Effectiveness Not Established

Colony-Stimulating Factors: G-CSF and GM-CSF Alteration in Schedule

for Prevention of Infection: General

Granulocyte–colony-stimulating factors (G-CSFs) and granulocyte macrophage–colony-stimulating factors (GM-CSF) are substances that bind to hematopoietic stem cells, activating them to proliferate and differentiate into granulocytes and macrophages—the specific cell type of interest. Colony-stimulating factors (CSFs) administered systemically have been evaluated and recommended for patients with cancer for the prevention of infection and febrile neutropenia. CSFs may be used for primary or secondary prophylaxis. A small body of emerging research is investigating the efficacy of different treatment timing and schedules of CSFs on various infection-related outcomes in patients with cancer.

Research Evidence Summaries

Aarts, M.J., Peters, F.P., Mandigers, C.M., Dercksen, M.W., Stouthard, J.M., Nortier, H.J., . . .  Mattijssen, V. (2013). Primary granulocyte colony-stimulating factor prophylaxis during the first two cycles only or throughout all chemotherapy cycles in patients with breast cancer at risk for febrile neutropenia. Journal of Clinical Oncology, 31, 4290–4296. 

Study Purpose

To evaluate whether neutropenia prophylaxis could be limited to the first two cycles of chemotherapy only, based on the observation that patient risk for febrile neutropenia (FN) is highest in the first two cycles

Intervention Characteristics/Basic Study Process

Patients receiving chemotherapy every three weeks with regimens associated with more than a 20% risk of FN were randomly assigned to receive a granulocyte–colony-stimulating factor (G-CSF) throughout all chemotherapy cycles (standard arm) or during the first two cycles only. Pegfilgrastim (6 mg) was given 24–30 hours after chemotherapy administration. Participating sites were stratified according to whether they used prophylactic antibiotics.

Sample Characteristics

  • N = 167   
  • MEDIAN AGE = 50 years
  • FEMALES: 100%
  • CURRENT TREATMENT: Chemotherapy
  • KEY DISEASE CHARACTERISTICS: All had breast cancer. The majority were receiving TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy.
 

 

Setting

  • SITE: Multi-site   
  • SETTING TYPE: Outpatient    
  • LOCATION: Netherlands

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active antitumor treatment

Study Design

  • Randomized, parallel-group, noninferiority trial

Measurement Instruments/Methods

  • Blood cell counts

Results

The incidence of FN was 10% with standard treatment and 36% in the experimental arm. Grade 3–4 neutropenia occurred in 6% of the standard arm versus 51% of the experimental arm, and confirmed infection occurred more often in the experimental arm. The study was closed prematurely because of an unacceptablely high rate of FN.

Conclusions

The findings showed that the incidence of FN was higher among patients who did not receive G-CSF during each cycle of chemotherapy.

Limitations

  • Risk of bias (no blinding)

 

Nursing Implications

The findings showed that patients who did not receive recommended CSF prophylaxis during each cycle of chemotherapy had significantly higher rates of FN. These results showed that the provision of prophylaxis according to recommended guidelines is important for FN prevention.

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Billingsley, C.C., Jacobson, S.N., Crafton, S.M., Crim, A.K., Li, Q., Hade, E.M., . . . O'Malley, D.M. (2015). Evaluation of the hematologic safety of same day versus standard administration (24- to 72-hour delay) of pegfilgrastim in gynecology oncology patients undergoing cytotoxic chemotherapy. International Journal of Gynecological Cancer, 25, 1331–1336. 

Study Purpose

To assess the effects of same-day pegfilgrastim administration compared to standard delayed administration among women being treated for gynecologic cancer

Intervention Characteristics/Basic Study Process

Medical records were used for data collection. Women received 6 mg pegfilgrastim on the same day as chemotherapy or within 24–72 hours of chemotherapy administration. Results of absolute neutrophil count (ANC), chemotherapy delay, regimen change related to neutropenia, and incidence of febrile neutropenia (FN) were compared. A 25% difference in risk of these outcomes was established as the noninferiority margin of interest. Sixty-one patients crossed over to the alternate timing of pegfilgrastim during treatment.

