تجزیه و تحلیل اقتصادی پگفیلگراستیم پروفیلاکتیک در بزرگسالان مبتلا به سرطان تحت شیمی درمانی

Objectives Neutropenia and its complications, including febrile neutropenia (FN), are a common side effect of cancer chemotherapy. Results of clinical trials showed that prophylactic use of granulocyte colony-stimulating factors (G-CSF) is effective in preventing FN. In this study, the cost effectiveness (measured as cost per quality-adjusted time [days]) of three treatment alternatives were evaluated: no G-CSF, filgrastim administered daily for 7–12 days after chemotherapy, and a pegylated form of G-CSF pegfilgrastim, administered once per cycle. Methods A cost-utility model based on standard clinical practice of treating FN with immediate hospitalization or with ambulatory treatment, from a societal perspective was developed. Direct medical cost estimates for hospitalization were derived from claims data reported by 115 US academic medical centers. Indirect medical costs, productivity costs, probabilities, and utilities are based on published literature. Results were subjected to sensitivity analyses and95% confidence intervals are based on a Monte Carlo simulation. Results Mean estimated costs/day of hospitalization were $1984 (SD $1040, N = 24,687) for surviving patients and $3139 (SD $2014, N = 1437) for dying patients. Under baseline conditions, pegfilgrastim dominated both filgrastim and no G-CSF, with expected costs and effectiveness of $4203 and 12.361 quality adjusted life-days (QALDs) for no G-CSF, $3058 and 12.967 QALDs for pegfilgrastim, and $5264 and 12.698 QALDs for filgrastim. Conclusions This cost-utility analysis provides strong evidence that pegfilgrastim is not only cost-effective but also cost-saving in most common clinical and economic settings. There appear to be both clinical and economic benefits from prophylactic administration of pegfilgrastim.

Neutropenia is a common chemotherapy-related complication. Neutropenia is defined as a below normal count of neutrophils (white blood cells), which are particularly important in fighting and preventing infection. Febrile neutropenia (FN), defined as the presence of both neutropenia and fever, routinely prompts immediate hospitalization for evaluation and administration of empirical broad-spectrum antibiotics [1] and may subsequently result in chemotherapy dose delays or reductions [2]. It is estimated that in the United States, more than 60,000 neutropenia-related hospitalizations occur each year [3]. The costs associated with those hospitalizations add significantly to the direct medical costs of cancer treatment and pose a great financial burden in the overall care of cancer patients [4]. Considerable attention has been given in recent years to identifying FN patients at low risk of complications who may be candidates for outpatient treatment with antibiotics [5]. Although replacing hospitalization and intravenous (IV) antibiotic treatment with outpatient oral antibiotics holds promise for savings, a formal cost analysis of outpatient treatment demonstrated only limited economic effect on the overall cost of cancer treatment as low-risk patients account for a small proportion of the overall costs of cancer patient care for FN [6]. Randomized controlled trials (RCTs) have demonstrated that prophylactic granulocyte colonystimulating factors (G-CSF; filgrastim) initiated after myelosuppressive chemotherapy and administered daily until neutrophil recovery is effective in reducing the incidence of FN by as much as 50% [7,8]. Patients treated with a G-CSF have shorter lengths of hospitalization (LOS) and shorter time to neutrophil recovery than control subjects [9]. Recently updated guidelines of the American Society of Clinical Oncology (ASCO) and the European Organization for Research and Address correspondence to: Gary H. Lyman, Duke University Medical Center and the Duke Comprehensive Cancer Center, Box 3645, Durham, NC 27705, USA. E-mail: Gary.Lyman@ duke.edu 10.1111/j.1524-4733.2007.00242.xTreatment of Cancer (EORTC) recommend primary (first cycle) prophylactic G-CSF administration for chemotherapy regimens associated with an FN incidence rate of 20% or greater, or when special circumstances exist, such as history of recurrent FN or more advanced cancer [10–12]. A new, long-acting pegylated form of G-CSF, pegfilgrastim (Neulasta; Amgen Inc., Thousand Oaks, CA) administered once per chemotherapy cycle, has been shown in recent RCTs to be at least as effective and safe as filgrastim [13,14], demonstrating a relative risk reduction (RRR) for FN greater than 90% [15]. Because of its convenient administration to both the patient and medical staff and potentially increased effectiveness, pegfilgrastim often displaces filgrastim in the United States whenever it is being reimbursed by payers [16]. Many patients receiving conventional systemic chemotherapy are not receiving primary prophylaxis with G-CSF [2,17], suggesting that many physicians still consider “watchful waiting” a valid treatment option during the first cycle of chemotherapy. Although the economic impact of filgrastim has been well studied, indicating that primary prophylaxis in patients receiving chemotherapy can be costeffective compared with “no G-CSF” (attributed mainly to a decreased risk of FN) [18,19], and despite considerable clinical interest and wide-scale use of pegfilgrastim, a thorough economic evaluation of pegfilgrastim has not been previously reported. The objective of this analysis is to evaluate the economic impact of pegfilgrastim compared with filgrastim and no G-CSF when administered prophylactically during the first cycle of chemotherapy.

