Figure 3 presents the scatterplot of the results of the probabilistic sensitivity analysis for the palo-based two-drug strategy. Nearly 96% of the simulations fell within the first quadrant of the chart (ie, on the upper right quadrant), which represents the scenario where the palo-based two-drug therapy is more costly but also more effective than the onda-based standard therapy. However, only 39% of the simulations fell below the $100,000/QALY dashed threshold line, which represents the scenario where the palo-based two-drug strategy is more cost-effective than the onda-based standard therapy at the $100,000/QALY benchmark.
Scatterplot of the Incremental Cost–Effectiveness Ratios Comparing the Palo-Based Two-Drug Strategy with the Onda-Based Two-Drug Therapy. The dashed line indicates the $100,000/QALY threshold, whereas the ellipse represents the 95% confidence ellipse, which includes 95% of the observations
Discussion
Our estimates of emesis-related costs and outcomes following four cycles of AC-based chemotherapy in women with breast cancer indicate that at current antiemetic prices and utilities placed on emesis, the additional costs of palo and aprepitant are not warranted at the $100,000/QALY threshold. In probabilistic sensitivity analysis, the palo-based two-drug strategy and the two-drug regimen plus aprepitant following the onset of emesis were shown to be cost-effective at the $100,000/QALY threshold in only 39% and 26% of the simulations, respectively. The model was sensitive to changes in the values of antiemetic effectiveness for the two-drug regimens and the risk of emesis-related hospitalization.
In threshold analysis, the two-drug palo-based regimen was cost-effective at the $100,000/QALY benchmark when the cost of palo is decreased by 11%. Because the use of the $100,000/QALY threshold is uncommon in clinical practice, the cost-effectiveness of the palo-based two-drug strategy (estimated at $115,490/QALY in our study) compares favorably with other commonly used supportive care measures for women with breast cancer. Such measures include primary prophylaxis with granulocyte colony-stimulating factor in women undergoing chemotherapy with moderate to high myelosuppressive risk (ICER of $116,000/QALY, or $125,948/QALY in 2008 U.S. dollars) and the use of bisphosphonates for the prevention of skeletal complications in breast cancer patients with lytic bone metastases (ICER ranging from $108,200/QALY with chemotherapy as systemic therapy to $305,300 in conjunction with hormonal systemic therapy, or $166,381/QALY to $469,466/QALY in 2008 U.S. dollars, respectively).[23] and [24] Both interventions are considered recommended standards of supportive care for patients with breast cancer and are widely used in breast oncology practices.[25] and [26]
Decision-analytic models, such as the Markov model presented in our study, aim to reflect the reality of clinical practice in a simplified way. Therefore, modelers often need to make decisions regarding the study time frame and model parameters based on the best use of available data. In our study, we obtained estimates for the probability of chemotherapy-induced emesis from studies in which the standard duration of follow-up is 5 days. By so doing, we may have underestimated the cost-effectiveness for the palo-based and aprepitant-based regimens. Although the risk of CINV after 5 days of chemotherapy is usually negligible, anticipation of vomiting may affect a patient's quality of life throughout the cycle of chemotherapy.
In addition, our estimates of costs, which were mostly obtained from Medicare, may differ from those of other third-party payers. However, Medicare is among the largest payers for breast cancer care as 42% of the women diagnosed with cancer in the United States are older than 64 years, and many private organizations set their own reimbursement rates based on the Medicare schedule. Therefore, we believe that Medicare reimbursement data provide a suitable estimate for emesis-related medical costs for all breast cancer patients in the United States.[27] and [28]
The present results should solely be interpreted in light of the cost–effectiveness benchmark of $50,000−$100,000/QALY, which has been frequently used in the context of the U.S. health-care system.[22] and [29] Such a benchmark, however, is a historic, precedent-based threshold set by the cost of caring for patients on dialysis, which was estimated at $50,000/QALY in 1982 ($74,000−$95,000 in 1997 U.S. dollars).[30] and [31] Given the arbitrariness of such a threshold, it has been suggested that the current willingness to pay for medical interventions in the United States probably exceeds $100,000/QALY, with values as high as $300,000/QALY being cited in some oncology publications.[22], [29], [31], [32], [33] and [34] In support of that argument is the public and policy makers' strong negative reaction to the National Institutes of Health Consensus Panel not recommending mammography screening for women aged 40−49 years, a procedure reported to provide an ICER of $105,000 per life-year gained.[35] and [36] As a result, if willingness to pay goes beyond $100,000/QALY, the alternative of adding aprepitant to palo plus dex may also be deemed attractive as the slope of its acceptability curve becomes substantially steep when the willingness to pay for a QALY exceeds $125,000 (Figure 2), suggesting that its marginal gain may exceed its marginal costs at higher thresholds.
