Alison Sexton Ward, PhD

 Febrile neutropenia (FN) is a life-threatening complication of chemotherapy that can lead to hospitalizations, chemotherapy dose reductions or delays, and mortality. Granulocyte colony-stimulating factor (G-CSF) prophylaxis reduces the incidence of FN, enabling patients to undergo and remain on myelosuppressive chemotherapy. We estimate the benefits of continuing current G-CSF use patterns and an alternative that aligns prophylactic G-CSF use with guideline recommendations.

 Using The Health Economics Medical Innovation Simulation microsimulation, we estimated lifetime social value (SV) of prophylactic G-CSF for a nationally representative US population with breast, lung, and gynecological cancers and non-Hodgkin lymphoma.

 SV estimates included the cost of G-CSF, FN, chemotherapy relative dose intensity (RDI) less than 85% (RDI<85%), medical spending, and deaths for 3 scenarios: current use (current G-CSF use), targeted use (100% G-CSF use among patients with high FN risk), and reduced use (current G-CSF use reduced by 20% across all FN risk categories).

 Over 10 years, current use, compared with no G-CSF use, would decrease cases of FN by 3.3 million, prevent 354,000 cases of RDI<85%, and generate $96 billion in SV. Compared with current use, targeted use would decrease cases of FN by an additional 3.3 million, prevent 355,000 more cases of RDI<85%, and generate another $119 billion in SV. Reduced use would increase FN and RDI<85%, lowering SV by $18 billion compared with current use.

 Current use of G-CSF prophylaxis would provide $96 billion in SV over the next 10 years. Targeting G-CSF prophylaxis to align with guidelines would more than double SV, highlighting the substantial value of appropriate FN risk assessment and targeted G-CSF prophylaxis.

We modeled the benefits of prophylactic granulocyte colony-stimulating factor (G-CSF) use among patients with breast, lung, and gynecological cancers and non-Hodgkin lymphoma.

Over 10 years, current use of G-CSF prophylaxis provides substantial benefit, reducing cases of febrile neutropenia (FN) by 3.3 million and cases of chemotherapy reduced dose intensity (RDI) less than 85% (RDI<85%) by 354,000, resulting in $96 billion in social value (SV).

Targeting G-CSF prophylaxis to patients at high risk of FN would increase these benefits over that period, resulting in 6.6 million fewer cases of FN, 709,000 fewer cases of RDI<85%, and an SV gain of $215 billion.

Appropriate FN risk assessment and targeted G-CSF prophylaxis use in patients presents an opportunity to provide substantial value to society.

Over the past 3 decades, medical and pharmaceutical innovations have made substantial strides in many disease areas that have increased both longevity and quality of life (QOL). However, these technological advancements are often met with criticism over high prices, and, despite research showing that the benefits can outweigh the costs of new therapies, these treatments may often be underutilized.

 For example, statins represent a huge technological breakthrough for the treatment of cardiovascular disease, and a large literature of clinical trial data and cost-effectiveness modeling demonstrates their wide-ranging cost-effectiveness, yet data still suggest that this breakthrough therapy is greatly underused.

Similarly, prophylactic administration of granulocyte colony-stimulating factor (G-CSF) is underutilized despite guideline recommendations and literature on the cost-effectiveness of varying options.

 G-CSF use is well established as the standard of supportive care among patients receiving myelosuppressive chemotherapy to prevent the onset of febrile neutropenia (FN; fever and infection),

 which subsequently can lead to hospitalizations, dose reductions, and increased risk of mortality.

 National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology guidelines recommend primary prophylactic G-CSF in patients receiving a chemotherapy regimen associated with more than a 20% risk of FN. The guidelines also suggest that G-CSF therapy should be considered for patients receiving a chemotherapy regimen with a 10% to 20% risk of FN and who have additional risk factors (eg, age ≥65 years, poor performance status, history of FN, comorbid conditions).

 Despite these clear and well-respected guidelines and evidence from meta-analyses supporting the favorable benefit—risk profile of G-CSFs,

 real-world use is lower than recommended. For example, only 51% of patients with breast cancer and 28% of patients with lung cancer with high risk of FN have been documented as receiving G-CSF prophylaxis.

G-CSF prophylaxis continues to be the subject of much debate due to the rising costs of cancer care. Although previous research has noted the clinical benefits of these therapies and has demonstrated their cost-effectiveness, it has failed to completely account for their potential indirect benefits in the form of improved productivity and QOL.

