• Gastrointestinal Disease Site Group. Germond C, Maroun J, Zwaal C, Wong S. Use of raltitrexed (Tomudex) in the management of metastatic colorectal cancer. Toronto (ON): Cancer Care Ontario (CCO); 2005 Feb 10. 13 p. (Practice guideline report; no. 2-17). [22 references]

Metastatic colorectal cancer

Assessment of Therapeutic Effectiveness
Management
Treatment

Gastroenterology
Oncology

Physicians

To make recommendations on the use of raltitrexed (Tomudex) in the management of metastatic colorectal cancer

Adult patients with metastatic colorectal cancer for whom chemotherapy is indicated

Raltitrexed (Tomudex)

• Survival
• Progression-free survival
• Response rate
• Toxicity
• Symptom improvement
• Quality of life

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

1998 Guideline

Three randomized controlled trials (RCTs) and one phase II study were reviewed.

2005 Update

Since the release of the guideline, two abstracts cited in the original guideline have been published in full, and one new randomized trial has been reported in abstract form. Three phase II studies, reported in abstract form only, have also been obtained.

Expert Consensus (Committee)

Not applicable

Meta-Analysis of Randomized Controlled Trials
Systematic Review with Evidence Tables

1998 Guideline

Data on survival time were not available to allow pooling using standard meta-analysis. Therefore, the median survival times of the patients in raltitrexed and 5 fluorouracil/leucovorin (5-FU/LV) treatment arms of the randomized controlled trials were pooled separately and weighted according to size of the treatment arms using the following formula:

weighted median survival = [m₁n₁+m₂n₂+m₃n₃]/N

where:

m=median survival within a treatment within a trial,

n=number of subjects within a treatment within a trial,

N=number of subjects within a treatment across trials.

Median survival times reported in the papers and abstracts were used. To estimate the overall effect on response rate of raltitrexed compared with 5-FU/LV, the results of the randomized trials were pooled using Metaanalyst^0.988 software provided by Dr. Joseph Lau, Tufts New England Medical Center, Boston, MA. Results were expressed as odds ratios (with 95% confidence intervals [CI]) such that estimates <1.0 favor 5-FU/LV and >1.0 favor raltitrexed. Data were analyzed using the random effects model.

2005 Update

Survival data from one randomized controlled trial were added to the pooled analysis of response rates. The pooled median survival rates were also recalculated using the updated data.

Expert Consensus

The Gastrointestinal Cancer Disease Site Group was most interested in addressing the observed inferior outcome with raltitrexed in one trial. Note was made of the fact that only one of the three studies showed a significant difference that was not in favor of raltitrexed. To address this, the results of the three randomized controlled trials (RCTs) were pooled. There was general agreement that raltitrexed appears to be as effective as 5-fluorouracil plus leucovorin (5-FU/LV) but is associated with lower rates of stomatitis and leukopenia.

Results of a Canadian cost-comparison study were reviewed. See the "Cost Analysis" field.

The Gastrointestinal Cancer Disease Site Group felt that raltitrexed is a safe and convenient alternative to 5-FU/LV in the treatment of symptomatic metastatic colorectal cancer. The use of raltitrexed should be considered where there are concerns about toxicity with standard 5-FU/LV, such as in older patients and females. Its use may also be preferred where the greater ease of administration is an advantage, such as for patients living a long distance from a treatment facility. Because of its convenient scheduling, raltitrexed may allow for more efficient use of institutional resources.

Not applicable

Results of a Canadian cost-comparison study were reviewed. This was a retrospective study of 60 patients from six institutions who participated in the North American trial. Patients were evaluated for pharmacy, nursing, physician and hospital costs. Overall health care costs were similar for patients treated with raltitrexed or 5-fluorouracil plus leucovorin (5-FU/LV). The higher drug acquisition costs of raltitrexed were offset by lower administration costs (pharmacy time and nursing administration time). In addition, there were lower hospitalization rates for patients treated with raltitrexed. Costs incurred directly by patients were significantly lower with raltitrexed.

External Peer Review
Internal Peer Review

The following describes the external review activities undertaken for the original guideline report.

Practitioner feedback was obtained through a mailed survey of 63 practitioners in Ontario. The survey consisted of items evaluating the methods, results and interpretive summary used to inform the draft recommendations and whether the draft recommendations should be approved as a practice guideline. Written comments were invited. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The results of the survey were reviewed by the Gastrointestinal Cancer Disease Site Group.

The final practice guideline was approved by the Gastrointestinal Cancer Disease Site Group and the Practice Guidelines Coordinating Committee.

• For patients with previously untreated metastatic colorectal cancer in whom chemotherapy is indicated, a combination of 5-fluorouracil (5-FU) plus leucovorin (LV) and irinotecan is now the standard treatment regimen.
• For patients with previously untreated metastatic colorectal cancer where monotherapy with fluoropyrimidines or other thymidylate synthase inhibitors (e.g. 5-FU/LV or capecitabine) appears appropriate, it is reasonable to offer raltitrexed as a therapeutic option. Suitable patients would include those for whom toxicity from 5-FU is a concern (such as patients who are over 60 years in age or women), or for whom the more convenient administration schedule of raltitrexed is important (one visit for raltitrexed every three weeks versus five daily visits with 5-FU every four weeks).
• At this time, there is insufficient evidence to make a recommendation for or against the use of raltitrexed in patients who progress on 5-FU/LV.

None provided

The recommendations are supported by randomized trials and meta-analyses.

Four randomized controlled trials (RCTs) of raltitrexed compared with 5 fluorouracil (5-FU) plus leucovorin (LV) were reviewed. Results of two trials have been published in full and two in abstract form. Reports of all four RCTs presented data on time to disease progression; three of these trials demonstrated that median time to disease progression was significantly shorter for raltitrexed compared with 5-FU/LV. The median survival times were not significantly different between raltitrexed and 5-FU/LV in three of the RCTs, but one trial showed that median survival time was significantly shorter with raltitrexed. The weighted median survival time from four RCTs with published survival data was 10.2 months for raltitrexed compared with 11.2 months for 5-FU/LV. A pooled analysis of response rates using data from 1965 patients in four RCTs revealed an odds ratio of 0.95 (95% confidence interval, 0.76 to 1.19; p=0.66) demonstrating no significant difference in response rates between raltitrexed and 5-FU/LV.

Data on toxicity from one of the randomized controlled trials (RCTs) indicate lower rates of leukopenia and stomatitis for raltitrexed compared with 5 fluorouracil (5-FU).

Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult the practice guideline is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or warranties of any kind whatsoever regarding their content or use or application and disclaims any responsibility for their application or use in any way.

An implementation strategy was not provided.

Living with Illness

Effectiveness

• Gastrointestinal Disease Site Group. Germond C, Maroun J, Zwaal C, Wong S. Use of raltitrexed (Tomudex) in the management of metastatic colorectal cancer. Toronto (ON): Cancer Care Ontario (CCO); 2005 Feb 10. 13 p. (Practice guideline report; no. 2-17). [22 references]

Not applicable: The guideline was not adapted from another source.

1998 May 22 (revised 2005 Feb)

Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]

The Program in Evidence-based Care (PEBC) is a project supported by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

Cancer Care Ontario, Ontario Ministry of Health and Long-Term Care

Provincial Gastrointestinal Cancer Disease Site Group

Not stated

This summary was completed by ECRI on August 19, 1999. The information was verified by the guideline developer as of September 17, 1999. This NGC summary was updated by ECRI on December 14, 2001, July 21, 2003, and September 8, 2005. The updated information was verified by the guideline developer on October 3, 2005.