Introduction
Irinotecan (CPT-11), a semisynthetic derivative of camptothecin, is a topoisomerase-I inhibitor, which is active against a variety of solid tumors, including advanced colorectal, pulmonary, gastric and ovarian cancer (1,2). Irinotecan is a prodrug, which is hydrolyzed by liver carboxylesterase to produce the active metabolite SN-38 (3). SN-38 is eliminated by glucuronidation, which depends on hepatic UDP glucuronosyltransferase family 1, member A1 cluster (UGTA1) enzymes (4). Genotype UGT1A1*28 has been found to be associated with decreased SN-38 glucuronidation; thus, irinotecan-induced diarrhea and neutropenia may be increased in patients with the UGT1A1*28/*28 genotype (5). While several UGT1A1 genotype-directed administration schedules of irinotecan are currently under evaluation (6–8), the concept of heritable biological marker-guided dosing is new and requires further evaluation prior to introduction in clinical practice (9).
Three schedules of irinotecan administration are currently in clinical use, namely weekly, bi-weekly and tri-weekly schedules, among which administration once every 3 weeks and a weekly 90-min infusion are the ones most commonly used and compared (10,11). The dose-limiting side effects of the two schedules are neutropenia and diarrhea. Several comparative clinical trials have been performed to investigate whether the efficacy of irinotecan is schedule-dependent and others have suggested that the toxicity profiles may be distinctive for different schedules irrespective of the genotype (5,12–18). However, these trials have not been conclusive regarding the differences between the two commonly used regimens. Therefore, a meta-analysis of all these individual data is required to determine the differences.
The objective of the present meta-analysis, which was based on all the data from randomized controlled trials (RCTs), was to compare the efficacy and toxicity profiles of the two different schedules of irinotecan, used alone or in combination with other drugs in the treatment of various solid tumors with the aim of determining the optimal administration schedule for this drug.
Discussion
The results of the present meta-analysis revealed that the 3-weekly and weekly regimens of irinotecan administration had a similar efficacy interms of ORR and OS, while the TTP tended to be longer with the 3-week regimen. Furthermore, the 3-weekly group had a lower incidence of grade 3/4 diarrhea compared with the weekly group, while the incidence of grade 3/4 neutropenia was higher in the 3-weekly group.
Irinotecan is a widely used chemotherapeutic drug that is effective against several solid tumors, with a single-agent response rate of 12–50% (20,21). The primary toxicities of irinotecan are diarrhea and neutropenia, the severity of which has been shown to be partly associated with UGT1A1*28, a germline genetic variant affecting the elimination of SN-38. Several trials and a meta-analysis demonstrated that the UGT1A1*28/*28 genotype is associated with an increased risk of neutropenia and diarrhea, and that this association was dose-dependent (5,22). Genotype-directed dosing has been investigated by a series of studies (6–8); however, its integration into the clinical practice remains scant and this drug is still dosed by body surface area according to almost all guidelines. Furthermore, SN-38 accounts for only 14% of the total interindividual variability in the absolute neutrophil count nadir (9), suggesting that additional factors may lead to neutropenia. Among the factors contributing to irinotecan-related toxicity, schedule-dependent toxicity has been most reliably confirmed (23). The present meta-analysis suggested that the toxicity patterns of the two different schedules were somewhat distinctive. The 3-weekly regimen was associated with a lower incidence of diarrhea but a higher rate of neutropenia compared with the weekly regimen. Furthermore, the 3-weekly regimen was superior in terms of TTP, although the OS was similar between the two regimens. Thus, the irinotecan treatment schedule should be selected according to the characteristics, physical status, convenience and preference of each patient.
The trials assessed in the present meta-analysis were heterogeneous in terms of OS. Treatment response not only depends on the chemotherapeutic schedule, but is also tumor type-dependent. Among the included trials, 5 investigated advanced or metastatic colorectal carcinoma (12–14,17,18), 1 investigated rhabdomyosarcoma (15) and 1 was on breast cancer (16). Furthermore, in 2 of the studies, irinotecan was used as first-line therapy in combination with capecitabine (12,13), while in the remaining studies, irinotecan monotherapy was used as a second- or further-line treatment. Moreover, OS tends to be affected by the subsequent treatment and several other unforeseen factors. Therefore, the differences in tumor type, treatment modality/schedule and patient characteristics may all contribute to the heterogeneity observed. In this context, ORR and TTP may reflect the acute efficacy of a therapy more accurately, in which heterogeneity was acceptable or absent. Mascarenhas et al (15) investigated rhabdomyosarcoma patients aged <21 years; therefore, a sensitivity analysis was performed. The result demonstrated that there was no difference in the overall effect with or without this trial.
The quality of the studies included in the present meta-analysis was relatively low, which may limit the reliability of the conclusions. Three trials did not report the details of randomization (13,15,17), whereas none of the trials specified whether allocated concealment was performed. Furthermore, 6 of the studies did not mention blinding, whereas the remaining study specified that blinding was not performed (17). In addition, 1 study reported loss to follow-up, while no ITT analysis was performed (12). All these factors may have led to selection, performance, measurement and attrition biases. Of the 7 the included trials, 3 were from the USA (14–16) and 4 from Europe (12,13,17,18), which may reduce the universality of the results. The relatively small sample size and the fact that most of the studies were relatively old (>10 years) are also considered as limitations of the present meta-analysis. Therefore, it is recommended that more RCTs of high quality from different countries and with improved design are performed in the future.
In conclusion, the present meta-analysis suggested that, compared to the weekly regimen of irinotecan, the 3-weekly regimen yielded a similar ORR and OS, but a longer TTP. The two regimens exhibited distinctly different toxicity profiles: While the 3-weekly regimen was associated with a lower incidence of diarrhea, it had a higher rate of neutropenia compared with the weekly regimen. Thus, when selecting an irinotecan treatment schedule, cost-effectiveness, the patients' performance status and convenience should be taken into consideration.