 FN can be very debilitating and often leads to inpatient hospital stays and potentially death. Although some previous studies have accounted for reductions in QOL, they have not included lost work or reductions in productivity. There has been much discussion recently about the importance of including these indirect benefits in any value calculation, and both the Second Panel on Cost-Effectiveness

 and the International Society for Pharmacoeconomics and Outcomes Research’s Special Task Force on Value Assessment Frameworks

 recommended doing so where possible. Our study builds upon the current literature by including these indirect sources of value in our model and estimating the accumulation of value over patients’ lifetimes.

Additionally, our model builds on the current literature by estimating the social value (SV) both at the US population level of current G-CSF prophylaxis use and at a level of use better aligned with NCCN guidelines. SV quantifies the resources that society would be willing to give up in order to achieve the health, QOL, and productivity benefits associated with G-CSF prophylaxis. This study represents the first comprehensive estimate of the benefit to society from G-CSF prophylaxis use that better aligns with guidelines.

We used The Health Economics Medical Innovation Simulation (THEMIS), an established microsimulation model based on the Future Elderly Model,

 to predict the lifetime value associated with use of G-CSF consistent with NCCN guidelines.

 A patient-level microsimulation like THEMIS allows costs and benefits to be estimated over individuals’ lifetimes within a variety of subgroups while capturing the heterogeneity that would be lost in a cohort simulation. Our model focused on 4 patient populations with high rates of use of myelosuppressive chemotherapy regimens categorized as high and intermediate FN risk,

 and it documented use of G-CSF prophylaxis that is not consistent with NCCN guidelines—overuse in the population at low risk of FN and/or underuse in the population at high risk of FN. Specifically, we focused on patients with breast, gynecological, and lung cancers and non-Hodgkin lymphoma (NHL) who were 25 years or older, and we simulated their health status, health spending, and mortality experience over their lifetimes.

THEMIS is based on data from the Panel Study of Income Dynamics (PSID)

 Both data sets are nationally representative panel surveys that have been ongoing since 1968 and 1992, respectively. The breast, gynecological, and lung cancer cohorts were modeled using the PSID data; however, the survey does not differentiate patients with NHL from patients with other lymphomas. Thus, we built a synthetic cohort for the NHL population based on Surveillance and Epidemiology End Results (SEER) data. A raking procedure, which adjusts the weights of the PSID cancer population to match the distributions of the NHL population in SEER, was combined with SEER NHL prevalence and incidence data and the National Cancer Institute lymphoma incidence projections to compute a population of prevalent and incident NHL cases.

 To estimate the potential impact of G-CSF prophylaxis on financial outcomes, we supplemented the PSID data with medical spending data from the Medicare Current Beneficiary Survey and Medical Expenditure Panel Survey, depending on the individual’s Medicare eligibility. This allowed us to estimate the change in medical costs that occurs with the use of G-CSF as well as the long-term effects over the lifetime of patients. Further detail on the mechanics and implementation of the model are described in Kabiri et al.

The risk of FN, and thus the appropriateness of G-CSF prophylaxis, depended on the toxicity of chemotherapy and other patient characteristics according to NCCN guidelines.

 We stratified patients with cancer into 3 groups based on risk of FN due to chemotherapy: high risk of FN, defined as greater than 20% risk, or 10% to 20% risk with additional risk factors (eg, being ≥65 years); intermediate risk of FN, defined as 10% to 20% risk without additional patient risk factors; and low risk of FN, defined as 0% to 10% risk. We incorporated the appropriate distribution of FN risk for each cancer type according to data presented in 

Simulated incident patients with cancer who received chemotherapy were at risk of developing FN and of decreased relative dose intensity (RDI) of treatment, depending on the individual’s cancer type, FN risk category, and use of G-CSF prophylaxis. We based the rates of FN and RDI less than 85% (RDI<85%) on the literature (Table 1).

We assumed that each FN event reduced patients’ QOL by 0.022 quality-adjusted life-years (QALYs). In addition, our model included FN mortality rates during treatment as the percentage of total deaths for each cancer type and included a calculated hazard ratio for death of 1.46 for RDI<85% across all cancer types. See the 

) for sources of model parameters and assumptions.

To model the SV of G-CSF use, we simulated 1 baseline and 3 G-CSF coverage scenarios. The baseline scenario assumed no G-CSF use, representing care in a world without G-CSF coverage. The first scenario, current use, incorporated current rates of G-CSF prophylaxis in each FN risk category, by cancer type, from the recent literature. The second scenario, targeted use, measured the SV from G-CSF coverage that aligned with the NCCN guidelines for primary prophylaxis with G-CSF. We assumed that all high-risk patients received G-CSF prophylaxis and all intermediate-risk and low-risk patients did not. Under the third scenario, reduced use, we assumed that current G-CSF use fell by 20% in each of the 3 FN risk categories, representing the potential impact of lower rates of G-CSF prophylaxis in response to cost concerns. The rates of G-CSF use by risk group and cancer type are presented in 

. The scenarios were run within each cancer population and aggregated for the results presented here. See the eAppendix for sources of model parameters and assumptions.

