Summary of published health economic studies of cetuximab as third line treatment for patients with metastatic colorectal cancer
Systematic review
|Updated
We have summarised published Norwegian and international studies of the cost-effectiveness of cetuximab in combination with irinotecan as third line treatment for patients with metastatic colorectal cancer. The present alternative to such treatment is supportive care.
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We have summarised published Norwegian and international studies of the costeffectiveness of cetuximab in combination with irinotecan as third line treatment for patients with metastatic colorectal cancer. The present alternative to such treatment is supportive care. The estimated number of patients with metastatic colorectal cancer eligible for treatment with cetuximab+irinotecan as third line therapy is 70.
Four studies covering the cost-effectiveness of cetuximab + irinotecan were identified, two of which satisfied the inclusion criteria. A considerable problem for all four studies was the lack of effectiveness data based on a direct comparisons of cetuximab+ irinotecan vs. supportive care or absence of third line therapy. The two included studies were from Norway; Norum 2006, and the UK: Starling et al. 2007. Calculation of incremental effect was in these studies based on different forms of indirect comparisons.
Norum estimated the benefit associated with cetuximab+irinotecan relative to absence of third line treatment to be between 1.7 and 2 life months gained in terms of median survival. The cost per life year gained was estimated to be between 1.7 and 2.6 million Norwegian kroner. This is however, based on the difference in effect between cetuximab+irinotecan and cetuximab monotherapy. In Starling et al., treatment with cetuximab+irinotecan was assessed relative to active/best supportive care (which may involve active chemotherapy). The results indicated that treatment with cetuximab+irinotecan was associated with an increase in average survival of 5.3 months, and 0,33 QALYs gained. The cost per life year gained was estimated to 508 000 Norwegian kroner. The cost per QALY gained was somewhat higher, at 681 000 Norwegian kroner.
In the two studies which were not included, the authors stated that they did not wish
to construct a health economic model when there is a lack of direct evidence with
respect to comparing the effectiveness of cetuximab+irinotecan versus ASC/BSC or the absence of third line treatment.
Conclusion: The evidence base regarding the cost-effectiveness of cetuximab is, at
the time of writing, weak, particularly with regard to relevant efficacy data. Treat-
ment with cetuximab+irinotecan as third-line therapy would not be cost-effective in
light of suggested thresholds for costs for an extra QALY/year in good health. However, such a view would not account for the notion that societal preferences regarding treatment of this patient group might differ from preference for other interventions. The cost-effectiveness of cetuximab as first- or second line treatment has not been considered here as no health economic evaluations were found for these stages.
Summary
Background
Colorectal cancer is the second most commonly diagnosed cancer in Norway. About 18% of patients present with metastases at the time of diagnosis, while another 20% develop metastases during the course of the disease. Five year survival rates for patients with distant metastases were approx. 10% during the 1990’s according to the National Cancer Registry. For most patients with irresectable metastases, palliative chemotherapy is appropriate; to postpone progression of disease, prolong survival and to maintain a satisfactory quality of life. Today, 5-FU and calcium folinate combined with oxaliplatin or irinotecan is the first line treatment for most patients younger than 75 years of age. The standard Nordic treatment regimes with irinotecan and oxaliplatin are called FLIRI and FLOX, respectively. These regimes are used in Norway and are considered equally effective. These drugs are used as first and second line treatment, where the sequence is determined by patients’ response and tolerance of adverse effects.
Cetuximab (Erbitux®) is a monoclonal antibody targeted at EGFR (Epidermal
Growth Factor Receptor), a receptor found on the surface of several types of cancer cells. EGFR signal paths are involved in the regulation of a number of cellular processes, such as cell growth, angiogenesis, metastasis development and rescue of a damaged cell. In Norway the drug is registered for treatment of irinotecan-refractory patients. The recommendation of the Norwegian Gastrointestinal Cancer Group is that treatment with cetuximab in combination with irinotecan may be considered as third-line treatment for patients who have previously been treated with oxaliplatin and who have progressed on irinotecan (alone or as part of a combination). The estimated number of patients with metastatic colorectal cancer eligible for treatment with cetuximab+irinotecan as third line therapy is 70.
Monoclonal antibodies such as cetuximab are costly drugs. According to the Norwegian patient rights law, there should be a reasonable trade-off between treatment costs and health gains to justify funding of the former. The objective of this analysis is to assess the incremental costs and health effects associated with offering cetuximab as third line treatment to patients with metastatic colorectal cancer. The treatment effect is measured in life years gained as this is a relevant outcome and because there are few good, relevant studies on quality of life effects currently available.
Methods
We have assessed the cost-effectiveness of cetuximab by means of a literature review of Norwegian and international health economic studies of treatment with cetuximab+ irinotecan for patients with metastatic colorectal cancer.
