, Volume 55, Issue 3, pp 423-435
Date: 27 Nov 2012

Raltitrexed

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Summary

Synopsis

Raltitrexed (ZD-1694) is a quinazoline-basedfolate analogue that exerts its cytotoxic activity by the specific inhibition of thymidylate synthase. In vitro studies show that raltitrexed is actively transported into cells and is then rapidly and extensively metabolised to a series of poly glutamates. These metabolites are significantly more potent inhibitors of thymidylate synthase than the parent drug and are retained intracellularly, producing prolonged cytotoxic effects without the need for continuous drug exposure.

Phase III clinical trials in patients with advanced colorectal cancer evaluated raltitrexed 3 mg/m administered as a 15-minute intravenous infusion once every 3 weeks. This schedule produced objective response rates of 14.3 to 19.3%, which were similar to those in patients treated with fluorouracil plus leucovorin (15.2 to 18.1%). Median survival durations ranged from 9.7 to 10.9 months with raltitrexed treatment and from 10.2 to 12.7 months with fluorouracil plus leucovorin.

The major toxicities associated with raltitrexed involve the haematological and gastrointestinal systems, although severe asthenia also occurred in 6 to 18% of patients receiving the drug. Grade 3 or 4 nausea or vomiting occurred in up to 13% of raltitrexed recipients and grade 3 or 4 diarrhoea in up to 14%. Similar incidences of grade 3 or 4 nausea or vomiting and diarrhoea were seen with fluorouracil plus leucovorin treatment. Raltitrexed generally showed significant advantages over fluorouracil plus leucovorin with respect to the incidence of leucopenia and mucositis. A greater proportion of raltitrexed than fluorouracil plus leucovorin recipients were able to receive the scheduled dosage.

Thus, with its similar efficacy to fluorouracil-based regimens, convenient administration schedule and favourable tolerability profile, raltitrexed provides clinicians with a worthwhile alternative to fluorouracil-based treatment for patients with advanced colorectal cancer.

Antitumour Activity

The antitumour agent raltitrexed (ZD-1694) is a quinazoline-based folate analogue that produces cytotoxic effects by the specific inhibition of thymidylate synthase. Raltitrexed is actively taken up into cells by the reduced folate-metho-trexate cell membrane carrier and then undergoes rapid, extensive metabolism by folylpolyglutamate synthetase to a series of polyglutamates. Polyglutamated forms of raltitrexed are significantly more potent inhibitors of thymidylate synthase than the parent drug, and their intracellular retention leads to prolonged inhibitory effects. Raltitrexed is a considerably more potent inhibitor of human colon tumour cell lines than fluorouracil. Raltitrexed given once daily for 15 days produced a growth delay of 15 days in 10 of 10 human tumour xenografts at doses lower than its maximum tolerated dose. In contrast, with a similar administration schedule, fluorouracil and methotrexate achieved this effect at their maximum tolerated doses in 4 and 2 xenografts, respectively.

Synergistic effects on antitumour efficacy in vitro were observed with certain combinations of raltitrexed and fluorouracil. The extent of the interaction depended on the administration schedule and dosage of the 2 drugs, although no consistent pattern that produced maximum synergism has emerged. Synergistic cytotoxic interactions have also been found between raltitrexed and the active metabolite of irinotecan.

Pharmacokinetic Properties

Maximum plasma concentrations (Cmax) and area under the concentration-time curve (AUC) for raltitrexed vary approximately linearly with dose, although there is considerable interpatient variation. Cmax is reached during or shortly after intravenous infusion, with a mean of 833 μg/L in patients with a variety of solid tumours receiving raltitrexed 3.0 mg/m2.

Plasma concentrations of raltitrexed declined in a triphasic manner. The distribution half-life (0.8 to 3 hours) and the terminal elimination half-life (t1/2γ; 8.2 to 105 hours) were independent of dose.

The major route of raltitrexed elimination is urinary excretion of the parent drug. Patients with mild to moderate renal impairment had a significantly prolonged t12γ and a 2-fold greater AUC than patients with normal renal function.

Clinical Efficacy

In a phase II clinical trial in 176 patients with advanced colorectal cancer, raltitrexed 3 mg/m2 once every 3 weeks demonstrated an overall response rate of 25.6%. The median time to disease progression was 4.2 months and the median survival duration was 11.2 months.

In 3 phase III clinical trials involving a total of more than 1300 patients with advanced colorectal cancer, raltitrexed (3 mg/m once every 3 weeks) and fluorouracil plus leucovorin regimens (fluorouracil 425 mg/m plus leucovorin 20 mg/m2 or fluorouracil 400 mg/m2 plus leucovorin 200 mg/m2, once daily for 5 days every 4 or 5 weeks) produced similar objective response rates of 14.3 to 19.3% and 15.2 to 18.1%, respectively. Median survival duration in patients treated with raltitrexed was similar to that in fluorouracil plus leucovorin recipients in 2 phase III studies (10.9 vs 12.3 months and 10.1 vs 10.2 months). In a third study median survival duration was 12.7 months for patients treated with fluorouracil plus leucovorin versus 9.7 months in recipients of raltitrexed, a significant difference. However, the duration of treatment with fluorouracil plus leucovorin was almost twice that of raltitrexed in this trial. Median time to disease progression ranged from 3.1 to 4.8 months with raltitrexed treatment and 3.6 to 5.3 months with fluorouracil plus leucovorin treatment.