Amid concerns over rising drug expenditures in the United States, a potential approach to minimize costs while still providing G-CSF prophylaxis could be to substitute the use of pegfilgrastim (long-acting G-CSF) with lower-cost, multidose filgrastim (short-acting G-CSF). Such a substitution would allow access to G-CSF therapies for a reduced cost. However, many studies have established the superior efficacy of pegfilgrastim over filgrastim. To test how such a strategy would affect patients, we simulated 1 additional scenario assuming a reduction in pegfilgrastim use by 20% and a corresponding increase in filgrastim use by 20%. We assumed that 6 doses of filgrastim were used per cycle, according to the median real-world utilization. We assumed that pegfilgrastim and filgrastim are associated with odds ratios of FN of 0.24 and 0.51, respectively, and that 4% and 5% of patients experience RDI<85%, respectively. See the eAppendix for sources of model parameters and assumptions.

We included estimates of the cost of FN-related inpatient and outpatient encounters by cancer type from the literature and adjusted to 2017 US$ using the Medical Consumer Price Index. We also estimated the costs of G-CSF prophylaxis assuming pegfilgrastim use in each cancer type. We assumed 6 cycles of chemotherapy and therefore 6 cycles of G-CSF prophylaxis for NHL and breast and gynecological cancers and 4 chemotherapy and G-CSF prophylaxis cycles for lung cancer. The model had a societal perspective, so the drug price represented the average price paid across all payers. We used the average wholesale acquisition cost for pegfilgrastim. To account for the introduction of biosimilar competition in the marketplace, we reduced the price of pegfilgrastim by 15% in 2019 and by an additional 15% in 2020.

 All cost estimates are shown in Table 1. See the eAppendix for sources of model parameters and assumptions.

We compared the incidence of FN, RDI<85%, and death across G-CSF scenarios. Productivity was measured through additional earnings from avoided deaths and reduced caregiver burden ($4413 per FN episode for patient and caregiver work loss).

 Additionally, we calculated QALYs, total prophylaxis cost, and medical spending under each modeling scenario. This allowed us to calculate the total SV generated under each scenario estimated as QALYs gained, which were each valued at $150,000

 plus increased total earnings minus increased medical spending (including treatment cost). We used the formula:

 represents each year of the simulation period. For an individual, this calculation is done over a lifetime, starting at treatment initiation. The results for G-CSF scenarios were calculated in 2017 US$ and compared with the baseline (no G-CSF) scenario. Lifetime SV of G-CSF was estimated over a 10-year horizon, between 2017 and 2027.

Both current and targeted use of G-CSF prophylaxis resulted in fewer annual cases of FN compared with the scenario of no G-CSF use. As seen in 

, the benefits of G-CSF prophylaxis can be observed immediately and continue to increase over time. By 2027 (after year 10), current use and targeted use of G-CSF prophylaxis were estimated to prevent about 340,000 and 700,000 FN cases per year, respectively. The cumulative cases of FN prevented over 2 and 10 years are displayed in 

Similarly, occurrences of RDI<85% were reduced under both current and targeted use of G-CSF prophylaxis compared with the scenario of no G-CSF use. As shown in 

, current use and targeted use of G-CSF prophylaxis led to an estimated 35,000 and 70,000 fewer occurrences of RDI<85%, on average, at year 10 (2027), respectively. The cumulative occurrences of RDI<85% prevented over 2 and 10 years are displayed in Table 3.

Reductions in both FN and RDI<85% reduced annual patient mortality. These benefits are shown as the cumulative number of deaths prevented at 2 and 10 years displayed in Table 3. Compared with no G-CSF use, current G-CSF use prevented more than 27,000 deaths after 2 years and more than 117,000 deaths after 10 years. Similarly, targeted G-CSF use prevented more than 48,000 and 222,000 deaths over 2 and 10 years, respectively.

QALYs, Prophylaxis Cost, Medical Spending, and SV

The average life expectancy gains for each of the G-CSF prophylaxis scenarios are shown in Table 3. Under the current G-CSF use scenario, patients treated over the next 10 years gained about 570,000 QALYs over their baseline counterparts. Targeted G-CSF use generated even greater life expectancy benefits than witnessed with current G-CSF use. Compared with no G-CSF use, patients treated under the targeted G-CSF scenario over the next 10 years generated 970,000 QALYs.

