Pharmacogenetic testing has the potential to fundamentally alter risk-benefit tradeoffs associated with pharmacotherapy, introducing “personalized medicine” concepts into clinical practice. Cost-effectiveness analyses of pharmacogenetic tests can provide important insights into the relative economic value of this new management paradigm, but few of these cost-effectiveness studies have been published.13, 44
This is the first cost-effectiveness study of UGT1A1*28 testing to guide chemotherapy dosing of irinotecan. Testing itself would cost up to $3 million per year, given the test cost and eligible population. We found that incorporating UGT1A1*28 testing in the clinical management of metastatic colorectal cancer treated with irinotecan may result in lower overall medical costs and higher quality-adjusted life expectancy, but our findings were sensitive to several uncertainties in the model’s parameter estimates as indicated by the sensitivity analyses. In particular, the maintenance of clinical efficacy of irinotecan after dose reduction in UGT1A1*28 homozygotes was a key determinant of cost-effectiveness results. That is, if treatment efficacy is not fully maintained after the FDA-recommended dose reduction of irinotecan, testing will not be a cost-effective alternative. The small reduction in treatment-related risks (severe neutropenia and/or death) gained by testing is outweighed by the risk of shortened survival due to under-treatment. However, limited data in this area do suggest that homozygotes experience slower glucuronidation and a greater plasma concentration of SN-38,6
and that response rates are not different between homozygotes, heterozygotes, or wild types, even with differential dose reductions across groups.17
Our analysis indicates that the federal government should be willing to invest in further research to reduce the uncertainty associated with UGT1A1 genotype testing and irinotecan dose-reduction. Specifically, at a WTP threshold of $100,000/QALY and with a 5-year time horizon for the genetic testing technology, the federal government should consider investing at least $13.8 million specifically to evaluate the efficacy of a reduced irinotecan dose in UGTA1*28 homozygous colorectal cancer patients ages 65 and older. In comparison, the estimated expected cost to conduct an average Phase III clinical trial is $27.1 million (in 2000 US$),45
although some analysts consider this to be a 2-4-fold overestimate.46, 47
The cost to conduct a clinical trial in homozygotes may differ substantially from this amount, however, because irinotecan is not a novel therapeutic entity and already has been proven effective in metastatic colorectal cancer patients. Alternatively, an observational clinical study could be considered that might provide valuable information more quickly.
This analysis is subject to limitations. First, the probabilities of severe neutropenia and death from neutropenia in colorectal cancer patients were difficult to estimate, because data were drawn from randomized controlled trials using different regimens, patients were more closely monitored in clinical trials than in usual care (with dose reductions for patients with adverse events), and the number of events or deaths in any one trial was small or nil. Because we used estimates drawn from clinical trials, our results may under-estimate the value of genetic testing to avoid these events. On the other hand, dose reductions reported in some studies were greater than the dose reduction we modeled based on the FDA label. Results were consistent, however, when we varied the amount of dose reduction benefit from avoiding adverse events. Second, there were only two published clinical trials reporting results in a relatively small number of genotyped patients. So, while genetic test sensitivity and specificity are fairly well established, estimates of clinical sensitivity and specificity – or the probabilities that a positive test predicts an adverse event or death – have a wide range. Although we accounted for the fact that a patient with severe neutropenia could be hospitalized versus treated on an outpatient basis, this is likely to depend on local care patterns and patient ability to self-manage at home. Varying this parameter, however, did not affect the model results.
We also did not consider alternative dosing approaches. For instance, the results of a study by Toffoli and colleagues8
indicated that successfully administering full-dose irinotecan in UGT1A1*28 homozygotes can produce superior response rates compared to non-homozygotes (OR 0.19, 95%CI: 0.04–0.89), albeit with higher rates of hematologic and non-hematologic toxicities (OR 4.9, 95%CI: 1.36–17.9). This suggests that the magnitude of the recommended dose reduction in homozygotes should be carefully considered, as a potential effectiveness advantage (i.e., improved response rate and/or survival) may be significantly compromised. In addition, alternative dosing regimens of irinotecan may have different safety profiles, with the importance of UGT1A1*28 status enhanced or reduced depending on pharmacodynamic parameters associated with the dosing schedule. Finally, prophylactic use of agents such as pegfilgrastim or filgrastim could help reduce the incidence of neutropenia in homozygotes,48
thereby allowing a full dose of irinotecan to be used in the first cycle, but also contributing to the cost of this treatment strategy.
Our analysis focused on the use of irinotecan for the treatment of metastatic colorectal cancer. The broad therapeutic application of irinotecan (e.g. tumors of the upper gastrointestinal tract and central nervous system49–51
) should also be taken into account when considering both the clinical impact of dosing recommendations and the potential economic value of pharmacogenetic testing. The proportion of metastatic colorectal cancer patients who will eventually receive irinotecan is not known; however, if fewer than 29,214 cancer patients were expected to receive irinotecan in a year, the value of future research would decrease.
Cost-effectiveness analysis can help policy makers evaluate the clinical utility of new medical technologies such as pharmacogenetic tests, make decisions about reimbursement, and identify priorities and investment levels for further research. In the case of UGT1A1*28 testing, we found that routine testing may slightly improve clinical outcomes and quality of life, but is only cost saving if clinical efficacy (survival) is maintained following an irinotecan dose reduction in homozygotes. Further studies to evaluate the impact of irinotecan dose reduction on clinical efficacy would be worth an investment of up to $13.8 million dollars, based on the impact of such testing on costs, life expectancy, and quality of life for Medicare beneficiaries alone, and even more if all use of irinotecan were considered.