A rapid and systematic review of the evidence for the clinical effectiveness and cost-effectiveness of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer

Background

Description of proposed service:

The service evaluated in this review is the use of irinotecan, oxaliplatin and raltitrexed, as both monotherapy and combination therapy, in the first- and second-line treatment of patients with advanced colorectal cancer.

Epidemiology:

Colorectal (large bowel) cancer is the second most common cancer in the UK after lung cancer. In 1992, a total of 29,664 new cases were registered in England and Wales, an incidence of 56.6 per 100,000 population. Colorectal cancer is also the second most common cause of cancer death in the UK, causing almost 15,000 deaths in England and Wales in 1998. It affects men and women almost equally. Incidence rises sharply with age but is fairly evenly distributed across the social classes, and within the UK there is little age-specific geographic variation.

Advanced colorectal cancer has been defined as colorectal cancer that, at presentation or recurrence, is either metastatic or so locally advanced that surgical resection is unlikely to be carried out with curative intent. Around 29% of patients who present with colorectal cancer have distant metastases at the time of presentation. About 80% of patients diagnosed with colorectal cancer undergo surgery. Many have potentially good survival outcomes following surgery (with adjuvant chemotherapy in some cases), but over 50% of patients who have undergone surgery with apparently complete excision will eventually develop advanced disease and distant metastasis (typically presenting within 2 years of initial diagnosis). Median survival from diagnosis of metastatic disease is 6–9 months, and during this time patients may develop a wide range of physical and psychological symptoms, which detract from their quality of life and often require hospital admission.

Colorectal cancer is rare below 40 years of age, and 41% of patients are over the age of 75 years. Although 52% of deaths from colorectal cancer occur in the over-75 age group, colorectal cancer is nonetheless a significant cause of premature death as well as of morbidity. The aim of treatment in patients with advanced disease is to improve both the duration and quality of the patient’s remaining life.

Objectives

The objectives of this review are:

1. to evaluate the relative clinical effectiveness of irinotecan, oxaliplatin and raltitrexed in terms of disease progression rates

2. to estimate their relative effect on overall survival and quality-of-life-adjusted survival

3. to evaluate their side-effect profiles

4. to estimate the incremental cost-effectiveness of the three drugs in comparison with conventional therapy

5. to estimate the overall cost associated with the use of these drugs in England and Wales.

Methods

A systematic review of the literature, involving a range of databases, was conducted. Full details are described in the main report.

Results

Number and quality of studies, and direction of evidence

Irinotecan

Six randomised controlled trials relating to the use of irinotecan as first-line treatment of advanced colorectal cancer were judged to have met the inclusion criteria. Only preliminary data were available for four of these, of which three had been published only in abstract form. The two completed studies found that the combination of irinotecan with fluorouracil and folinic acid (FU/FA) was associated with significantly longer median overall and progression-free survival than FU/FA alone. Irinotecan alone appeared comparable with FU/FA alone. However, irinotecan plus FU/FA was associated with a higher level of toxicity than FU/FA alone. Seven studies relating to the use of irinotecan as second-line treatment of advanced colorectal cancer were judged to have met the inclusion criteria. Full reports were available for only two of these; for the remainder, only preliminary data were available in abstract form. One of the two completed studies compared irinotecan with best supportive care (BSC), and the other compared it with FU/FA. Irinotecan was found to significantly increase median overall survival compared with FU/FA, although it did not increase median progression-free survival significantly. Irinotecan was associated with increased overall survival compared with BSC, but it is not clear to what extent this should be attributed specifically to irinotecan and to what extent to other factors. Irinotecan significantly increased pain-free survival and time to deterioration of performance status in comparison with BSC, but not in comparison with FU/FA. There is also some preliminary evidence that combination second-line irinotecan/FU/FA therapy may increase progression-free survival compared with FU/FA alone. As second-line treatment, irinotecan was again associated with a higher level of toxicity than FU/FA.

Oxaliplatin

Seven studies relating to the use of oxaliplatin as first-line treatment of advanced colorectal cancer were judged to have met the inclusion criteria. Of these, two studies compared only chronomodulated versus fixed-rate oxaliplatin plus FU/FA. Full reports were available for only two of the remaining studies; for the remainder, only preliminary data were available in abstract form. Oxaliplatin plus FU/FA was found to increase median progression-free survival compared with FU/FA alone. In both studies for which final results were available, so many patients received chemotherapy subsequent to the study medication that the impact of oxaliplatin on overall survival has been obscured. Oxaliplatin appeared to be associated with increased toxicity compared with FU/FA regimens.