Cumulative prophylaxis costs and medical spending for each scenario over 2 and 10 years are shown in Table 3. Compared with no G-CSF prophylaxis, both current and targeted use of G-CSF reduced medical spending (excluding prophylaxis cost) over 10 years, such that total spending (including prophylaxis cost) was less than in the scenario of no G-CSF use. These results suggested that the cost offsets from G-CSF prophylaxis are greater than the prophylaxis costs; thus, G-CSF prophylaxis is cost-effective at all positive QALY thresholds.

Finally, we measured SV as the estimated benefits that G-CSF prophylaxis generated for society net of its costs. The components of this calculation are shown in Table 3. SV was positive for all G-CSF use scenarios, but targeted use generated substantially more value than current and reduced G-CSF use across all periods.

After only 2 years, we estimated that the current use of G-CSF prophylaxis would generate more than $15 billion in value to society, or $9700 per patient. However, if G-CSF use were targeted to patients with a high risk of FN, the value to society would more than double to almost $40 billion, or $16,400 per patient. After 10 years, the SV increased to $96 billion ($14,700 per patient) and $215 billion ($21,000 per patient) for current and targeted G-CSF use scenarios, respectively, compared with baseline. The per-patient SV increases over time as a result of the decrease in mortality due to G-CSF prophylaxis use.

A 20% reduction in pegfilgrastim use in favor of filgrastim saved $2.0 billion and $3.5 billion in prophylaxis costs over 2 and 10 years, respectively, compared with current G-CSF use. However, the shift also led to an additional $4.0 billion and $17.0 billion in medical spending from FN events over 2 and 10 years, respectively. Ultimately, reduced use of pegfilgrastim resulted in a loss of $2.7 billion and $14.9 billion in SV over 2 and 10 years, respectively.

We used a microsimulation model to examine the SV of aligning primary prophylactic G-CSF use with guideline recommendations over a 10-year period. Our model estimated that current use of G-CSF prophylaxis would decrease the total number of FN cases by 3.3 million, prevent more than 350,000 cases of RDI<85%, and generate $96 billion in net SV over 10 years compared with a no G-CSF scenario. We estimated that the targeted use of G-CSF prophylaxis, defined according to the NCCN guidelines, would reduce the total number of FN cases and cases of RDI<85% by 6.6 million and 709,000, respectively, in addition to gaining $215 billion in SV. Finally, our model estimated that shifting from pegfilgrastim to filgrastim would result in increased rates of FN and RDI<85%, in addition to higher medical spending and lower net SV.

We note that the large reduction in cases of FN relative to the reduction in cases of RDI<85% is due to the fact that cases of FN were estimated per cycle of chemotherapy and cases of RDI<85% were estimated per course of chemotherapy treatment.

Previous cost-effectiveness analyses of G-CSF prophylaxis have been conducted across a variety of treatment conditions, including specific tumor types as well as solid tumors more broadly; different clinical contexts; primary versus secondary prophylaxis; and long-acting pegfilgrastim versus short-acting filgrastim. Across all of these options, primary prophylaxis with pegfilgrastim has been identified as being cost-effective at traditionally accepted thresholds for the prevention of FN in patients with cancer receiving myelosuppressive chemotherapy

; however, these studies have several limitations. First, they fail to fully capture the impact of FN and G-CSF prophylaxis on patient productivity. Second, they assume 100% compliance with the G-CSF prophylaxis options being evaluated, despite mounting evidence suggesting that compliance is far less.

 Our analysis modeled increased productivity and health-related QOL due to reduced incidence of FN, which provides a more comprehensive evaluation of G-CSF prophylaxis. We also incorporated estimates of suboptimal use of G-CSF prophylaxis (specifically underuse in high-risk patients and overuse in low-risk patients) to provide an estimate of inclusive SV.

Our study does have limitations worth noting. First, parameters for the model were taken from the current literature. When published estimates did not exist for parameters by tumor type, we relied on reasonable assumptions and input from clinical experts. Second, the PSID data do not include information on most of the patient risk factors for FN. Thus, our FN risk group categorization relied solely on chemotherapy risk and patient age. Additionally, we were unable to account for the differential rates of FN and RDI<85% by cancer stage and histology. Although we recognize that RDI<85% may not equally affect survival across cancer types, disease stages, and regimens, the literature supports that RDI≥85% has a favorable impact on survival.

 Third, the efficacy of G-CSF prophylaxis on the risk of FN is not as well defined for intermediate- and low-risk groups. Thus, we assumed the same impact of G-CSF on the incidence of FN for all risk groups. This could potentially over- or underestimate the impact of G-CSF prophylaxis in these groups. Fourth, we did not account for the impact of newer G-CSF administration options on guideline adherence from a prescribing perspective or medication adherence at the patient level. For example, the on-body injector allows patients and caregivers to remain at home and thus avoid the caregiver burden and lost work days associated with next-day clinic visits, which have been identified as both a patient- and practice-related rationale for suboptimal prophylaxis.

