1University Medical Centre, St Radboud, Nijmegen, The Netherlands; 2Oregon Health and Science University, Portland, OR; 3MedImmune Oncology, Inc., Gaithersburg, MD, USA
Received 7 September 2001; accepted 11 September 2001.
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Abstract |
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Two randomised studies were performed with trimetrexate (TMTX) as a biochemical modulator of 5-fluorouracil (5-FU)/leucovorin (LV) in advanced colorectal cancer (ACC), one in Europe and one in the United States. Both studies were similarly designed to detect a statistically significant difference in progression-free survival (PFS). Overall survival (OS), however, was later adopted as the primary outcome measure for approvability of agents for first-line treatment of ACC. Therefore, an integrated analysis of survival data from the European and USA trials was performed to detect a clinically relevant difference in survival.
Patients and methods
The experimental arm was identical in both studies and consisted of TMTX 110 mg/m2 intravenously (i.v.) followed 24 h later by i.v. LV 200 mg/m2/5-FU 500 mg/m2 plus oral LV rescue. The 5-FU dose in the control arm was 600 mg/m2 in the European study and 500 mg/m2 in the USA study, and the USA study was placebo-controlled. Treatment was given weekly for 6 weeks every 8 weeks.
Results
A total of 746 patients were analysed. Median OS was 13.0 months for 5-FU/LV and 14.6 months for TMTX/5-FU/LV (P = 0.15; Wilcoxon). Median PFS was 4.4 months and 5.4 months, respectively (P = 0.07; Wilcoxon).
Conclusions
The addition of TMTX to a weekly regimen of 5-FU/LV does not improve the outcome for patients with ACC.
Key words: biochemical modulation, colorectal cancer, 5-fluorouracil, leucovorin, randomised trial, trimetrexate
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Introduction |
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Patients and methods |
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Both studies were conducted in accordance with the principles of the Declaration of Helsinki, as adopted by the 29th World Medical Assembly, Helsinki, Finland, and revised at the 48th World Medical Assembly in Somerset West, Republic of South Africa, 1996. These principles are consistent with those set forth in the International Conference on Harmonization Guidelines on Good Clinical Practice, and the current USA Code of Federal Regulations (21 CFR Parts 56 and 50) regarding the requirements for independent ethics committees and institutional review boards and protection of the rights and welfare of human subjects involved in clinical investigations.
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Results |
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Discussion |
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First, the European study was not placebo-controlled, and thus open to greater bias. The fact that the median number of cycles in both treatment arms was exactly the same in both studies, however, argues against this, as well as the fact that an independent computed tomography scan review, which was performed in the majority of patients in the European study, was not significantly different from the results as provided by the investigators.
Secondly, as a consequence of the placebo-control design of the USA study, patients in the control arm also received oral LV rescue. We consider it unlikely that these extra doses of LV may have influenced the study outcome, since there are no data from previous studies to support this, and also the results on median PFS in the control arms were comparable in both studies (4.1 months and 4.4 months, respectively).
Thirdly, the result on OS in the European study may have been influenced by a more frequent use of second-line irinotecan in its experimental arm and lower exposure to 5-FU in its control arm. The longer median OS in the USA study compared with the European study is probably caused by a 2.5 times more frequent use of irinotecan in the former study, as this drug was not available for routine use during the larger accrual period of the European study, which completed accrual at an earlier time than did the USA study. The fact that the median PFS times in both studies were much more in the same range compared with the median OS times supports this view. Furthermore, it cannot be excluded that the frequent use of second-line irinotecan in the USA study has obscured a small OS benefit of TMTX.
Fourthly, the incidence of grade 3 or 4 diarrhoea in the TMTX/5-FU/LV arm was significantly higher in the USA study (41%) compared with the European study (22%). Although the percentage of patients that received loperamide did not differ between the two studies, it cannot be excluded that patients with diarrhoea in the USA study may have received a less intensive dosing of loperamide. No data on this are available. The lower median dose intensity (DI) for 5-FU in the experimental arm of the USA study (82%) compared with that in the European study (92%), while the median DI in the control arms (86% and 87%, respectively) were quite comparable, probably reflects the effect of diarrhoea on the dosing in the TMTX/5-FU/LV arm of the USA study and may therefore have negatively influenced the outcome of this study.
Fifthly, the criteria that were used for disease progression differed among the studies: in the European study, progression was defined as an increase of 25% or more in the sum of all lesions, while in the USA study, such an increase in a single lesion was sufficient for termination of the study medication. As a result, several patients were withdrawn from the USA study because one small lesion progressed while more bulky disease remained stable. Since the margins of error in measuring small lesions is known to be greater compared with larger lesions, this may have caused a suboptimal exposure to the study medication in patients. The comparable results on the median number of administered cycles as well as median PFS between the two studies does not support this, however, although a small impact of this difference in study design cannot be ruled out.
In conclusion, this integrated analysis did not demonstrate any advantage in terms of PFS or OS for the addition of TMTX to a weekly regimen of bolus 5-FU plus LV. Although some factors were identified that may have influenced the outcome of both studies, it is unlikely that TMTX/5-FU/LV at this schedule is a more effective treatment than 5-FU/LV alone for the general patient population with ACC.
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Footnotes |
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References |
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2.
Punt CJA, Keizer HJ, Douma J et al. Trimetrexate as biochemical modulator of 5-fluorourail/leucovorin in advanced colorectal cancer: final results of a randomised European study. Ann Oncol 2002; 13: 8186.
3.
Blanke CD, Shultz J, Cox J et al. A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer. Ann Oncol 2002; 13: 8791.