Three studies relating to the use of oxaliplatin as second-line, or first- and second-line treatment of advanced colorectal cancer were judged to have met the inclusion criteria. Only preliminary results have been published, in abstract form, in relation to these studies. These preliminary results suggest that median progression-free survival may be longer in patients receiving oxaliplatin plus 5FU than in those receiving either 5FU or irinotecan monotherapy.

Raltitrexed

Four studies relating to the use of raltitrexed as first-line treatment of advanced colorectal cancer were judged to have met the inclusion criteria. Full reports were available for only two of these studies. When the results were statistically significant, raltitrexed was associated with shorter progression-free and overall survival than FU/FA. Although raltitrexed was associated with less toxicity than the Mayo bolus FU/FA regimen, it was associated with more deaths that were considered to be possibly treatment related.

Summary of benefits

There is good evidence to suggest that the use of a combination of irinotecan and FU/FA in the first-line treatment of advanced colorectal cancer can extend both median progression-free and overall survival by 2–3 months compared with either FU/FA alone or irinotecan alone, although at the cost of increased toxicity compared with FU/FA alone. As second-line treatment, irinotecan monotherapy appears to extend median progression-free survival by approximately 1 month and overall survival by approximately 2 months compared with FU/FA alone, again at the cost of increased toxicity. There is also some preliminary evidence to suggest that combination irinotecan/ FU/FA therapy after FU/FA failure may extend median progression-free survival by approximately 2 months and overall survival by almost 3 months compared with FU/FA alone.

There is also good evidence to suggest that, when used as first-line therapy, the combination of oxaliplatin with an infusional FU/FA regimen extends median progression-free survival by 2–3 months compared with FU/FA alone, although again with increased toxicity. This combination may also prolong overall survival, although this is not clear because of the extensive use of secondline oxaliplatin in patients randomised to FU/FA alone, which would dilute the evidence of the efficacy of oxaliplatin in the oxaliplatin arm. In addition, the improved response rate achieved by the addition of oxaliplatin to FU/FA may enable larger numbers of patients to undergo potentially curative surgical resection of liver metastases.

Preliminary data suggest that, as second-line treatment, oxaliplatin plus 5FU may extend median progression-free survival compared with either 5FU or irinotecan monotherapy.

In comparison with FU/FA, raltitrexed used as first-line therapy appears to reduce both progression-free and overall survival, and is associated with a higher mortality rate. Thus, there seems no advantage in using raltitrexed to treat advanced colorectal cancer in patients who raltitrexed is compared with 5FU, a costeffectiveness analysis is not appropriate.

Conclusions

When used as first-line therapy, the combination of either irinotecan or oxaliplatin with an infusional FU/FA regimen appears to extend median progression-free survival by 2–3 months compared with FU/FA alone, although with increased toxicity; irinotecan has also been shown to extend overall survival. However, raltitrexed appears to reduce both progression-free and overall survival compared with FU/FA. When used as second-line treatment, irinotecan monotherapy appears to extend median progression-free survival by approximately 1 month and overall survival by approximately 2 months compared with FU/FA alone, again at the cost of increased toxicity. Preliminary data suggest that, as second-line treatment, oxaliplatin plus 5FU may extend median progression-free survival compared with either 5FU or irinotecan monotherapy.

Recommendations for research

Evidence is needed of the relative merits of irinotecan and oxaliplatin for patients with advanced colorectal cancer, the best time to introduce these drugs (as first- or second-line therapy), and whether both should routinely be offered to a single patient and, if so, in what order. Randomised controlled trials are also required to explore:

• the relative efficacy of second-line 5FU plus mitomycin C versus irinotecan or oxaliplatin

• whether raltitrexed is beneficial compared with either BSC alone or other agents in patients with specific metabolic intolerance of 5FU

• the relative efficacy of different sequences of therapies

• the optimum duration of therapy (i.e. whether it should be continued to disease progression, death or unacceptable toxicity, or only until response, with or without consolidation)

• the relative efficacy of oxaliplatin and 5FU in patients with a family history of colorectal cancer caused by the HNPCC gene mutation.

Given the palliative objectives of therapy, research is required to address the issue of measuring quality of life in patients with terminal cancer.