 Finally, we did not account for the evolving treatment landscape in cancer. As more targeted therapies and immunotherapies become available, chemotherapy treatment may decline, although these therapies also can be used with combinations of myelosuppressive chemotherapy.

 Thus, we show the value gained over 2 years and over 10 years. Treatment patterns are not likely to change drastically in the next 2 years, and the introduction of newer therapies over the next decade does not change our conclusions.

Our results suggest that G-CSF therapies provide tremendous value to society. Better targeting G-CSF to align with current guidelines would double this value. Rather than reducing G-CSF use or switching use to less-costly short-acting G-CSFs, efforts to support appropriate FN risk assessment in all patients receiving myelosuppressive chemotherapy, with consequent targeted G-CSF prophylaxis, could add considerable value.

 Precision Health Economics (ASW, MK, ARS, EvE, DG), Los Angeles, CA; Global Health Economics (AY, MB) and US Medical (CB), Amgen, Thousand Oaks, CA.

 Amgen Inc provided funding for this research.

 Drs Ward and Kabiri, Ms Silverstein, and Ms van Eijndhoven are employees of Precision Health Economics, which received consulting fees for this study. Drs Yucel, Bowers, and Bensink are employees of and own stock in Amgen. Dr Goldman is a consultant to Precision Health Economics and a scientific advisor to ACADIA Pharmaceuticals; owns equity (<1%) in Precision Medicine Group, the parent company of Precision Health Economics; received honoraria from The Aspen Institute and lecture fees from Celgene; and is funded through the Leonard D. Schaeffer Center for Health Policy & Economics, which is supported by gifts and grants from individuals, corporations, and associations; by government grants and contracts; and by private foundations (specific information about funding sources is available at healthpolicy.usc.edu).

 Concept and design (ASW, MK, AY, ARS, CB, MB, DG); acquisition of data (ASW, MK, ARS); analysis and interpretation of data (ASW, MK, AY, EvE, CB, MB, DG); drafting of the manuscript (ASW, MK, AY, ARS, EvE, MB); critical revision of the manuscript for important intellectual content (ASW, MK, AY, ARS, EvE, CB, MB, DG); statistical analysis (EvE); administrative, technical, or logistic support (MK, ARS); and supervision (ASW, AY, MB, DG).

Articles

Although currently underutilized, granulocyte colony-stimulating factor prophylaxis as supportive cancer care provides substantial value to society. Aligning utilization with clinical guidelines would increase this value considerably.

The Long-term Social Value of Granulocyte Colony-Stimulating Factors

To provide a comprehensive estimate of the total social value (TSV) delivered by granulocyte-colony stimulating factor (G-CSF) therapies in the United States in 2014.

Estimation of the TSV of G-CSF, based on a targeted literature review of pivotal studies.

A literature review was conducted to obtain estimates of the adverse outcomes associated with myelosuppressive chemotherapy-induced febrile neutropenia (FN) and the positive impacts of G-CSFs. We monetized each outcome into a set of mutually exclusive value components that were aggregated to estimate the TSV. To estimate the share of TSV captured by manufacturers, we estimated 2014 profits from G-CSF using measures of industry revenues and operating costs.

In 2014, approximately 314,440 patients received G-CSFs. Compared with what they would have experienced without G-CSFs, these patients were less likely to be hospitalized or die from FN, incur reductions in chemotherapy relative dose intensity, receive antibiotics, miss work, or experience reduced health-related quality of life. We estimated the social value from fewer FN hospitalizations to be $770 million; from fewer FN-related deaths, $2.65 billion; from fewer deaths due to higher effective chemotherapy doses, $4.83 billion; from reductions in antibiotics, $2.3 million; from reductions in indirect costs, $230 million; and from improvements in health-related quality of life, $1.9 million. The estimated 2014 US TSV of G-CSFs was $8.5 billion. Industry profits associated with G-CSFs were estimated at $1.3 billion, accounting for approximately 15% of the TSV.

Based on our calculations, the TSV generated by G-CSFs in the United States in 2014 was substantial, with the majority of this value accruing to patients.

	Granulocyte-colony stimulating factors (G-CSFs) can significantly reduce the risk of febrile neutropenia (FN) among certain patients receiving chemotherapy. FN is associated with significant clinical and nonclinical complications. This study provides a comprehensive analysis of the total social value of G-CSFs, accounting for the nonclinical, as well as clinical benefits captured by these therapies. 

