Irinotecan or oxaliplatin for ﬁrst-line treatment of advanced colorectal cancer?

In this issue of Annals of Oncology, two studies by the Southern Italy Cooperative Oncology Group (SICOG) and the Hellenic Cooperative Oncology Group (HECOG) are presented in which treatment with irinotecan and oxaliplatin, both in combination with 5-fluorouracil/leucovorin (5-FU/LV), is compared in patients with advanced colorectal cancer [1, 2]. The choice of the first-line regimen may be important, since not all patients are eligible for salvage treatment, which obviously provides a rationale to first administer the most effective treatment. The study by Goldberg et al. [3], which showed an overall survival benefit for FOLFOX when compared with IFL, has convinced many colleagues that oxaliplatin should be the preferred choice. However, both the fact that in this study a bolus 5-FU regimen (IFL) was compared with a prolonged 5-FU infusion regimen (FOLFOX), and the fact that salvage treatment in the IFL arm was inferior to the FOLFOX arm, do not allow such a straightforward conclusion [4]. The GERCOR study in which irinotecan and oxaliplatin were compared using the same schedule of prolonged 5-FU infusion and LV with both drugs did not show any significant differences in response rates or survival [5]. The originality of the current studies lies in the fact that a bolus 5-FU regimen was used with both drugs. This has the advantage that central venous access devices and ambulatory pumps are not required. Both studies had response rate as the primary end point, and are comparable in the patient selection criteria and baseline patient characteristics. Yet, the authors come to different conclusions. Some important study characteristics and results are as follows. The SICOG study [1] used a 2-weekly schedule, with irinotecan or oxaliplatin administered on day 1 and 5-FU/LV on day 2. The rationale to administer these drugs on consecutive days as opposed to administration on the same day is unclear. The oxaliplatin arm showed superior results in terms of response rate (44% versus 31%; P= 0.029), failure-free survival (7 versus 5.8 months; P= 0.046) and overall survival (18.9 versus 15.6 months; P= 0.032). This caused the authors to select the oxaliplatin schedule as the regimen of choice. The dose of oxaliplatin was decreased after a planned interim analysis, without apparent detrimental effect on efficacy. The HECOG [2] used a weekly schedule for 6 weeks followed by 2 weeks of rest, and no difference between the oxaliplatin and irinotecan arm was found in terms of response rate (unconfirmed 32% versus 33%, confirmed 22% versus 23%), time to progression (7.6 versus 8.9 months) and overall survival (17.4 versus 17.6 months). The main problem with this study lies in its design: with response rate as the primary end point, a scheduled interval between tumour evaluations of 16 weeks is simply too long. Moreover, confirmation of response had to wait for another 16 weeks. This is most probably the explanation for the lower response rate when compared with the SICOG study while the overall survival in both studies was in the same range. Likewise, results on time to progression are likely to be less accurate when such a long interval is used for tumour evaluation. What other remarks can be made on these studies? First, despite the comparable results on overall survival between the two studies the dose intensity for the used drugs was lower in the HECOG study, most markedly for irinotecan: the planned total irinotecan dose over an 8-week period was 800mg/m in the SICOG study versus 420mg/m in the HECOG study. Results from small studies have suggested a dose–response relationship for irinotecan [6, 7]. As mentioned, the response rates are not comparable between the current studies, and any relationship between irinotecan dose and survival based on these studies should be interpreted with caution in any case, since only a direct comparison between the regimens would allow a definite conclusion. Secondly, a difference in the occurrence of severe diarrhoea between the study arms was only observed in the SICOG study, with a higher incidence in the irinotecan arm. The incidence of diarrhoea in the irinotecan arm was higher compared with the HECOG study (28% versus 12.3%), which may be related to the lower dose of irinotecan in the latter study. As expected, neurotoxicity was observed more frequently in the oxaliplatin arms of both studies. Together with the comparable results on efficacy, the increased incidence of neurotoxicity caused the authors of the HECOG study to select the irinotecan schedule as the regimen of choice. How do the results of the current studies contribute to the ongoing discussion of which drug is to be preferred for firstline treatment? When only comparative studies between irinotecan and oxaliplatin are taken into account in which the 5-FU/LV schedule was similar in both arms, only the SICOG study [1] shows a benefit for oxaliplatin. The HECOG [2] and GERCOR [5] studies, as well as the preliminary results from a randomized phase II study in which capecitabine was used instead of 5-FU/LV [8], do not show significant differences in efficacy between irinotecan and oxaliplatin. It is not clear why the SICOG study stands out in this respect. The median number of cycles, as well as the percentage of patients receiving salvage treatment, was comparable between the two study arms. This shifts the focus towards the toxicity of the regimens. Results of a phase III study comparing a 3-weekly with a weekly irinotecan schedule when given as a single agent showed comparable efficacy but significantly less diarrhoea and fewer dose reductions for the 3-weekly schedule [9]. Annals of Oncology 16: 845–846, 2005 doi:10.1093/annonc/mdi196 Published online 12 May 2005