Sample Characteristics

  • N = 421   
  • MEAN AGE = 59.4 years (SD = 12.1)
  • FEMALES: 100%
  • CURRENT TREATMENT: Chemotherapy
  • KEY DISEASE CHARACTERISTICS: Seventy-nine percent had ovarian cancer. The majority had stage III or IV disease.

Setting

  • SITE: Single site   
  • SETTING TYPE: Outpatient    
  • LOCATION: United States

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active antitumor treatment

Study Design

  • Retrospective cohort comparison, noninferiority

Measurement Instruments/Methods

  • FN was ANC < 1000/mcl and a single temperature of 101 or sustained temperature of at least 100.4 for over one hour

Results

Grade 3 or 4 neutropenia was observed more often in the same-day administration group (2.6% versus 1.8%, risk ratio [RR] = 1.62, p = 0.05). No significant differences in treatment delays or dose modifications existed within the established margin.

Conclusions

Same-day pegfilgrastim administration was associated with slightly higher grade 3 or 4 neutropenia.

Limitations

  • Baseline sample/group differences of import
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)
  • Key sample group differences that could influence results
  • Much smaller number of patients who received same-day pegfilgrastim

Nursing Implications

This study did not provide sufficient evidence to establish safety and effectiveness of same-day pegfilgrastim administration. The findings suggest that altered timing may be safe in terms of looking at treatment delays related to neutropenia. Prospective studies are needed to determine whether same-day administration is appropriate. This approach can be very helpful for patients who need to travel long distances for treatment and may reduce the number of visits required for treatment.

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Li, Y., Klippel, Z., Shih, X., Wang, H., Reiner, M., & Page, J.H. (2016). Trajectory of absolute neutrophil counts in patients treated with pegfilgrastim on the day of chemotherapy versus the day after chemotherapy. Cancer Chemotherapy and Pharmacology, 77, 703–712. 

Study Purpose

To compare absolute neutrophil count (ANC) and febrile neutropenia (FN) in patients who receive pegfilgrastim on the same day of chemotherapy versus the next day

Intervention Characteristics/Basic Study Process

Data from a prior randomized, controlled trial was pooled for analysis. The trajectory of ANC and incidence of FN and related events were analyzed.

Sample Characteristics

  • N = 192   
  • MEAN AGE = 58.9 years (SD = 12.7)
  • MALES: 32.3%, FEMALES: 67.7%
  • CURRENT TREATMENT: Chemotherapy
  • KEY DISEASE CHARACTERISTICS: Multiple tumor types—most were breast, lung, and non-Hodgkin lymphoma
  • OTHER KEY SAMPLE CHARACTERISTICS: Sixty-two percent were at intermediate FN risk, and 38% were at high risk.

Setting

  • SITE: Multi-site   
  • SETTING TYPE: Not specified    
  • LOCATION: United States

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active antitumor treatment

Study Design

  • Secondary analysis of four phase-II, randomized, controlled trials

Measurement Instruments/Methods

  • Grade 3–4 FN defined at body temperature greater than or equal to 38.2 degrees Celsius, infection-related hospitalization, or infection related adverse event occurring within one day of grade 3–4 neutropenia
  • Common Terminology Criteria for Adverse Events (CTCAE) for neutropenia grade

Results

ANC at nadir was significantly lower in those who received same-day pegfilgrastim (p = 0.003). Time to nadir was slightly lower in those with same-day pegfilgrastim (p = 0.019). ANC at nadir was much lower among those who got same-day treatment (0.27 compared to 0.74 x 109/l, p < 0.001).  Risk of grade 4 neutropenia was higher among those who got same-day treatment (odds ratio [OR] = 0.23, 95% CI [0.1, 0.49]). No significant difference existed between groups in incidence of FN as defined for this pooled analysis; however, the actual incidence was lower among those who received next-day treatment. ANC recovery was faster in those who received next-day pegfilgrastim.