		In 2014, approximately 314,440 patients received G-CSFs, and compared with individuals who did not, they were less likely to be hospitalized or die from FN, incur chemotherapy dose reductions, receive antibiotics, miss work, or experience reduced health-related quality of life.

		The estimated 2014 US total social value of G-CSFs was $8.5 billion.

Despite major advances in cancer treatment, neutropenia is a life-threatening complication of chemotherapy.

 Severe neutropenia is a below-normal count of neutrophils in the blood (less than 500 per mm), which impairs the body’s ability to combat opportunistic infections.

 Neutropenia can progress to febrile neutropenia (FN) when accompanied by a temperature of 38ËšC (100.4°F) or higher, and can lead to hospitalizations, mortality, and chemotherapy dose reductions or delays, all of which adversely affect patient outcomes

 The risk of FN is determined by the chemotherapy regimen (CR) and patient factors, such as age and comorbidities.

For patients with solid tumors or nonmyeloid malignancies, granulocyte-colony stimulating factors (G-CSFs) can enable them to undergo and remain on myelosuppressive chemotherapy with lower risk of FN and infection. Despite well-established clinical benefits of G-CSFs,

 these therapies have been the subject of recent concern due to large variation in their utilization. Research has indicated that G-CSFs may be overprescribed for patients at a low risk of FN (≤20%) and underprescribed for high-risk (≥20%) patients.

Several studies have evaluated the cost-effectiveness of G-CSFs in particular tumor types, from a payer’s perspective

; however, these studies may understate the value of G-CSFs from a societal perspective. For example, reductions in lost workdays or disability provide tremendous value to society, but may be excluded from existing studies.

 Therefore, a better understanding of the total social value (TSV) of G-CSFs is needed to appropriately determine the cost-effectiveness and value afforded to patients and others affected by chemotherapy-induced neutropenia. In this study, we estimated the TSV of G-CSFs delivered to patients with cancer in the United States in 2014 by combining various components of value derived from the literature.

To identify evidence on the value of G-CSFs, we conducted a targeted literature review of pivotal studies. Specifically, we limited the search to articles published between 1991 (the year G-CSFs were approved in the United States) and 2014 that examined both adverse outcomes associated with myelosuppressive chemotherapy-induced FN, as well as the impacts of G-CSFs on these outcomes.

The searches yielded 77 potentially relevant articles that were narrowed to 58 for data extraction (Table 1 summarizes the articles by type of analysis). Articles were selected if they investigated patients with nonmyeloid cancers at risk of the clinical definition of chemotherapy-induced FN who were treated with G-CSFs. We focused on studies that compared outcomes for patients who received G-CSFs with patients who did not.

Our literature review provided information on 6 clinical outcomes: FN hospitalization, neutropenia events, length of hospital stay, reductions in relative dose intensity of chemotherapy, overall mortality, and antibiotic use. To associate these outcomes with savings or social value (SV), we mapped them to 4 clinical value components: savings from reductions in FN hospitalizations, reductions in FN mortality, reductions in mortality due to the ability to deliver higher-dose chemotherapy, and reductions in antibiotic use. Then, using cost estimates from the literature, along with clinical improvements, we estimated the SV for all 4 components and, in aggregate, the TSV of G-CSFs.

Using the limited literature on nonclinical outcomes associated with G-CSFs, we collated information on productivity loss and quality of life.

 These outcomes were mapped into similar SV components: savings from reduced indirect costs (productivity loss) and improved quality of life. Again, we calculated the value for each component and in total for the nonclinical SV of G-CSFs.

The TSV of G-CSFs was calculated as the sum of all clinical and nonclinical value components. All reported estimates were adjusted to 2014 US dollars using the Medical Care Consumer Price Index, which is a measure of changes in the price level of medical care commodities and services.

 To maintain the integrity of the outputs derived from the literature and to facilitate replication of our study methods, we kept all decimal places of the estimates, recognizing that the level of precision implied by our estimates is less than should be expected of our modeling exercise.

In both the United States and the European Union, G-CSFs are indicated for patients with nonmyeloid malignancies receiving myelosuppressive chemotherapy associated with a clinically significant (≥20%) risk of FN. They also may be considered for patients with a 10% to 20% risk and certain individual factors, such as age or stage of cancer.

 We derived an estimate of this population using the Surveillance, Epidemiology, and End Results (SEER) program, which estimated the overall cancer incidence in 2014 at 1,665,540 cases.

 To account for patients with myeloid malignancies who fall outside the approved indication, we used an incidence rate of 0.015% (15 individuals with myeloid malignancies per 100,000 population), as reported by the 2014 World Trade Center Health Program.

