From Specialty Pharmacy News

Study Questions Prophylactic G-CSF Use in Certain Regimens

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November 2016Volume 13Issue 11

Many people undergoing chemotherapy are at risk of infection, but that risk varies depending on the actual regimen. For people whose treatments put them at high risk of developing febrile neutropenia, it makes sense to treat them prophylactically with granulocyte colony-stimulating factor (G-CSF) to boost their white blood cell count and hopefully prevent them from being hospitalized. But people at a lower risk should not be given G-CSF prophylaxis because it has little to no benefit and it drains valuable health care resources, according to a recent study. Anthem, Inc., which had representatives among the study authors, has a new utilization management tool that is helping make sure G-CSF dosing is appropriate.

In fact, the issue is part of the ABIM (American Board of Internal Medicine) Foundation’s Choosing Wisely campaign. That initiative, which also includes the American Society of Clinical Oncology (ASCO), focuses on helping clinicians provide care that is “supported by evidence, not duplicative of other tests or procedures already received, free from harm [and] truly necessary,” according to the Choosing Wisely website. “CSFs are not recommended for chemotherapy patients who do not have a high risk,” it contends. “High risk” is defined as causing febrile neutropenia in more than 20% of people treated with a particular regimen.

CSFs include Neupogen (filgrastim), Neulasta (pegfilgrastim), Zarxio (filgrastim-sndz), Granix (tbo-filgrastim) and Leukine and Prokine (sargramostim). And while they can help lower the risk of hospitalization due to febrile neutropenia, they also have side effects — and they can cost as much as $4,000 for a single dose.

The study, titled “Risk of Neutropenia-Related Hospitalization in Patients Who Received Colony-Stimulating Factors With Chemotherapy for Breast Cancer,” was published in the Nov. 10 issue of ASCO’s Journal of Clinical Oncology. Researchers from Anthem, its HealthCore, Inc. subsidiary and ASCO analyzed medical and pharmacy claims for 8,745 women in 14 commercial health plans who began first-cycle chemotherapy for breast cancer from 2008 to 2013. The patient population was narrowed down to 4,815 patients receiving one of three regimens: docetaxel and cyclophosphamide (TC); docetaxel, carboplatin, and trastuzumab (TCH); or doxorubicin and cyclophosphamide (conventional dose AC). Those regimens were selected based on the fact that they pose an intermediate or low risk of causing neutropenia-related complications.

Specialty Pharmacy News

Yet despite that relatively low risk, a majority of people in each treatment group was given prophylactic G-CSF treatment: 59.2% on the TC regimen, 63.0% on the TCH regimen and 52.3% on AC treatment. The findings do show the risk of hospitalization related to neutropenia within 21 days after the initial chemotherapy treatment was lower in two of the regimens for people receiving prophylaxis than those who were not:

  • On the TC regimen, 2.0% of those treated prophylactically had a neutropenia-related hospitalization versus 7.1% among those untreated.

  • On the TCH regimen, 1.3% of women receiving treatment were hospitalized as opposed to 7.1%.

  • On the AC regimen, 4.7% of the treatment group had a hospitalization compared with 3.8% of the untreated.

However, when researchers conducted a number-needed-to-treat (NNT) analysis, they found that “in the TC regimen, 20 patients…would need to be treated for 21 days to avoid one neutropenia-related hospitalization versus patients with no prophylaxis. In the TCH regimen, 18 patients…would need to be treated to avoid one neutropenia-related hospitalization versus patients with no prophylaxis. NNT analysis was not applicable to the AC regimen” because the treated group had a higher percentage of neutropenia-related hospitalization.

And among all breast cancer regimens except dose-dense doxorubicin and cyclophosphamide (ddAC) within the database, 48 patients “would have to be treated for 21 days to avoid one neutropenia-related hospitalization versus patients with no prophylaxis.”

Value of Treatment Is Not Clear

Researchers concluded that although prophylactic treatment provided “low-to-modest clinical benefit,” its value in “low-to-intermediate risk regimens may be less clear. For example, for a patient who received treatment with the TCH regimen, mean expenditure during 21 days for G-CSF was $4,423.…Because 18 patients in the TCH regimen need to be treated to prevent one neutropenia-related hospitalization versus no prophylaxis,” the total G-CSF cost would be $79,614.

“Similarly, mean expenditure of G-CSF prophylaxis for those in the TC regimen was $4,024.…By using this value, for 20 patients who were treated with the TC regimen, G-CSF expenditure at more than 21 days that was needed to prevent one neutropenia-related hospitalization versus no prophylaxis would equate to $80,480,” the researchers explained. “When all breast cancer regimens, excluding ddAC, were considered, the estimated cost of G-CSF prophylaxis for 48 patients to avoid one neutropenia-related hospitalization at more than 21 days over no prophylaxis would be $209,184. It is important to note that the potential expenditure for G-CSF use across all cycles will be higher than that reported on the first cycle to prevent one neutropenia-related hospitalization.”

According to Abiy Agiro, lead author of the study and research manager for HealthCore, researchers decided to study breast cancer “because that is where the most frequent use of growth factor is observed. We also did study lung cancer and non-Hodgkin’s lymphoma, but we have not yet published. We studied all regimens together for breast cancer and then eliminated the high-risk regimens and finally selected the three most commonly used regimens with low-to-intermediate risk for infection.”

Agiro tells SPN that researchers didn’t study why providers would give G-CSFs with regimens posing a low to intermediate risk of febrile neutropenia, but she says that “guidelines on intermediate and high-risk regimens are pretty straightforward. For low-risk regimens, growth factors are not considered appropriate unless there are unusual circumstances.” However, she adds, “We also know that change takes time. Some studies have indicated an average of 17 years is needed before new knowledge generated through research is incorporated into widespread clinical practice. As a society, we need to find ways to accelerate that timetable if we want to make a greater impact on health quality and costs.”

The Choosing Wisely recommendation around G-CSFs was issued in September 2012, and the study went from 2008 through 2013. When asked if there was enough time between the recommendation and the study period to know whether it had influenced prescribing practices, Agiro says that “there was little time and a smaller set of patients to evaluate whether this Choosing Wisely recommendation had made an impact.”

The study was limited to the first chemotherapy cycle, since this is when the greatest risk of febrile neutropenia occurs. So could there potentially be unneeded G-CSF dosing happening during subsequent regimens? “We didn’t study subsequent cycles,” Agiro says. “However anecdotally it appears that once providers give [G-CSF] in one cycle, they have a tendency to persist in prescribing with future cycles.”

Treatment Can Have Side Effects

“What was really interesting was that fever and infection among these women was so low without the use of any growth factor. Then, when you add on the fact that growth factor had no to very little benefit for most women receiving treatment with low-infection risk, it makes you question why it is still such a common practice. For example, among women receiving the most common low risk treatment, more than half received growth factor. Growth factor can have negative side effects for women, and it’s a drain on our limited health care resources.”

Ann Nguyen, Anthem oncology solutions director, tells SPN that the health plan “is already using a new utilization management tool from AIM Specialty Health [another Anthem subsidiary] that evaluates the growth factor requests in real time and automatically applies the guideline-based appropriateness criteria that apply to the specific regimen being prescribed. This provides oncologists with clear, timely feedback about growth factor use and helps them stay aligned with health plan medical policies based on accepted guidelines. By making this information available to providers during treatment planning, we hope to see better concordance with national guidelines and shifts in practice patterns.”

View the study at

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