Aapro, M.S., Cameron, D.A., Pettengell, R., Bohlius, J., Crawford, J., Ellis, M., . . . Zielinski, C. (2006). EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. European Journal of Cancer, 42, 2433–2453.

PURPOSE: To evaluate the use of granulocyte-colony stimulating factor (G-CSF) in adult patients receiving chemotherapy for cancer

TYPES OF PATIENTS ADDRESSED: Adult patients receiving chemotherapy for cancer

PROCESS OF DEVELOPMENT:

The following questions were applied by the European Organisation for Research and Treatment of Cancer (EORTC) G-CSF Guidelines Working Party.

In adult patients with cancer receiving chemotherapy:

1. Is there evidence that patient-related factors increase the risk of febrile neutropenia (FN)?
2. Is there evidence that certain chemotherapy regimens increase the risk of FN?
3. Is there evidence that some patients are more at risk for severe morbidity as a result of an FN episode?
4. Is there evidence to support the use of G-CSF when there is a 20% risk level for FN?
5. Is there evidence to support the use of G-CSF to
   1. Maintain the correct dose of chemotherapy and relative dose intensity and density?
   2. Improve overall and progression-free survival?
6. Is there evidence to support the use of G-CSF to enable the delivery of dose-dense and -intense chemotherapy
   1. By increasing the dose?
   2. By withdrawing one drug and increasing the dose of the remaining drugs?
   3. By increasing the dose frequency?
7. Is there evidence to support the use of G-CSF to reduce the risk of infection-related mortality?
8. Is there evidence to support the use of G-CSF to reduce the incidence of FN?
9. Is there evidence to support the use of G-CSF for the treatment of ongoing FN?
10. Is there evidence to support the use of different G-CSFs?

The article describes guidelines prepared by the G-CSF Guidelines Working Party of the EORTC to systematically review available published data and derive evidence-based recommendations on the appropriate use of G-CSF in adult patients receiving chemotherapy for cancer.

The following are levels of evidence applied by the EORTC G-CSF Guidelines Working Party.

• Level I: Evidence obtained from meta-analysis of multiple, well-designed, controlled studies or from high-power randomized, controlled clinical trial
• Level II: Evidence obtained from at least one well-designed experimental study or low-power randomized, controlled clinical trial
• Level III: Evidence obtained from well-designed, quasi-experimental studies such as nonrandomized, controlled single-group, pre-post, cohort, time, or matched case-control series
• Level IV: Evidence obtained from well-designed, non-experimental studies such as comparative and correlational descriptive and case studies
• Level V: Evidence obtained from case reports and clinical examples

The following grades of recommendations were applied by the EORTC G-CSF Guidelines Working Party.

• Grade A: There is evidence of type I or consistent findings from multiple studies of types II, III, or IV.
• Grade B: There is evidence of types II, III, or IV, and findings are generally consistent.
• Grade C: There is evidence of types II, III, or IV, but findings are inconsistent.
• Grade D: There is little or no systematic empirical evidence.

DATABASES USED: MEDLINE, PreMEDLINE, EMBASE, and the Cochrane Library.

INCLUSION CRITERIA: Articles selected were published in English from December 31, 1994–September 16, 2005. Reference lists of the identified meta-analyses were interrogated manually, and any primary papers considered relevant were included. Abstract books from key international congresses were searched manually to identify relevant evidence presented at meetings from 2003–2005.

EXCLUSION CRITERIA: Studies involving children younger than 18 years of age or patients with leukemia were excluded, as were cost analyses, as these lack international applicability. Relevant articles “in press” and additional papers identified by members of the working party were included in limited instances.

Recommendation 1: Patient-related risk factors for increased incidence of FN

• Patient-related risk factors should be evaluated in the overall assessment of FN risk prior to each cycle of chemotherapy. Particular consideration should be given to the elevated risk of FN for patients aged 65 years or older. Other adverse risk factors that may influence FN risk based on level I and II evidence included advanced stage of disease, experience of previous episode(s) of FN, and lack of G-CSF use and antibiotic prophylaxis. However, please note that the indiscriminate use of antibiotic prophylaxis is not recommended by either the Working Party or the EORTC Infectious Disease Group. Risk factors that may influence FN risk based on level III and IV evidence included poor performance and/or nutritional status, female gender, hemoglobin less than 12 g/dl, and liver, renal, or cardiovascular disease.
• Recommendation grade B

Recommendation 2: Chemotherapy regimens associated with increased risk of FN

• Consideration should be given to the elevated risk of FN with certain chemotherapy regimens. The risk of FN for certain chemotherapy regimens is summarized in Table 4 of the original paper.
• Recommendation grade A/B (depending on the evidence for each chemotherapy regimen)

Recommendation 3: G-CSF to support chemotherapy

• In situations in which dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF should be used as a supportive treatment. If reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis should be used to maintain chemotherapy. Examples of this could be when the patient is receiving adjuvant or potentially curative treatment, or when the treatment intent is to prolong survival. When this is not crucial, use of less myelosuppressive chemotherapy or dose and schedule modifications should be considered.
• Recommendation grade A

Recommendation 4: Impact of the overall FN risk on G-CSF use

• The risk of complications related to FN should be assessed individually for each patient. When assessing FN risk, the clinician should take into account patient-related risk factors, the chemotherapy regimen and associated complications, and treatment intent. If the patient is at more than 20% overall risk of FN, prophylactic G-CSF is recommended. With chemotherapy regimens associated with an FN risk of 10%–20%, particular attention should be given to the assessment of patient characteristics that may increase the overall risk of FN.
• Recommendation grade A

Recommendation 5: G-CSF in patients with existing FN

• Treatment with G-CSF for patients with solid tumors and ongoing FN is indicated only in special situations. These are limited to those patients who are not responding to appropriate antibiotic management and who are developing life-threatening infections (e.g., severe sepsis, septic shock).
• Recommendation grade B

Recommendation 6: Choice of formulation

• Filgrastim, lenograstim, and pegfilgrastim have clinical efficacy, and the authors recommend the use of any of these agents to prevent FN and FN-related complications, where indicated.
• Recommendation grade A