 Subtracting the myeloid malignancies from the SEER all-cancer incidence suggests that, in 2014, there were approximately 1,617,665 individuals diagnosed with nonmyeloid malignancies in the United States. Given that not all of these individuals would receive a CR associated with a significant risk of FN, we applied a G-CSF usage rate of 19.4%, as reported in Naeim et al (2013), to estimate a 2014 population of patients eligible for GSCFs of 314,442.

 The occurrence of FN often results in immediate hospitalization to treat the associated infection.

 Crawford et al (2008) used medical claims data to estimate that 10.7% of patients with breast, lung, colorectal, and ovarian cancers, as well as lymphoma, develop FN in the first 3 cycles of chemotherapy.

 We found that patients with nonmyeloid malignancies receive 6 cycles of chemotherapy on average. Thus, we used the growth rate in incidence of FN from cycles 1 to 2 and cycles 2 to 3, reported in Crawford et al, to predict the growth rate from cycles 3 to 4, 4 to 5, and 5 to 6 in order to estimate a 6-cycle incidence rate (I

Further, many trials have demonstrated that, when used prophylactically, G-CSFs significantly reduce the incidence of FN. Cooper et al (2011) and Kuderer et al (2007) both reviewed randomized controlled trials and reported relative risk ratios (RRs) for developing FN (RR

) for all solid tumor patients receiving primary G-CSFs of 0.51 and 0.44, respectively.

 We applied the average of these RRs (0.48) to our calculated incidence measure to estimate that G-CSFs reduce the incidence of FN to 10%. Using cost estimates from Dulisse et al (2013), we used the following equation to estimate that G-CSFs prevented 35,988 FN hospitalizations in 2014, thus creating $768 million in SV derived from avoided FN hospitalizations

FN Hospitalizations Value = [{0.22 — (0.22 × 0.48)} × 314,442] × $21,341 = $768,000,000

 In addition to hospitalizations, FN is also associated with high mortality. Using claims data, Dulisse et al (2013) found that the inpatient mortality rate (MR) for patients with breast cancer, lung cancer, colorectal cancer, ovarian cancer, non-Hodgkin lymphoma, and Hodgkin lymphoma with FN was 10.6%.

 Similarly, Kuderer et al (2006) and Caggiano et al (2005) reviewed discharge data for all patients with cancer with FN and reported mortality (MR

 We used the average of all 3 rates (8.6%) to estimate that in the absence of G-CSFs, there would have been 5872 FN-related deaths in the United States in 2014.

G-CSFs reduce the chances of developing FN and the probability of death among patients who develop FN. In their systematic review of the G-CSF literature, Kuderer et al (2007) estimated a 0.55 RR of FN-related mortality (RR

 Applying this estimate to the reduced FN population derived above, we calculated that G-CSFs prevented approximately 4171 deaths in 2014.

To calculate the SV generated from the reduction in FNM, we estimated the average value of each life saved. Specifically, we used estimates of average life expectancy from diagnosis for several types of cancers.

 Weighting these values using patient populations provided in Dulisse et al (2013) and Caggiano et al (2005), we estimated that, on average, a patient who dies because of FN has lost 8.81 years of life (LYL).

 Valuing each year of life (VLY) in perfect health at $100,000

 and adjusting it to account for the average long-term quality-adjusted life-years (QALYs) weight of 0.72 for patients with cancer,

 we used the following equation to estimate a total annual value of reduced FN deaths of $2.65 billion:

 M)]} × LYL FNM] × VLY = $2,645,923,449

FNM Value = [{([0.22 — (0.22 × 0.55)] × 314,442) × [0.086 × (1 – 0.55)]} × 8.81] × 100,000 = $2,645,923,449

Mortality Due to Reduced Chemotherapy Relative Dose Intensity

Many patients receiving chemotherapy do not achieve their planned relative dose intensity (RDI) because of treatment toxicity complications. Lower RDI has been associated with adverse clinical outcomes, including reduced life expectancy.

 We identified several studies that estimated an incidence of chemotherapy dose reductions (I

) greater than 15% among some cancer types, including an estimate of 40% based on a systematic literature review by Kuderer et al (2007) in a robust cancer population.

Several studies have also found that G-CSFs significantly reduce a patient’s risk of a chemotherapy dose reduction. Although our literature review identified 3 separate estimates of the odds ratio of a dose reduction (OR

) from 2 different systematic literature reviews, these were all based on very select populations.

 Assuming that patients in our population would experience similar reductions in risk, we calculated the average of all 3 reported  estimates (0.63). This estimate suggests that G-CSFs reduced the number of patients requiring chemotherapy dose reductions (I

) by approximately 45,979 patients in 2014, or nearly 25% of our total G-CSF population.