Raltitrexed also provides similar palliative benefits to fluorouracil plus leucovorin in patients with advanced colorectal cancer. Gains in bodyweight of ≥5% were observed in 13 to 21.1% of raltitrexed recipients compared with 15.7 to 27.4% of those receiving fluorouracil plus leucovorin. Improvements in WHO performance status scores were seen in 36.4 to 39.1% of raltitrexed recipients and in 29.7 to 40.8% of patients receiving fluorouracil plus leucovorin.

Pharmacoeconomic Considerations

The mean direct monthly costs of raltitrexed treatment (£1117.85, 1994/1995 pounds sterling) were similar to or less than those of various fluorouracil regimens (£954.03 to 2028.52) in a retrospective audit of patient notes in a large English hospital. The greater acquisition costs of raltitrexed compared with fluorouracil plus leucovorin were at least partially offset by lower outpatient costs. The combined in- and outpatient costs of raltitrexed treatment were lower than those of any of the other regimens.

Raltitrexed was quicker and less costly to prepare than fluorouracil-based regimens and consequently was associated with significantly lower pharmacy charges.

Drug costs for management of raltitrexed-related toxicity were approximately half those for toxicity associated with an intermittent fluorouracil-based administration regimen.

Tolerability

The most common adverse events associated with raltitrexed (3 mg/m2 once every 3 weeks) in phase III trials were gastrointestinal and haematological in nature. Grade 3 or 4 diarrhoea occurred in 10 to 14% of patients and grade 3 or 4 nausea or vomiting in 9 to 13% of raltitrexed recipients. These events were seen in a similar proportion of patients receiving fluorouracil 425 mg/m2 plus leucovorin 20 mg/m2 or fluorouracil 400 mg/m2 plus leucovorin 200 mg/m once daily for 5 days every 4 or 5 weeks.

Markedly fewer raltitrexed recipients experienced grade 3 or 4 mucositis (2 to 3%) than patients treated with fluorouracil plus leucovorin (10 to 22%), although the incidence of severe asthenia was higher in those receiving raltitrexed (6 to 18%) than in those treated with fluorouracil plus leucovorin (2 to 10%).

The incidence of grade 3 or 4 leucopenia associated with raltitrexed treatment (6 to 18%) was approximately half that with fluorouracil plus leucovorin (13 to 41%).

Treatment-related deaths occurred in similar proportions of patients treated with either raltitrexed (3.8%) or fluorouracil plus leucovorin (2.6%).

In phase III trials, 62 to 71% of raltitrexed recipients were able to receive the planned dosage without the need for dosage modification or delay because of toxicity, in contrast to 32 to 53% of fluorouracil plus leucovorin recipients.

One phase III trial found significant benefits in favour of raltitrexed over fluorouracil plus leucovorin for a range of quality-of-life parameters including physical symptoms, psychological condition, general activity and mobility during the first treatment cycle. However, no clear differences between treatments in terms of quality of life were noted in the other 2 trials.

Dosage and Administration

In phase II and III clinical trials, patients with advanced colorectal cancer received raltitrexed 3 mg/m2 as a 15-minute intravenous infusion once every 3 weeks. Dosage was reduced in patients who developed severe haematological or gastrointestinal toxicity and was delayed for up to 21 days to allow resolution of toxicity.

Patients with mild to moderate renal impairment should have the dose of raltitrexed reduced by 50% and the frequency of administration reduced to every 4 weeks.

Various sections of the manuscript reviewed by: P. Beale, Department of Medical Oncology, CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, England; H. Bleiberg, Centre des Tumeurs de l’Université Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium; H. Ford, CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, England; A.J. Groves, Department of Pharmacy, Lenox Hill Hospital, New York, New York, USA; A.L. Jackman, CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, England; I.R. Judson, Department of Medical Oncology, CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, England; D.J. Kerr, CRC Institute for Cancer Studies, University of Birmingham, Birmingham, England; G.M. Mead, Wessex Medical Oncology Unit, Royal South Hants Hospital, Southampton, England; F.M. Muggia, Department of Medical Oncology, Kaplan Comprehensive Cancer Center, New York, New York, USA; M. Ogawa, Aichi Cancer Center, Chikusa-ku, Nagoya, Japan; Y.M. Rustum, Roswell Park Cancer Institute, Buffalo, New York, USA; E. Van Cutsem, Department of Internal Medicine, University Hospital Gasthuisberg, Leuven, Belgium; J.R. Zalcberg, Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia.