+ Site Statistics
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Mature results from three large controlled studies with raltitrexed ('Tomudex')

Mature results from three large controlled studies with raltitrexed ('Tomudex')

British Journal of Cancer 77 Suppl 2: 15-21

Since the publication of the results of phase I dose-finding studies, an extensive phase II and III clinical study programme has been undertaken to study the clinical efficacy and tolerability of the quinazoline folate analogue raltitrexed ('Tomudex'), a novel direct and specific inhibitor of thymidylate synthase. Two international phase III trials, studies 3 and 12, have compared raltitrexed 3 mg m(-2) with 5-fluorouracil (5-FU) plus low-dose leucovorin (LV) (Mayo regimen) or high-dose LV (Machover regimen) respectively. A North American study (study 10) was originally set up to compare two raltitrexed dosage arms (3.0 and 4.0 mg m[-2]) with 5-FU and low-dose LV, but the 4.0 mg m(-2) arm was discontinued prematurely because of excessive toxicity. Minimum follow-up times for studies 3, 10 and 12 were 15.5, 12 and 9 months, respectively (for data other than survival), with corresponding survival follow-up times of 26, 12 and 17 months. Objective response rates were similar for raltitrexed and 5-FU + LV, and palliative improvements were seen to a similar extent with both treatments in all phase III studies. Survival was statistically similar for raltitrexed and 5-FU + LV in both studies 3 and 12. Raltitrexed was, however, associated with inferior survival to 5-FU + low-dose LV in study 10, but there appears to be evidence that this was linked to an unconscious effect on investigator behaviour of early toxicity problems in this trial, in that patients appeared to be withdrawn from raltitrexed treatment without progression or protocolled toxicity. Moreover, it appeared that 5-FU + LV patients were continued on treatment after disease progression. 5-FU-based therapy was associated with a higher incidence of mucositis than raltitrexed in all studies, with the attainment of statistical significance in studies 3 and 12. Elevations in hepatic transaminase levels were seen with raltitrexed, but these are thought to be of no clinical significance. Overall, much greater levels of toxicity were seen with 5-FU + LV than with raltitrexed in early treatment cycles. In addition, retrospective UK audit data have shown the monthly cost of raltitrexed therapy to be similar to that of Mayo and continuous infusion 5-FU regimens, and appreciably lower than that of the de Gramont regimen of 5-FU (bolus + 22-h infusion) + high-dose LV. Thus, raltitrexed is an effective alternative to 5-FU-based therapy in patients with advanced colorectal cancer, with an acceptable and, unlike 5-FU, predictable toxicity profile. In particular, patients receiving raltitrexed may benefit from the minimization or avoidance of mucositis, and both patients and healthcare providers may find the convenient administration schedule of the drug advantageous.

Accession: 046631910

Download citation: RISBibTeXText

PMID: 9579851

DOI: 10.1038/bjc.1998.421

Related references

Raltitrexed (Tomudex) concomitant with radiotherapy as adjuvant treatment for patients with rectal cancer: preliminary results of phase I studies. European Journal of Cancer 35 Suppl 1: S19-S22, 2000

Final results of a randomised trial comparing 'Tomudex' (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. "Tomudex" Colorectal Cancer Study Group. Annals of Oncology 7(9): 961-965, 1996

'Tomudex' (raltitrexed) development: preclinical, phase I and II studies. Anti-Cancer Drugs 8 Suppl 2: S5-S9, 1997

Phase II study of raltitrexed (Tomudex) in chemotherapy-pretreated patients with advanced colorectal cancer. Tomudex Cooperative Study Group. Anti-Cancer Drugs 10(8): 741-748, 1999

Raltitrexed (Tomudex) in combination with platinum-based agents and/or anthracyclines: preliminary results of phase I clinical trials. European Journal of Cancer 35 Suppl 1: S14-S18, 2000

Raltitrexed (Tomudex) in combination with 5-fluorouracil for the treatment of patients with advanced colorectal cancer: preliminary results from phase I clinical trials. European Journal of Cancer 35 Suppl 1: S9-13, 2000

Leucovorin rescue from raltitrexed (tomudex)-induced antiproliferative effects: in vitro cell line and in vivo mouse studies. Clinical Cancer Research 6(9): 3646-3656, 2000

Raltitrexed (Tomudex) versus standard leucovorin-modulated bolus 5-fluorouracil: Results from the randomised phase III Pan-European Trial in Adjuvant Colon Cancer 01 (PETACC-1). European Journal of Cancer 44(15): 2204-2211, 2008

Raltitrexed (Tomudex). Expert Opinion on Investigational Drugs 7(5): 823-834, 2005

Future developments with 'Tomudex' (raltitrexed). Anti-Cancer Drugs 8 Suppl 2: S33-S38, 1997

Efficacy and tolerability of a new inhibitor of thymidylate synthase: 'Tomudex' (raltitrexed). Tumori 83(1 Suppl): S70-S71, 1997

A phase II study of raltitrexed ('Tomudex') in patients with hepatocellular carcinoma. Annals of Oncology 8(5): 500-502, 1997

The use of raltitrexed (tomudex) in a patient with 5-fluorouracil induced myocardial ischaemia. Clinical Oncology ) 11(1): 66-66, 1999

Raltitrexed (Tomudex) in combination treatment for colorectal cancer: new perspectives. European Journal of Cancer 35 Suppl 1: S1-S2, 2000

Clinical efficacy of 'Tomudex' (raltitrexed) in advanced colorectal cancer. Anti-Cancer Drugs 8 Suppl 2: S11-S15, 1997