In addition, it is worth noting that the present analysis has been conducted from the perspective of a third-party payer within the context of the U.S. health-care system. The large difference in the acquisition cost of palo-based and onda-based therapy observed in the United States is mostly driven by the differential stage of product life cycles for palo and onda. Although at the time of this study palo was still under patent protection, generic onda had entered the U.S. market prior to our study. The large price discrepancy between brand and generic drugs explains the difference in drug costs in this U.S.-based analysis. As such, our results may not reflect the situation in countries with a widely different cost structure, in which the acquisition cost of palo may be substantially lower. When that is the case, the cost–effectiveness profile of the palo-based prophylactic therapy may be deemed substantially more favorable than the profile presented here. Similarly, we anticipate finding a more attractive cost–effectiveness profile for the palo-based therapies as palo reaches the end of its product life cycle in the U.S. market.37 Also of note is that the cost–effectiveness of the palo-based therapy may greatly differ when different perspectives (other than the third-party payer's perspective) are adopted.
Our study, however, has several limitations. First, the utility scores used in our model were derived with a VAS instrument, which does not incorporate patients' preferences under uncertainty. Nevertheless, the VAS approach has been shown to provide utility scores for nausea and vomiting with more variability than scores derived using other methods such as the Standard Gamble (personal communication, Grunberg SM et al, CALGB study 309801). Notwithstanding that, it remains unclear which method gives utility scores for transient health states, such as CINV, with the greatest validity.
Also of note is that due to a lack of information on emesis-related utilities among breast cancer patients in the literature, we used utilities elicited from patients with ovarian cancer. To the best of our knowledge, the utilities in Sun et al20 were the only ones available in the literature that were elicited from a homogeneous population of cancer patients (ie, solely patients with ovarian cancer) and were based on a wide range of health states combining the presence and absence of emesis during either the acute or the delayed period. In addition, the participants in the Sun et al study were treated with carboplatin, which, like the regimen used in our model, is classified as moderately emetogenic in established antiemetic guidelines.[8], [9] and [38] It is also important to emphasize that the population in that study, like our study's population, was composed exclusively of women, who are known to be at increased risk for developing CINV.39
Second, in the absence of clinical trial data, we assumed conservatively that dex and aprepitant add the same relative benefit to both onda and palo. This assumption results in an imperfect estimate of cost–effectiveness. As such, we may have overestimated or underestimated the cost–effectiveness of palo as dex and aprepitant may potentially add less value to the intrinsically more active 5-HT3 antagonist or uniquely complementary mechanisms of action could contribute to even greater activity with the palo-based therapy. However, our study's estimate of the relative effectiveness of the palo-based two-drug prophylactic therapy versus the onda-based two-drug therapy for preventing delayed emesis is consistent with that reported in a recently published clinical trial comparing palo and granisetron when both drugs are combined with dex following chemotherapy with either AC or cisplatin (1.18 vs 1.17, respectively).6
Third, our study did not include the outcomes associated with the adverse effects of antiemetics, and by so doing, we may have underestimated the costs associated with antiemetic prophylaxis. However, the incidence and duration of treatment-related adverse events occurring in the two RCTs comparing palo with either onda or dolasetron were mild and similar across treatment cohorts.[4] and [5]
Fourth, we assumed that changes in emesis control in subsequent cycles of AC for the palo-based regimens were the same as for the onda-based therapy. By so doing, we may have underestimated the cost–effectiveness of palo as the superiority of the more active 5-HT3 antagonist could be maintained in the subsequent cycles of chemotherapy (or even increased, as seen in the aprepitant-based arm of Herrstedt et al's14 study). As a result, if future prospective trials of palo-based antiemetic prophylaxis confirm its superiority in maintaining antiemetic efficacy over multiple cycles of AC, the cost–effectiveness profiles for the palo-based strategies may be more favorable than the profiles presented herein.
Last, the incremental gains in QALY observed in cost–utility analysis of interventions associated with transitory and non-life-threatening health states, such as the antiemetic regimens analyzed in our study, tend to render small denominators to be used in the incremental cost–effectiveness ratios. The issue of small denominators has led some researchers to question whether the current methodology of cost–effectiveness analysis is appropriate to determine the cost–effectiveness of treatments for terminal or supportive care.32 However, despite this shortcoming, these types of analysis benefit from having a wider scope as they allow comparisons over different types of health interventions across various diseases. In addition, by incorporating patients' utility levels over different health states (instead of merely looking into cost per additional patient controlled), cost–utility analysis makes explicit the impact of the target population's preferences for the different outcomes. Of importance is that both the Panel on Cost–Effectiveness in Health and Medicine and the Institute of Medicine (IOM) Committee on Regulatory Cost–Effectiveness Analysis recommend the use of QALY as the preferred outcome measure for economic evaluation of health-care interventions.
Conclusion
Although our base-case analysis suggests that, from a third-party payer perspective within the context of the U.S. health-care system, the cost–utility of the palo-based two-drug prophylactic therapy for breast cancer patients receiving four cycles of AC-based chemotherapy exceeds the $50,000–$100,000/QALY threshold, it is comparable to other commonly used supportive care interventions for women with breast cancer. In sensitivity analyses, such a strategy was associated with a 39% chance of being cost-effective at the $100,000/QALY threshold, and the model was sensitive to changes in the values of antiemetic effectiveness and of the probability of emesis-related hospitalization. In threshold analysis, the combination of palo and dex was shown to become cost-effective (at the $100,000/QALY benchmark) when the cost of palo is decreased by 11%. As a result, future research incorporating the price structure of all antiemetics following the recent expiration of onda's patent is needed.