Conclusions

Patients who received pegfilgrastim the day after chemotherapy had less severe ANC suppression and more rapid ANC recovery. No clear differences in incidence of FN were reported.

Limitations

Initial trials were not designed to capture the incidence of FN and infections, so pooled analysis capability was limited.

Nursing Implications

This study adds to the body of evidence supporting the administration of pegfilgrastim as recommended, one to three days after chemotherapy.

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Weycker, D., Li, X., Figueredo, J., Barron, R., Tzivelekis, S., & Hagiwara, M. (2016). Risk of chemotherapy-induced febrile neutropenia in cancer patients receiving pegfilgrastim prophylaxis: Does timing of administration matter? Supportive Care in Cancer, 24, 2309–2316. 

Study Purpose

To evaluate the timing of pegfilgrastim administration

Intervention Characteristics/Basic Study Process

Data from two large claim systems repositories obtained from 2003 to 2011 were pooled for analysis. Patients included were adults receiving at least one course of chemotherapy for a solid tumor or non-Hodgkin lymphoma. Patients were identified as receiving intermediate or high-risk regimens, and pegfilgrastim use was determined using Healthcare Common Procedure Coding System (HCPCS) codes on claims with service dates up to three days after the last chemotherapy administration of a cycle. Patients were grouped based on whether pegfilgrastim was given on the same day as the last chemotherapy dose or on days 2–4 after chemotherapy. Chemotherapy cycles that used different colony-stimulating factors (CSFs) were excluded from the analysis. The analysis was done for all cases in the first cycle and for all febrile neutropenia (FN) episodes.

Sample Characteristics

  • N = 45, 592 patients–179, 152 chemotherapy cycles   
  • MEAN AGE = 55 years
  • MALES: 10.9%, FEMALES: 89.1%
  • CURRENT TREATMENT: Chemotherapy
  • KEY DISEASE CHARACTERISTICS: Seventy-eight percent had metastatic breast cancer.
  • OTHER KEY SAMPLE CHARACTERISTICS: Nine percent had cardiovascular comorbidities, and 11% had diabetes.

Setting

  • SITE: Multi-site   
  • SETTING TYPE: Other    
  • LOCATION: United States

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active antitumor treatment

Study Design

  • Retrospective cohort comparison

Measurement Instruments/Methods

  • FN episodes requiring inpatient care were determined based on admissions with a diagnosis of neutropenia, fever, or infection.
  • FN episodes in the outpatient setting were identified by any ambulatory encounter with a diagnosis of neutropenia, fever, or infection and a HCPCS code on the same day for the IV administration of an antibiotic. 
  • A narrower definition including only diagnoses of neutropenia and antibiotic administration was also evaluated.

Results

The study was shown to be sufficiently powered. Overall, FN occurred in 3.9% of those receiving same-day prophylaxis in the first cycle compared to 2.8% of those receiving pegfilgrastim on days 2–4 after chemotherapy (p < 0.001). Across all cycles, FN occurred in 2.5% of the same-day patients versus 1.9% of the prophylaxis patients on days 2–4 (p < 0.001). Overall, pegfilgrastim was given on the same day as the last chemotherapy dose in 12% of the cases.

Conclusions

The findings suggest that the timing of pegfilgrastim administration does matter, and that administration according to prescribing information is more effective than administration on the last day of the chemotherapy cycle.

Limitations

  • Risk of bias (no random assignment)
  • Measurement validity/reliability questionable
  • Reliance on claims data is known to be prone to errors
  • The definition of FN is somewhat questionable, as no specific diagnosis code exists for FN. The use of the combination of documented fever, use of antibiotics, etc., may not accurately represent clinical FN.

Nursing Implications

The findings suggest that the administration of pegfilgrastim according to the timing outlined in prescription information is more effective than administration on the last day of the chemotherapy cycle. While an additional patient visit for this injection may not be convenient, it is worth the reduction in risk for FN and attendant infectious complications. The findings point to the need for the development of practical alternatives to facilitate adherence to essential schedules, such as simple devices for patients to self-administer CSFs as needed, as is done with medications like insulin.

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