Irinotecan

Irinotecan (CPT-11) is a campthotecin derivative with anti-tumour activity via inhibition of topoiso-merase-I, a nuclear enzyme that facilitates DNA uncoiling for replication and transcription by binding to DNA and causing reversible single-stranded DNA breaks. Because of the different mechanism of action from that of FU, at the beginning it was evaluated in FU-refractory disease.

A total of 304 patients with FU-refractory colorectal tumour had a major response rate of 13% with 49% of minor response or stable disease when treated with weekly doses of 125 mg/m2 for 4 weeks followed by a 2-week break. Diarrhoea and neutropenia were the major dose-limiting toxicities [12].

In two European trials CPT-11 has been compared to best supportive care or retreatment with FU CI in patients with colorectal cancer refractory to FU bolus. The CPT-11 schedule of 350 mg/m2 every 3 weeks was used for these trials.

In the first study the overall survival was significantly better in the CPT-11 group (1-year survival of 36.2% and 13.8% respectively in CPT-11 and supportive care arms, p=0.0001). In a quality of life (QoL) analysis, all significant differences, except on the diarrhoea score, were in favour of the CPT-11 group [13].

In the second study, patients treated with CPT-11 lived for significantly longer than patients treated with FU (p=0.035). Survival at 1 year was increased from 32 to 45% and median survival from 8.5 to 10.8 months in the CPT-11 group. Median progressionfree survival was longer with CPT-11 (4.2 vs. 2.9 months, p=0.030). Both treatments were equally well tolerated and QoL was similar in both groups [14].

Another phase III trial has investigated the efficacy and tolerability of two CPT-11 dosing regimens (weekly 125 mg/m2 for 4 weeks or once 300-350 mg/m2 every 3 weeks) in patients with FU-refractory colorectal cancer. There was no significant difference in 1-year survival (46% vs. 41%, respectively, p=0.42), median survival (9.9 vs. 9.9 months, p=0.43) or median time to progression (4.0 vs. 3.0 months, p=0.54) between the two regimens. Every 3-week regimen was associated with a significantly lower incidence of severe diarrhoea (p=0.002). Treatment-related mor

Table 2. Phase III randomised trials of CPT-11 in patients with metastatic colorectal cancer

Authors

Trial

Response rate (%)

Progression-free survival (months)

Median survival (months)

Cunningham et al. [13]

CPT+BSC

-

-

9.2

vs. BSC

-

-

6.5

Rougier et al. [14]

CPT-11

-

-

10.8

FU CI

-

-

8.5

Saltz et al. [16]

CPT-11+FU+LV

39 pS

7.9 pS

14.8 pS

FU+LV

21

4.3

12.6

CPT-11

18

4

12

Douillard et al. [17]

CPT-11+FU+LV

49 pS

6.7 pS

17.4 pS

FU+LV

31

4.4

14

pS, p value statistically significant pS, p value statistically significant tality occurred in 5.3% receiving weekly CPT-11 and in 1.6% receiving CPT-11 every 3 weeks [15].

CPT-11 was then introduced in the first line for the treatment of previously untreated colorectal cancer. Three phase III prospective randomised trials were designed to compare the efficacy and toxicity of the combination of FU, LV and CPT-11 to FU and LV alone.

The American trial compared bolus FU-LV-CPT-11 (IFL) to bolus FU-LV and to CPT-11 alone. The trial demonstrated significant benefit in terms of confirmed response rates, progression-free survival and overall survival. IFL showed confirmed responses in 39% of patients, compared with 21% in patients treated with FU-LV and 18% in patients treated with CPT-11 (p<0.001). In addition, progression-free survival was significantly prolonged with IFL (7.9 vs. 4.3 months, p=0.004). Median survival was also improved: 14.8 months for IFL and 12.6 months for FU-LV (p=0.042) [16].

The first European trial compared CPT-11, using AIO or Douillard regimen (weekly or every 2 weeks infusion) with infusional FU-LV using the same schedule. The CPT-11 regimen had a significantly longer time-to-progression (median 6.7 months vs. 4.4 months, p<0.001), a higher response rate (49% vs. 31%, p<0.001) and a higher overall survival (median 17.4 vs. 14.1 months, p=0.031) [17] (Table 2).

Was this article helpful?

0 0
Dealing With Erectile Dysfunction

Dealing With Erectile Dysfunction

Whether you call it erectile dysfunction, ED, impotence, or any number of slang terms, erection problems are something many men have to face during the course of their lifetimes.

Get My Free Ebook


Post a comment