In the study reported here, a decision analytic model was used to conduct a CU analysis of primary prophylaxis pegfilgrastim compared with primary prophylaxis filgrastim and to no prophylactic G-CSF in cancer patients receiving systemic chemotherapy. Two common clinical practices for treating FN were considered: immediate hospitalization or ambulatory treatment followed by hospitalization, if needed. The results of the model suggest that despite the added cost of pegfilgrastim, the overall cost of care is reduced when pegfilgrastim is used prophylactically with chemotherapy regimens associated with approximately a 16% or greater risk of FN. Monte Carlo simulation suggests that prophylactic pegfilgrastim is associated with an actual cost savings in approximately threequaters of patients receiving prophylactic pegfilgrastim compared with patients without prophylactic G-CSF, and with increases in QALDs whenever G-CSFs are used. These cost savings and increased effectiveness are primarily due to the reduction in hospitalization for FN along with a reduction in severity of FN, allowing for shorter hospitalization. The results reported here, in addition to the compelling evidence for clinical benefit from several RCTs, are consistent with current recommendations of ASCO guidelines to use prophylactic pegfilgrastim when the risk of FN is 20% or greater. In the model presented here, the two comparison groups shown in Figure 2 fall within two quadrants of the cost-effectiveness plane; no G-CSF versus pegfilgrastim falls within the upper left and lower left quadrants, indicating that about 80% of the joint density is associated with cost savings for pegfilgrastim with all of the contrasts yielding gains in QALDs for pegfilgrastim. Filgrastim versus pegfilgrastim falls only within the upper left quadrant, indicating that pegfilgrastim is always less expensive and more effective than filgrastim. These results are relatively unique because in the current cost-effectiveness literature, only a small fraction of reported interventions are actually cost-saving [37]. Moreover, even in the 20% of iterations where pegfilgrastim was more expensive, it may still be cost-effective. As with other interventions, if they indeed provide improved health, it may be reasonable to have net increases in cost associated with them. The analysis presented here is focused on the first cycle of chemotherapy for two reasons: first, it is the first cycle when most patients receive full-dose chemotherapy generally without growth factor prophylaxis. As a result, the first cycle of chemotherapy has been consistently associated with a greater risk of FN than subsequent cycles. Parameter estimates change little over multiple cycles, unless there is a change in delivered dose intensity or the addition of G-CSF. Therefore, in settings where maintaining chemotherapy dose intensity is thought to be important for disease control, subsequent cycles of chemotherapy administered at full-dose intensity will be accompanied by the same or greater risk of FN unless growth factors are administered prophylactically. Second, the majority of patients experiencing neutropenia or its complications in the first cycle also experience dose reductions, treatment delays, or the addition of G-CSF on subsequent cycles and, as a result, FN episodes in successive cycles may be related. Recent studies have demonstrated that prophylactic antibiotics may also reduce the risk of FN among patients receiving chemotherapy, especially among those with hematologic malignancies [38,39]. Nevertheless, prophylactic antibiotics do not address the underlying neutropenia and are not currently recommended by any medical professional society because of evidence that such treatment may increase the risk of developing antibiotic resistance [1,10]. In addition, a recent randomized phase III trial investigating the role of adding primary prophylaxis G-CSF to antibiotic prophylaxis in small-cell lung cancer demonstrated that the incidence of FN was further reduced during the first cycle with G-CSF (24% vs. 10%, P = 0.01), and as noted previously, the risk of FN was the highest during the first cycle and decreased substantially in subsequent cycles [32]. These findings emphasize the importance of the first cycle of chemotherapy and the role of preventing FN during this cycle as discussed