1University Medical Centre, St. Radboud, Nijmegen; 2University Medical Centre, Leiden; 3Rijnstate Hospital, Arnhem, The Netherlands; 4Herlev Hospital, University Hospital of Copenhagen, Denmark; 5Rudolf Hospital, Vienna, Austria; 6Slingeland Hospital, Doetinchem; 7Medisch Spectrum, Twente Enschede; 8Bosch Medicentrums, Hertogenbosch, The Netherlands; 9University Hospital Charite, Berlin, Germany; 10MedImmune Oncology, Inc., Gaithersburg, MD, USA
Received 7 September 2001; accepted 11 September 2001.
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Abstract |
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Trimetrexate (TMTX) is a biochemical modulator of 5-fluorouracil (5-FU) and leucovorin (LV). Phase II trials have shown promising activity of 5-FU/LV/TMTX in patients with advanced colorectal cancer (ACC). This trial evaluated the effect of TMTX in combination with 5-FU/LV as first-line treatment in ACC.
Patients and methods
Patients with ACC were randomised to receive either intravenous LV 200 mg/m2/5-FU 600 mg/m2 or TMTX 110 mg/m2 followed 24 h later by LV 200 mg/m2/5-FU 500 mg/m2 plus oral LV rescue. Both schedules were given weekly for 6 weeks every 8 weeks. Patients were evaluated for progression-free survival (PFS), overall survival (OS), tumour response, quality of life (QoL) and toxicity.
Results
A total of 365 patients were randomised. A statistically significant prolongation of median PFS was seen in patients treated with TMTX/5-FU/LV compared with 5-FU/LV (5.4 months versus 4.1 months, respectively; P = 0.03), and a trend towards a significant benefit for OS (13.4 months versus 10.5 months, respectively; P = 0.08). Tumour response, QoL and toxicity were comparable between the two arms. Diarrhoea was the most frequently occurring grade 3 or 4 toxicity (22% and 30%, respectively).
Conclusions
The addition of TMTX to a weekly regimen of 5-FU/LV results in a small but significant improvement in PFS without adding toxicity or worsening QoL in patients with ACC.
Key words: biochemical modulation, colorectal cancer, 5-fluorouracil, leucovorin, trimetrexate, randomised trial
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Introduction |
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In a study with escalating doses of TMTX and 5-FU in combination with LV, Conti et al. [4] showed that the maximum tolerated dose of a weekly schedule of TMTX/LV/5-FU was TMTX at 110 mg/m2 followed 24 h later by LV and 5-FU, both at 500 mg/m2, and oral LV rescue starting 6 h after 5-FU at 10 mg/m2 every 6 h for seven doses. Treatment was given weekly six times followed by a 2-week rest period. The dose-limiting toxicity was diarrhoea. Also, hypersensitivity reactions to TMTX were observed in several patients. A partial response occurred in seven of 35 pretreated patients (20%) with advanced colorectal cancer (ACC) and in several patients with other gastrointestinal malignancies as well. This phase I schedule was then tested in phase II studies with the only differences being that the dose of intravenous (i.v.) LV was decreased to 200 mg/m2 and the dose of oral LV was fixed at 15 mg. Two phase II studies in previously untreated patients with ACC have been performed. Blanke et al. [5] observed a response rate of 50% in 36 evaluable patients (95% confidence interval (CI) 32% to 68%), with a median overall survival (OS) of 53 weeks. Analysis by intention-to-treat showed a response rate of 42% (95% CI 26% to 58%). The major toxicity was grade 3 or 4 diarrhoea, which occurred in 58% of patients. Although haematological toxicity was infrequent, two patients died from sepsis. Szelényi et al. [6] found a partial response rate of 36% (95% CI 25% to 49%), and an incidence of severe diarrhoea of 22%, decreasing to 8% with early loperamide treatment in 34 patients. Based on these promising results, two independent phase III studies were initiated, one in Europe and one in the United States [7]. In both studies the same schedule of TMTX/5-FU/LV was used as in the phase II studies. Here, we report on the European study, which differs from the USA study in two aspects: (i) it was not placebo-controlled and therefore no oral LV rescue was administered in the control arm, and (ii) the 5-FU dose in the control arm was higher compared with that in the TMTX-containing arm (600 mg/m2 versus 500 mg/m2, respectively). This 5-FU dose has commonly been used in weekly 5-FU/LV regimens in randomised trials [8, 9]. Therefore, in contrast to the USA study, a higher 5-FU dose was used in the control arm, reflecting the intention to investigate a meaningful biomodulation effect of TMTX.