To value survival gains associated with avoided chemotherapy dose reductions, we used estimates from Havrilesky et al (2014) who found that an RDI greater than 85% was associated with increased survival for patients with breast and lung cancers.

 Using population weights from Naeim et al (2013), we calculated an average survival gain (S

) of 17.5 months per G-CSF patient, attributable to chemotherapy dose reductions avoided.

 We then used an estimate of the average cost of CRs ($24,392) calculated from data provided in Naeim et al to account for higher treatment costs associated with this increased dosing (assuming a 15% increase).

 Clinical experts suggested these increased costs should only apply to the roughly 50% of patients receiving chemotherapy from multi-use vials. Applying the value of a cancer-adjusted life-year at $72,000, we used the following equation to estimate the value of lowering the incidence of chemotherapy dose reductions (dose-related mortality [DRM value]) to be $4.8 billion, annually:

DRM Value = {([0.4 — (0.4 × 0.63)] × 314,442) × 1.46} × 100,000 – [($24,392 × 0.15) × [0.4 – (0.4 ×  0.63)] × 314,442] = $4,827,749,599

Myelosuppressive chemotherapy is associated with antibiotic use (AU) to fight infection. According to a randomized controlled trial published by Vogel et al (2005) and a claims analysis by Almenar et al (2009), 10% of patients with breast cancer receive antibiotics.

 Our literature review did not provide estimates of the incidence of AU (I

) for other cancer types; therefore, to derive a proxy estimate, we assumed that other patients with nonmyeloid malignancies receive antibiotics at a similar rate. The estimate would be that 31,444 patients received antibiotics in our 2014 population.

G-CSFs have been estimated to reduce the use of antibiotics substantially. We identified 3 studies that reported relative RRs for AU (RR

) from randomized controlled trials of 0.64 for patients with small cell lung cancer,

 and 0.80 for patients with breast cancer receiving G-CSFs.

 Assuming all tumor types respond similarly, the average of these 2 estimates (0.72) suggests that G-CSFs prevented antibiotic use in roughly 8837 patients in 2014, an incidence rate of 7%. Using the equation below and the cost of AU (Cost

) reported in Elder-Lissai (2008), we estimated G-CSFs generated $2.3 million in value due to fewer patients receiving antibiotics

AU Value = [{0.1 — (0.1 × 0.72)} × 314,442] × $260 = $2,297,596

Table 2 reports the estimated total clinical SV of G-CSFs in 2014. The annual value for each component ranged from $2.3 million for AU to $4.8 billion for reduction in mortality related to chemotherapy dose reductions avoided, summing to a total value of $11 billion.

 Our literature review identified 1 article that analyzed the ICs associated with neutropenia events. Calhoun et al (2001) define total ICs (TICs) as the sum of patient work loss, caregiver work loss, and payments for caregivers.

 Using a sample of patients with ovarian cancer, they estimated the cost of each component was, on average, $4038, $1185, and $1170 per patient per event, respectively, for a TIC of $6393 per patient. We multiplied this by the reduction in FN events due to G-CSFs using the following equation to estimate a total value of $230 million:

)} × GCSF Population] × TIC = $230,087,690

IC Value = [{0.22 — (0.22 × 0.48)} × 314,442] × 6393 = $230,087,690

 Few studies have measured how FN and G-CSF usage affect patients’ health-related quality of life (HRQoL). Our review identified 1 study that used the difference in Short Form Health Survey 36 (SF-36) scores for a group of patients with neutropenia in the last 7 days and a control group. Fortner et al (2005) found the only significant difference in responses between the groups was for bodily pain.

To associate this difference in SF-36 scores with a dollar value, we used a published algorithm to calculate the equivalent QALY reduction.

 we estimated that neutropenia and FN are associated with an $85 reduction in HRQoL per FN event (HRQoL

). Multiplying this amount by the reduction in FN events due to G-CSFs, we used the following equation to estimate a total annual value of $1.9 million:

HRQoL Value = [{0.22 — (0.22 × 0.48)} × 314,442] × $85 = $1,930,031

Although literature on the nonclinical value of G-CSFs was limited, we used all available data to create what can be viewed as a conservative estimate of the nonclinical SV from G-CSF use.

 Table 2 shows that the indirect costs avoided account for 99% of our estimates, with an annual savings of $232 million.

Granulocyte-colony stimulating factors (G-CSFs) reduce the risk of febrile neutropenia in patients with cancer. This study evaluates the clinical and nonclinical value associated with G-CSFs.

Alison Sexton Ward, PhD

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