above. The model presented here has several limitations. The baseline model combines estimates of FN, RRR of filgrastim, andRRRof pegfilgrastim from clinical trials. Those studies differ in their chemotherapy regimen, creating different baseline risk levels of FN. Because the association between baseline risk of FN and clinical effectiveness of G-CSF is not fully determined, the baseline results may vary. Using a RRR of filgrastim, which is a weighted summary across different chemotherapy regimens as calculated in a meta-analysis, should reduce the potential variability. The estimates of RRR for pegfilgrastim are also based on the metaanalysis but include only one published RCT [15,21]. This multicenter, multinational study, however, represents the largest RCT of a myeloid growth factor reported to date. Moreover, as the sensitivity analyses show, even when varying the values mentioned above across their plausible clinical values, or when equating their clinical effectiveness (i.e., RRR), pegfilgrastim remains dominant under most values. Although it is estimated that more than half of cancer patients in the United States are older than65 years, the modeled population is defined as patients between 18 and 65 years of age, which limits the generalizability of the model. The fact that the study population was limited to the 65-years-and-less age group permitted a better definition of the costs incorporated into the model (e.g., productivity cost, a component of which would be problematic to estimate when dealing with elderly population). In addition, comorbidities among different age groups may vary, implicating great variability in length and costs of hospitalization. The meta-analysis of RCTs of prophylactic G-CSF used to estimate RRRs incorporates data from 17 RCTs in adult cancer patients, including six that excluded elderly patients more than 65 years of age, four that included only patients older than the age of 60, and the rest, which allowed patients of all ages. No significant difference in clinical efficacy among different age groups was found. By specifying the defined study population considered here, the accuracy of “real-world” costs based on our model should be increased. Another limitation of the model is the derivation of hospitalization cost per day from an administrative data set of hospitalization charges of academic hospitals. Although the charges are adjusted based on a department-specific cost-to-charge ratio to appropriately address the societal perspective our analysis takes, the estimates may still be somewhat higher than when treating FN in a nonacademic hospital. Further analysis that takes into consideration a longer time horizon and the potential long-term effects of pegfilgrastim and filgrastim on chemotherapy dose reductions or delays and survival should be undertaken. The model presented here compares only two treatment alternatives—prophylactic G-CSF (either filgrastim or pegfilgrastim) versus no G-CSF at all—and does not consider the cases where patients are given G-CSF only secondarily after already presenting to the hospital with FN. Our estimates of FN risk and hospitalization while using pegfilgrastim or filgrastim are based largely on evidence from RCTs. These trials are designed primarily to test the safety and efficacy of a treatment, and are usually restricted to highly selected patients, leading to a potential bias when applying results to the general disease population. Nevertheless, estimates of infection-related mortality in the control arm of the RCTs were similar to those reported in cohort or observational studies of cancer patients experiencing FN [4]. This analysis provides evidence that pegfilgrastim is not only cost-effective but, in most cases, also costsaving across a wide range of estimates of clinical and economic values. Therefore, in addition to compelling evidence for considerable clinical benefit with moderately myelosuppressive regimens, primary prophylaxis with pegfilgrastim reduces costs in settings where maintaining treatment dose intensity is consideredimportant to providing patients with optimal longterm disease control or cure. The authors would like to thank Drs Barry V. Fortner and Ling Zhu for sharing the data from their studies. Source of financial support: The study received research support from Amgen Inc., Thousand Oaks, CA, USA.