Irinotecan or Oxaliplatin Combined with Leucovorin and 5-Fluorouracil
Irinotecan or Oxaliplatin Combined with Leucovorin and 5-Fluorouracil
Abtract & Commentary
Stuart M. Lichtman, MD, FACP, Associate Attending, Memorial Sloan-Kettering Cancer Center, Commack, New York, is on the Editorial board for Clinical Oncology Alert.
Dr. Lichtman reports no financial relationship with this field of study.
Synopsis: The IRI/LV/5-FU and OXA/LV/5-FU regimens demonstrated equally substantial efficacies and manageable toxicity profiles in the first-line treatment of patients with advanced CRC. However, IRI/LV/5-FU may be the preferable regimen to avoid significant neurotoxicity associated with OXA/LV/5-FU.
Source: Kalofonos HP, et al. Irinotecan or oxaliplatin combined with leucovorin and 5-fluorouracil as first-line treatment in advanced colorectal cancer. Ann Oncol. 2005;16: 869-877.
Advanced colorectal carcinoma (crc) ranks second behind lung cancer in the number of cancer deaths. The beneficial effects of systemic chemotherapy on objective response rates, time to disease progression, overall survival, and quality of life are now well documented in advanced CRC. The standard agent used in the management of CRC for many years was 5-fluorouracil (5-FU) combined with the modulator leucovorin. Attempts to further improve the clinical results have included the use of new active agents such as irinotecan and oxaliplatin.1-4
The safety and efficacy of both irinotecan and oxaliplatin have been evaluated in several studies in patients with advanced CRC; these agents have demonstrated acceptable toxicity and significant antitumor activity. An even larger number of studies have been performed using the combination of irinotecan or oxaliplatin plus leucovorin and bolus, or infusional 5-FU in patients with advanced CRC. Combination chemotherapy with LV-modulated 5-FU and irinotecan or oxaliplatin provides significant antitumor activity and a survival advantage over bolus and continuous-infusion 5-FU modulated with leucovorin. Newer agents have significantly increased the median overall survival in patients with advanced colorectal cancer and survival times of beyond 20 months have been reported in randomized trials with 5-FU, irinotecan and oxaliplatin. Since there is no consensus regarding the optimum regimen for the treatment of advanced CRC, the challenge for the immediate future is to identify the most effective regimens and use them as the basis on which to add new promising antitumor agents. A randomized, phase II clinical study was performed to compare directly leucovorin/5FU with either irinotecan or oxaliplatin. The primary objective of this randomized, multicenter trial was to compare the tumor response rate in non-pretreated patients. Secondary objectives were to compare TTP, OS and toxicity profiles of the 2 regimens.
COMMENTARY
Patients with advanced, recurrent, or metastatic adenocarcinoma of the colon or rectum, previously untreated, and bidimensionally measurable disease located outside of a previously irradiated field were eligible. Patients were required to have normal endorgan function and a performance status > 2. Patients were randomized to 1 of 2 treatments. In treatment arm A, irinotecan was administered at a dose of 70 mg/m2 followed by LV 200 mg/m2 as a 2-h IV infusion and 5-FU 450 mg/m2 as an IV bolus at the end of LV infusion. In treatment arm B, oxaliplatin was administered at a dose of 45 mg/m2, followed by LV 200 mg/m2 and 5-FU 450 mg/m2 as an i.v. bolus at the end of LV infusion. Treatment was administered weekly for 6 weeks, followed by a 2-week rest period. Of the 295 eligible patients, 182 were men and 113 were women. Demographics and baseline characteristics were balanced between the 2 groups. Second-line chemotherapy was administered in 141 patients (47.8%): 64 (21.7%) in arm A and 62 (21.0%) in arm B. There were no significant differences between arms A and B in overall response rate. In the intent-to-treat analysis, the overall response rates were 33% (95% CI, 25.1% to 40.9%) in arm A and 32% (24.3% to 39.9%) in arm B, based on responses that were demonstrated on a single evaluation. The response rate was 23% in arm A and 22.3% in arm B, based on responses confirmed according to the WHO criteria. Median time to disease progression values were 8.9 months in arm A and 7.6 in arm B. Median OS values were 17.6 months in arm A and 17.4 in arm B (P = NS). With the exception of peripheral neuropathy, which was only seen in patients receiving oxaliplatin (P = 0.003), there were no significant differences in toxicities between the two regimens. The most frequently recorded grade 3/4 toxicity was diarrhea in both treatment arms, followed by bone marrow toxicity in both arms, and peripheral neuropathy in arm B. Severe adverse events requiring early discontinuation of study treatment occurred in 4 (3%) and 12 (8%) patients in arms A and B, respectively (P = NS).
