 36.2% versus 13.8% with supportive care only; P=0.0001).¹⁶ Patients in the irinotecan group did significantly better in terms of survival without performance status deterioration (P=0.0001),survival without weight loss of more than 5% (P=0.018), and pain-free survival (P=0.003). Rougier et al compared treatment with irinotecan or continuous infusion of 5-FU in patients with metastatic CRC whose disease had progressed while they were on first-line bolus 5-FU therapy.¹⁷ Irinotecan monotherapy significantly improved overall survival in comparison with infusional 5-FU (P=0.035). Median survival was 10.8 months with irinotecan and 8.5 months with 5-FU. Survival at one year was 45% in the irinotecan group and 32% in the 5- FU group. Based on these two clinical studies, irinotecan was initially approved in the US as second-line monotherapy for the treatment of advanced CRC.

First-line Combination Therapy with 5- FU/LV

Two Phase III studies in patients with metastatic CRC provided evidence that first-line irinotecan–5-FU/LV (IFL) therapy is associated with a higher response rate and greater overall and progression-free survival than 5- FU/LV. Douillard et al used an infusional schedule of IFL and reported a response rate of 35% in the IFL group and 22% in the 5-FU/LV group for the intention-to-treat analysis (P=0.005). Overall survival times were 17.4 months and 14.2 months, respectively (P=0.031).¹⁸ Time to treatment failure or progression was a median of 6.7 months with IFL and 4.4 months with 5-FU/LV (P<0.001). Using a bolus weekly regimen of IFL, Saltz et al reported similar results, with response rates of 39% versus 21% (P<0.001), overall survival times of 14.8 versus 12.6 months (P=0.04), and median progression- free survival times of 7.0 months versus 4.3 months (P=0.004) for the IFL and 5-FU/LV treatment groups, respectively.¹⁹ In the Saltz study, irinotecan monotherapy was included as a third treatment, and results for these patients were similar to those treated with 5-FU/LV. These studies demonstrated the superiority of IFL over 5- FU/LV and established IFL as a new standard in the first- line treatment of metastatic CRC.

Irinotecan in Combination with Capecitabine

The combination of irinotecan-capecitabine (XELIRI) is being actively investigated in an attempt to replace the more complicated and potentially more toxic 5-FU/LV regimens with the oral fluoropyrimidine. Borner et al presented the clinical results of a Phase II trial comparing weekly irinotecan 70mg/m2 (days one, eight, 15, 22, and 29) with every three week irinotecan 300/240mg/m2 (day one and 22) in combination with capecitabine 1,000mg/m2 bid (days one to 14 and 22 to 35) in 75 patients with good performance status.20 Preliminary response rates were 42% and 41%, respectively, and median TTP was 7.2 months and 9.9 months. The most common grade 3/4 toxicity was diarrhea, at rates of 32% and 19% respectively.

In a Phase II study conducted by Patt et al in the US, patients under age 65 received capecitabine 1,000 mg/m2 bid (days one–14) plus irinotecan 250mg/m² (day 1) in a 21-day cycle; those over age 65 received capecitabine 750mg/m2 bid plus irinotecan 200 mg/m2.21 Treatment with XELIRI yielded a 42% overall response rate, and median TTP was 7.1 months. Disease control (i.e. complete response/partial response plus stable disease) was achieved in 71% of evaluable patients. XELIRI demonstrated a predictable and manageable safety profile. The most common grade 3/4 toxicities included diarrhea (20%) and neutropenia (18%).These results suggest that capecitabine may be a reasonable alternative to bolus or infusional schedules of 5-FU/LV in combination with irinotecan in the metastatic setting.

Oxaliplatin

Oxaliplatin is a third-generation platinum compound that exerts its cytotoxic effects through the formation intrastrand and interstrand DNA cross-links.It is the only platinum drug effective against CRC, and it exhibits a different spectrum of toxicity when compared with other platinum compounds. In particular, it does not cause the nephrotoxicity associated with cisplatin, or the degree of myelosuppression and alopecia observed with carboplatin. The main dose-limiting toxicity of this agent is neurotoxicity, and this particular adverse event presents as both an acute and chronic sensory neuropathy. The acute form is exhibited by nearly all patients, and typically presents as transient paresthesias that are exacerbated upon exposure to cold. In addition, about 3% to 4% of patients experience laryngopharyngeal spasms. In contrast, the chronic form is a cumulative sensory neuropathy that develops in up to 12% to 15% of patients. In vitro and in vivo tumor models indicate that combining oxaliplatin with 5-FU or SN-38 (the active metabolite of irinotecan) results in additive or synergistic cytotoxicity.