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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.
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.
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.
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.
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.
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.
- Jackman AL, Taylor GA, Gibson W, et al. ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in. vitro and in vivo: a new agent for clinical study. Cancer Res 1991 Oct 15; 51: 5579–86
- Jackman AL, Gibson W, Brown M, et al. The role of the reduced-folate carrier and metabolism to intracellular polyglutamates for the activity of ICI D 1694. Adv Exp Med Biol 1993; 339: 265–76 CrossRef
- Gibson W, Bisset GMF, Marsham PR, et al. The measurement of polyglutamate metabolites of the thymidylate synthase inhibitor, ICI D1694, in mouse and human cultured cells. Biochem Pharmacol 1993; 45(4): 863–9 CrossRef
- Jackman AL, Marsham PR, Moran RG, et al. Thymidylate synthase inhibitors: the in. vitro activity of a series of heterocyclic benzoyl ring modified 2-desamino-2-methyl-N10-substi-tuted-5,8-dideazafolates. Adv Enzyme Regul 1991; 31: 13–27 CrossRef
- Ward WHJ, Kimbell R, Jackman AL. Kinetic characteristics of ICI D1694: a quinazoline antifolate which inhibits thymidylate synthase. Biochem Pharmacol 1992 May 8; 43: 2029–31 CrossRef
- Jackman AL, Kelland LR, Kimbell R, et al. Mechanisms of acquired resistance to the quinazoline thymidylate synthase inhibitor ZD1694 (Tomudex) in one mouse and three human cell lines. Br J Cancer 1995 May; 71: 914–24 CrossRef
- Jackman AL, Farrugia DC, Gibson W, et al. ZD1694 (Tomudex): a new thymidylate synthase inhibitor with activity in colorectal cancer. Eur J Cancer A 1995 Jul–Aug; 31A: 1277–82 CrossRef
- Jackman AL, Boyle FT, Harrap KR. Tomudex (ZD1694): from concept to care, a programme in rational drug discovery. Invest New Drugs 1996; 14(3): 305–16 CrossRef
- Jackman AL, Kimbell R, Brunton L, et al. Tomudex (ZD1694): a specific inhibitor of thymidylate synthase designed to overcome resistance to the non-specific inhibitor, 5-fluorouracil [abstract]. Ann Oncol 1996; 7 Suppl. 1: 88
- Chang YM, Zielinski Z, Izzo J, et al. Pretreatment of colon carcinoma cells to D1694 (Tomudex) markedly enhances 5-fluorouracil cytotoxicity [abstract]. Proc Am Assoc Cancer Res 1994 Mar; 35: 330
- Harstrick A, Schleucher N, Gonzales A, et al. Interactions and cross resistance patterns between various schedules of 5-FU and the new, folate-based thymidilate synthase inhibitor Tomudex (D1694). Eur J Cancer 1995 Oct 30; 31A Suppl. 5: S30 CrossRef
- Aschele C, Sobrero A, Baldo C, et al. In vitro synergism between SN-38 and Tomudex: importance of scheduling and dose ratio [abstract]. Ann Oncol 1996; 7 Suppl. 5: 129
- Kimbell R, Jackman AL. in vitro studies with ZD1694 (Tomudex) and SN38 in human colon tumour cell lines: chemistry and biology of pteridines and folates 1997. Proceedings of the Eleventh International Symposium on Pteridines and Folates; 1997 Jun 15–20; Berchtesgaden
- Harstrick A, Schleucher N, Vanhoefer U, et al. Cytotoxic interactions of SN38, the active metabolite of irinotecan, and 5-FU or tomudex in 5-FU sensitive and 5-FU resistant colorectal carcinoma cell lines [abstract]. Ann Oncol 1996; 7 Suppl. 5: 5
- Stephens TC, Smith MN, Waterman SE, et al. Use of murine L5178Y lymphoma thymidine kinase mutants for in vitro and in vivo antitumour efficacy evaluation of novel thymidylate synthase inhibitors. Adv Exp Med Biol 1993; 338: 589–92 CrossRef
- Stephens TC, Calvete JA, Janes D, et al. Antitumour activity of a new thymidylate synthase inhibitor, D1694 [abstract]. Proc Am Assoc Cancer Res 1990 Mar; 31: 342
- Jackman AL, Jodrell DI, Gibson W, et al. ICI D1694, an inhibitor of thymidylate synthase for clinical study. Adv Exp Med Biol 1991; 309A: 19–23
- Stephens TC, Valcaccia BE, Sheader ML, et al. The thymidylate synthase inhibitor ICI D1694 is superior to CB3717, 5-fluorouracil (5-FU) and methotrexate (MIX) against a panel of human tumour xenografts [abstract]. Proc Am Assoc Cancer Res 1991 Mar; 32: 328