This study was designed to assess the efficacy of irinotecan or oxaliplatin combined with LV-modulated bolus 5-FU in non-pretreated patients with advanced CRC. The rationale for comparing these combination chemotherapy regimens was based on previous studies demonstrating improved response rates and survival compared with LV/5-FU alone in advanced CRC. The results revealed no significant differences in tumor response rates between the irinotecan/LV/5-FU and oxaliplatin/LV/5-FU treatment groups. However, a significantly greater number of patients (P = 0.003) experienced neurotoxicity with oxaliplatin/LV/5-FU than with irinotecan/LV/5-FU, whereas other grade 3/4 toxicities were comparable between study arms. The authors suggested that the irinotecan/LV/5-FU regime may have a superior therapeutic index.
The efficacy results reported here are consistent with the study by Tournigand et al,3 which showed no significant differences in overall response rate, TTP, and OS between 2 groups of patients treated with either LV-modulated infusional 5-FU plus irinotecan, followed by LV/5-FU plus oxaliplatin, or with the same schedule with oxaliplatin replacing irinotecan. The present results are also in agreement with those of Grothey et al,6 who found no differences in overall response rate and progression-free survival between patients treated with either capecitabine plus irinotecan or capecitabine plus oxaliplatin. In contrast, a large randomized trial (n = 795) by the US Intergroup, demonstrated that oxaliplatin plus infusional 5-FU with LV (FOLFOX4) was more active than irinotecan with bolus-administered 5-FU plus LV (IFL). In the latter study, FOLFOX4 had a response rate of 45% versus 31% with IFL (P = 0.002), a median TTP of 8.7 vs 6.9 months (P = 0.0014), and an OS of 19.5 vs 15.0 months (P = 0.0001). The US Intergroup Study, however, offered irinotecan as second-line treatment for the FOLFOX4 arm, whereas oxaliplatin was not available as a second-line treatment in the IFL arm. Therefore, the survival difference favoring oxaliplatin as first-line treatment may have been skewed because of the availability of an effective second-line treatment in the FOLFOX4 arm. Furthermore, it is also important to note the different routes of 5-FU administration in the US Intergroup Study (bolus 5-FU in IFL vs infusional 5-FU in FOLFOX4); as the investigators noted, this difference made it unfeasible to compare directly the relative efficacies of irinotecan and oxaliplatin.
Treatment-related grade 3/4 toxicities were acceptable and corresponded to the known toxicities of irinotecan/LV/5-FU and oxaliplatin/LV/5-FU, as recorded in previous trials. The incidence of severe (grade 3/4) toxicity was similar between treatment regimens, except for neurotoxicity, which was higher in the oxaliplatin/LV/5-FU regimen, presumably due to the cumulative toxicity from oxaliplatin. Myelotoxicity was also acceptable, with severe neutropenia affecting 8.2% and 4.9% of patients treated with irinotecan/LV/5-FU and oxaliplatin/LV/5-FU, respectively.
This study showed that the weekly schedules of irinotecan/LV/5-FU and oxaliplatin/LV/5-FU were equally efficacious regimens in the first-line management of previously untreated patients with advanced CRC. Both treatments demonstrated generally manageable toxicity profiles. The irinotecan regimen may be the preferable choice in patients where the greater incidence of grade 3 peripheral neuropathy observed with oxaliplatin is important. Further studies are needed to compare the efficacy and tolerability of irinotecan or oxaliplatin combined with infusional 5-FU plus LV or capecitabine in advanced CRC, keeping in mind the superior convenience of oral fluoropyrimidines with similar efficacy and toxicity profiles.
References
1. Andre T, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. Eur J Cancer. 1999;35: 1343-1347.
2. Douillard JY, et al. Metastatic colorectal cancer: integrating irinotecan into combination and sequential chemotherapy. Ann Oncol. 2003;14(Suppl 2): ii7-ii12.
3. Tournigand C, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized gercor study. J Clin Oncol. 2004;22:229-237.
4. de Gramont A, et al. Oxaliplatin/5-fu/lv in adjuvant colon cancer: Results of the international randomized mosaic trial. Proc Annu Meet Am Assoc Cancer Res. 2003;22:1015a.
5. Kalofonos HP, et al. Irinotecan or oxaliplatin combined with leucovorin and 5-fluorouracil as first-line treatment in advanced colorectal cancer: A multicenter, randomized, phase ii study. Ann Oncol. 2005;16: 869-877.
6. Grothey A, et al. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol. 2004;22:1209-1214.
The IRI/LV/5-FU and OXA/LV/5-FU regimens demonstrated equally substantial efficacies and manageable toxicity profiles in the first-line treatment of patients with advanced CRC. However, IRI/LV/5-FU may be the preferable regimen to avoid significant neurotoxicity associated with OXA/LV/5-FU.Subscribe Now for Access
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