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The American Journal of Managed Care October 2016
Cost-Effectiveness of a Statewide Falls Prevention Program in Pennsylvania: Healthy Steps for Older Adults
Steven M. Albert, PhD; Jonathan Raviotta, MPH; Chyongchiou J. Lin, PhD; Offer Edelstein, PhD; and Kenneth J. Smith, MD
Economic Value of Pharmacist-Led Medication Reconciliation for Reducing Medication Errors After Hospital Discharge
Mehdi Najafzadeh, PhD; Jeffrey L. Schnipper, MD, MPH; William H. Shrank, MD, MSHS; Steven Kymes, PhD; Troyen A. Brennan, MD, JD, MPH; and Niteesh K. Choudhry, MD, PhD
Benchmarking Health-Related Quality-of-Life Data From a Clinical Setting
Janel Hanmer, MD, PhD; Rachel Hess, MD, MS; Sarah Sullivan, BS; Lan Yu, PhD; Winifred Teuteberg, MD; Jeffrey Teuteberg, MD; and Dio Kavalieratos, PhD
Patients' Success in Negotiating Out-of-Network Bills
Kelly A. Kyanko, MD, MHS, and Susan H. Busch, PhD
Connected Care: Improving Outcomes for Adults With Serious Mental Illness
James M. Schuster, MD, MBA; Suzanne M. Kinsky, MPH, PhD; Jung Y. Kim, MPH; Jane N. Kogan, PhD; Allison Hamblin, MSPH; Cara Nikolajski, MPH; and John Lovelace, MS
A Call for a Statewide Medication Reconciliation Program
Elisabeth Askin, MD, and David Margolius, MD
Postdischarge Telephone Calls by Hospitalists as a Transitional Care Strategy
Sarah A. Stella, MD; Angela Keniston, MSPH; Maria G. Frank, MD; Dan Heppe, MD; Katarzyna Mastalerz, MD; Jason Lones, BA; David Brody, MD; Richard K. Albert, MD; and Marisha Burden, MD
Mortality Following Hip Fracture in Chinese, Japanese, and Filipina Women
Minal C. Patel, MD; Malini Chandra, MS, MBA; and Joan C. Lo, MD
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Estimating the Social Value of G-CSF Therapies in the United States
Jacqueline Vanderpuye-Orgle, PhD; Alison Sexton Ward, PhD; Caroline Huber, MPH; Chelsey Kamson, BS; and Anupam B. Jena, MD, PhD
Does Medicare Managed Care Reduce Racial/Ethnic Disparities in Diabetes Preventive Care and Healthcare Expenditures?
Elham Mahmoudi, PhD; Wassim Tarraf, PhD; Brianna L. Maroukis, BS; and Helen G. Levy, PhD

Estimating the Social Value of G-CSF Therapies in the United States

Jacqueline Vanderpuye-Orgle, PhD; Alison Sexton Ward, PhD; Caroline Huber, MPH; Chelsey Kamson, BS; and Anupam B. Jena, MD, PhD
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.

Objectives: 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.

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

Methods: 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.

Results: 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.

Conclusions: 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.

Am J Manag Care. 2016;22(10):e343-e349
Take-Away Points

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.1-3 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.4 Neutropenia can progress to febrile neutropenia (FN) when accompanied by a temperature of 38˚C (100.4°F) or higher, and can lead to hospitalizations, mortality, and chemotherapy dose reductions or delays, all of which adversely affect patient outcomes4-7 and medical costs.3,8 The risk of FN is determined by the chemotherapy regimen (CR) and patient factors, such as age and comorbidities.9

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,10-14 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.15,16

Several studies have evaluated the cost-effectiveness of G-CSFs in particular tumor types, from a payer’s perspective1,17-21; 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.11,22 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.


Targeted Literature Review

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.23-26

Using the limited literature on nonclinical outcomes associated with G-CSFs, we collated information on productivity loss and quality of life.27,28 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.23-26

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.29 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.

G-CSF Population

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.11,22 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.30 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.31 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 314,442.32


Clinical SV

FN hospitalization. The occurrence of FN often results in immediate hospitalization to treat the associated infection.33 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.34 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 (IFN)  of 22%.34

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 (RRFN) for all solid tumor patients receiving primary G-CSFs of 0.51 and 0.44, respectively.35,36 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 hospitalizations24:

FN Hospitalizations Value = [{IFN – (IFN  × RRFN)} × GCSF Population] × CostFN = $768,000,000

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

FN mortality. 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%.24 Similarly, Kuderer et al (2006) and Caggiano et al (2005) reviewed discharge data for all patients with cancer with FN and reported mortality (MRFN) rates of 8.3% and 6.8%, respectively.3,8 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 (RRFNM) with G-CSFs.36 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.37 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).3,24 Valuing each year of life (VLY) in perfect health at $100,00025,26 and adjusting it to account for the average long-term quality-adjusted life-years (QALYs) weight of 0.72 for patients with cancer,38 we used the following equation to estimate a total annual value of reduced FN deaths of $2.65 billion:

FNM Value = [{([IFN – (IFN × RRFN M)] × GCSF Population) × [MRFN × (1 – RRFN 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.39 We identified several studies that estimated an incidence of chemotherapy dose reductions (IDR) 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.36

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 (ORDR) from 2 different systematic literature reviews, these were all based on very select populations.7,20 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 (IDR) by approximately 45,979 patients in 2014, or nearly 25% of our total G-CSF population.

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