A systematic search was conducted for Norwegian and international studies covering cetuximab+irinotecan and bevacizumab, covering relevant electronic databases as well as Nordic HTA websites. The quality of the identified studies was considered on the basis of the Norwegian Knowledge Centre for the Health Services’ checklist for health economic evaluations.
Results
Four studies were identified, of which two satisfied the inclusion criteria: A Norwegian study, (Norum) from 2006 and a British study (Starling et al.) from 2007. The quality of the two studies was judged to be low (Norum) and medium (Starling et al.), respectively. A considerable problem with regard to both studies is the lack of effectiveness data on survival and quality of life based on direct comparisons of cetuximab+irinotecan vs. supportive care or absence of third line treatment. The effectiveness data used in the studies was based on various forms of indirect comparisons. Both studies estimated costs from a health services perspective.
Norum compared treatment with cetuximab+irinotecan with absence of third line treatment and calculated a net benefit in the area of 1.7 to 2 life months gained in terms of median survival. Quality of life data were not reported. The cost per life year gained was estimated to be between 205 536 and 323 040 euro (2005-prices), which amounted to between 1.7 and 2.6 million Norwegian kroner in 2006. In Starling et al., treatment with cetuximab+irinotecan was assessed relative to active/ best supportive care (ASC/BSC, supportive care which may involve active chemotherapy). The outcome measure was expected average survival, but the study also incorporated quality of life data and calculated the number of quality-adjusted life years (QALYs) gained. The results indicated that treatment with cetuximab+ irinotecan was associated with an increase in average survival of 5.3 months, and 0,33 QALYs gained. The cost per life year gained was estimated to 42 975 pounds sterling which corresponds to 508 000ii Norwegian kroner (2006-prices). The cost per QALY gained was somewhat higher, at 57 608 pounds sterling or 681 000 Norwegian kroner (2006-prices).
Discussion
The two included studies have common features in that both present health economic models developed from the perspective of the third party payer. Moreover, both were mainly based on the same source of clinical effectiveness estimate, the Cunningham 2004 trial. This clinical trial is nevertheless not particularly suitable as a foundation for health economic evaluations. The reason for this is that the trial comparator arm comprised cetuximab monotherapy, rather than supportive care – or “absence of third line treatment” - which would have been the most relevant comparator in this context. This poses a challenge, which the two studies handle somewhat differently. Norum considers the effectiveness of cetuximab monotherapy to be marginal, and therefore employs the difference between this therapy and cetuximab+ irinotecan as his measure of incremental effectiveness. In practice, however, this entails calculating the effectiveness of irinotecan as third line therapy. Starling et al., on the other hand, incorporate data on active/best supportive care from another Cunningham study from 1998, using these as their model comparator. Furthermore, they estimate survival beyond the data reported in the Cunningham 2004 study with the aid of statistical methods. It follows that the benefit of average survival reported by Starling et al. appears to be larger than the increase in median survival reported by Norum.
In the two studies which were not included the authors stated that they did not wish
to construct a health economic model when there is a lack of direct evidence with
respect to comparing the effectiveness of cetuximab+irinotecan versus ASC/BSC or the absence of third line treatment.
One of them, Tappenden et al., instead presents a so-called threshold analysis which showed that the incremental effect required for cetuximab+irinotecan to be deemed cost-effective subject to a UK threshold of 30 000 pounds was at least 0.41 life years gained, or 4.9 months relative to treatment with ASC/BSC. Meanwhile, the effect of ASC/BSC with respect to survival must at most be 0.38 life years/4.6 months for the criterion to be met.
The other study, from Denmark, does not include any such analysis, but estimated
the treatment cost associated with cetuximab+irinotecan to 263 289 Danish kroner
(NOK 285 000). This may be perceived as a large sum, especially for therapy which may only extend life for a few months. There are nevertheless valid reasons to claim that society’s willingness to pay for such treatment may be higher than for other treatment.
Conclusion
The evidence base regarding the cost-effectiveness of cetuximab is, at the time of
writing, weak, particularly with regard to relevant efficacy data. Treatment with
cetuximab+irinotecan as third-line therapy would not be cost-effective in light of
suggested thresholds for costs for an extra QALY/year in good health. However,
such a view would not account for the notion that societal preferences regarding
treatment of this patient group might differ from preference for other interventions.
The cost-effectiveness of cetuximab as first- or second line treatment has not been
considered here as no health economic evaluations were found for these stages. Further research needs to be conducted with regard to, inter alia:
• Clinical trials relevant to health economic evaluations comparing cetuximab with
the alternative of best supportive care or no third line therapy.
• The effect derived from cetuximab on quality of life of metastatic colorectal cancer
patients.