- Clarke SJ, Hanwell J, de Boer M, et al. Phase I trial of ZD1694, a new folate-based thymidylate synthase inhibitor, in patients with solid tumors. J Clin Oncol 1996 May; 14: 1495–503
- Judson IR, Aherne GW, Maughan T, et al. Pharmacokinetic studies with Tomudex (ZD1694) [abstract]. Ann Oncol 1996; 7 Suppl. 1: 88
- Judson IR. ‘Tomudex’ (raltitrexed) development: preclinical, phase I and II studies. Anticancer Drugs 1997; 8 Suppl. 2: S5–9 CrossRef
- Zalcberg JR, Cunningham D, Van Cutsem E, et al. ZD1694: a novel thymidylate synthase inhibitor with substantial activity in the treatment of patients with advanced colorectal cancer. J Clin Oncol 1996 Mar; 14: 716–21
- Cunningham D, Zalcberg JR, Rath U, et al. Final results of a randomised trial comparing Tomudex (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. Ann Oncol 1996 Nov; 7: 961–5 CrossRef
- Cocconi G. Results of a European multicentre trial of Tumodex versus 5-FU/high dose LV (Machover regimen). Tumori 1997 Jan–Feb; 83 Suppl.: S72
- Pazdur R, Vincent M. Raltitrexed (Tomudex) versus 5-fluorouracil and leucovorin (5-FU + LV) in patients with advanced colorectal cancer (ACC): results of a randomized, multicenter, North American trial [abstract no. 801]. Proc Am Soc Clin Oncol 1997 17–20 May; 16: 228a
- Hayward JL, Carbone PP, Heuson JC, et al. Assessment of response to therapy in advanced breast cancer. Eur J Cancer 1977; 13: 89–94 CrossRef
- Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer 1981 Jan 1; 47: 207–14 CrossRef
- Kerr DJ. Clinical efficacy of ’Tomudex’ (raltitrexed) in advanced colorectal cancer. Anticancer Drugs 1997; 8 Suppl. 2: S11–5 CrossRef
- Zalcberg J. Overview of the tolerability of ‘Tomudex’ (raltitrexed): collective clinical experience in advanced colorectal cancer. Anticancer Drugs 1997; 8 Suppl. 2: S17–22 CrossRef
- Zeneca, London, 1998. (Data on file)
- Sorensen JM, Jordan E, Grem JL, et al. Phase I trial of ZD1694 (Tomudex), a direct inhibitor of thymidylate synthase [abstract]. Ann Oncol 1994; 5 Suppl. 5: 132
- Ross P, Heron J, Cunningham D. Cost of treating advanced colorectal cancer: a retrospective comparison of treatment regimens. Eur J Cancer A 1996; 32A Suppl. 5: S13–17 CrossRef
- Summerhayes M, Wanklyn SJ, Shakespeare RA, et al. Reduced pharmacy resource utilization associated with raltitrexed treatment of advanced colorectal cancer. J Oncol Pharm Practice 1997; 3(1): 24–30 CrossRef
- Kerr DJ, O’Connor KM. The costs of managing advanced colorectal cancer: a broad perspective. Anticancer Drugs 1997; 8 Suppl. 2: S23–6 CrossRef
- Elliott R. An analysis of drug costs for the management of chemotherapy-related side effects in advanced colorectal cancer. J Oncol Pharm Practice 1996; 2(3): 186–90 CrossRef
- Cunningham D, Zalcberg JR, Rath U, et al. Tomudex (ZD1694): results of a randomised trial in advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopenia. Eur J Cancer 1995; 31A(12): 1945–54 CrossRef
- Wingo P, Tong T, Bolden S. Cancer statistics, 1995. CA Cancer J Clin 1995 Jan/Feb; 45(1): 8–30 CrossRef
- Estève J, Kricker A, Ferlay J, et al. Facts and figures of cancer in the European Community. Lyon: International Agency for Research on Cancer, 1993
- Boring CC, Squires TS, Tong T, et al. Cancer statistics, 1994. CA Cancer J Clin 1994 Jan/Feb; 44(1): 7–26 CrossRef
- Moertel CG. Chemotherapy for colorectal cancer. N Engl J Med 1994 Apr 21; 330(16): 1136–42 CrossRef
- Labianca R, Pessi MA, Zamparelli G. Treatment of colorectal cancer: current guidelines and future prospects for drug therapy. Drugs 1997 Apr; 53(4): 593–607 CrossRef
- van Triest B, van Groeningen CJ, Pinedo HM. Current chemotherapeutic possibilities in the treatment of colorectal cancer. Eur J Cancer A 1995 Jul-Aug; 31A: 1193–7 CrossRef
- Scheithauer W, Rosen H, Kornek GV, et al. Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ 1993; 306: 752–5 CrossRef
- Van Cutsem E. Future developments with ‘Tomudex’ (raltitrexed). Anticancer Drugs 1997; 8 Suppl. 2: S33–8 CrossRef
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