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Patients and methods |
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The primary objective of the study was to detect a difference of a minimum of 3 months in progression-free survival (PFS), with a power of 79% and = 0.05. An interim analysis on PFS and toxicity was planned for the European study after the first 200 patients were followed for a minimum of 6 months [10]. Secondary objectives were response rate, response duration, OS, and quality of life (QoL). Stratification was performed for treatment centre, PS (0, 1 or 2), site of primary (colon or rectum), site of metastases (liver dominant with <30% involvement, or liver dominant >30%, or lung dominant or other dominant), disease evaluability (measurable or evaluable), prior adjuvant treatment (yes or no), and serum LDH value (
300 U/l or >300 U/l).
Patients were randomised to either LV 200 mg/m2 as a 1-h i.v. infusion followed directly by 5-FU 600 mg/m2 as an iv bolus (control arm) or TMTX 110 mg/m2 as a 1-h i.v. infusion followed 2224 h later by LV 200 mg/m2 as a 1-h i.v. infusion followed directly by 5-FU 500 mg/m2 as an i.v. bolus and LV 15 mg orally every 6 h for seven doses, starting 6 h after 5-FU administration (experimental arm). At the onset of any diarrhoea, patients were instructed to use an intensive dosing schedule of loperamide: 4 mg after the first liquid stool and 2 mg every 2 h until 12 h after the last passage of liquid stool up to a maximum of 48 h. Treatment was given for 6 weeks every 8 weeks. Treatment was continued until disease progression with a maximum of 1 year. Patients were followed weekly for toxicity and every 8 weeks for tumour response. Computed tomography (CT) scans were required for the evaluation of liver metastases. National Cancer Institute Common Toxicity Criteria for toxicity and WHO criteria for tumour response were used. Dose reductions were performed as follows: for haematological toxicity grade 2, 5-FU was reduced to 75%; for haematological and non-haematological toxicity grade 3 or 4, treatment was withheld for a maximum of 2 weeks until recovery to grade 1 or less and then resumed with 5-FU at 50% of the dose. If at 50% dose reduction of 5-FU no toxicities greater than grade 2 occurred, increases in 5-FU by 25% increments were allowed. If treatment was withheld for 3 weeks (not including rest weeks), the patient was removed from the study. Patients were asked to complete the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) at baseline and at week 5 and 8 of each cycle and every 3 months during follow-up. Information on any subsequent antitumour treatment was collected in the case report forms. An independent review of CT scans was planned.
This study was 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 Harmon-isation 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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Toxicity
Grade 3 or 4 toxicities are summarised in Table 3. The most prominent toxicity was diarrhoea, which occurred less frequently in patients treated with TMTX/5-FU/LV. There was an equal use of loperamide in both study arms (46% in the control arm, 45% in the experimental arm). Of note, there was a low incidence of hypersensitivity reactions. Five deaths were probably or certainly treatment-related, three in the TMTX arm and two in the control arm. In the TMTX arm, two deaths were due to neutropenic sepsis and one death was due to heart attack. In the control arm, one death was due to neutropenic sepsis and one death was due to cerebrovascular accident. The percentage of patients who discontinued treatment due to adverse events was 16% in the TMTX arm and 20% in the control arm.
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Discussion |
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TMTX also has biochemically modulating effects on 5-FU and has several advantages over MTX. Based on promising phase II results of TMTX/5-FU/LV in ACC [5, 6], two independent randomised studies were initiated, and both were designed to detect a statistically significant difference in PFS of TMTX/5-FU/LV over 5-FU/LV. In our European study, we found an increase in median PFS of 1.3 months. Although this difference was statistically significant with a P value of 0.03 (based on the Wilcoxon test), the clinical relevance of this difference is questionable. We found an increase in median OS of 2.9 months, which showed a trend towards significance (P = 0.08; Wilcoxon test). It should be noted that our study was not designed to detect a statistically significant difference of this magnitude for this end point. An integrated analysis on the OS and PFS of the European and the USA studies has been performed [16]. A possible bias of OS in our study by the more frequent use of second-line irinotecan in the experimental arm cannot be excluded since irinotecan has been shown to increase survival in this setting [17]. The somewhat lower median OS compared with more recent randomised studies using irinotecan [12, 13] or oxaliplatin [14, 15] can be explained by the fact that these agents were not yet commonly available for salvage treatment during the larger part of our study accrual period, and a more unfavourable patient population in our study with almost 50% of our patients with three or more metastatic sites, compared with approximately 10% to 15% in these other studies [1215].
The high incidence, up to 58%, of severe diarrhoea in previous phase II studies [5, 6] prompted us to prescribe intensive dosing of loperamide at the onset of diarrhoea, which occurred in both treatment arms. This resulted in a marked decrease in the incidence of diarrhoea, as was shown by others [6]. The slightly lower incidence of diarrhoea in the experimental arm was unexpected, and cannot be explained by a difference in the use of loperamide. In general, treatment with TMTX/5-FU/LV was well-tolerated, and the results on toxicity in the 5-FU/LV arm are very comparable with those of another randomised study using this schedule [8].
In conclusion, this study shows that the addition of TMTX to a weekly schedule of 5-FU/LV results in a small but signifi-cant improvement of PFS, with a trend towards a significant benefit in OS. Treatment with TMTX/5-FU/LV is feasible with an acceptable incidence of severe diarrhoea. Given this safety profile, a combination of this schedule with other cytotoxic drugs appears feasible.
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Acknowledgements |
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Footnotes |
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References |
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