STUDY PURPOSE: To provide a detailed assessment of the efficacy and toxicity of regimens based on rolapitant in the prophylaxis of chemotherapy-induced nausea and vomiting (CINV)

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 4 
• TOTAL PATIENTS INCLUDED IN REVIEW = 2,856
• SAMPLE RANGE ACROSS STUDIES: 454–1,332 patients
• KEY SAMPLE CHARACTERISTICS: Three studies included patients taking highly emetogenic chemotherapy, one study included patients administered moderately emetogenic chemotherapy. Patients ethnicities are unknown.

PHASE OF CARE: Active antitumor treatment

The pooled RR for the complete response (CR) was 1.23 (95% CI [1.18, 1.33], p < 0.00001) in the overall phase, 1.12 (95% CI [1.02, 1.24], p = 0.02) in the acute phase, and 1.19 (95% CI [1.13, 1.26], p < 0.00001) in the delayed phase. The pooled RR for no significant nausea in the overall phase was 1.17 (95% CI [1.04, 1.32], p = 0.008), and the pooled RR for no emesis in the overall phase was 1.24 (95% CI [1.18, 1.31], p < 0.00001). The efficacy analyses demonstated that rolapitant-based regimens are associated with higher rates of CR (both in overall, acute, and delayed phases). No significant nausea was present and no emesis was present compared with control regimens in highly and moderately emetogenic chemotherapy. The pooled RR of all grade constipation was 1 (95% CI [0.55, 1.82], p = 0.61), and the pooled RR of all grade headache was 1.05 (95% CI [0.57, 1.96], p = 0.87). Therefore, rolapitant-based regimens are not associated with an increased RR for constipation or headache compared with antiemetic control regimens.

This analysis demonstrated that rolapitant-based regimens are associated with higher rates of CR, no significant nausea, and no emesis compared with control regimens in highly and moderately emetogenic chemotherapy. In addition, no increased risk of toxicity with constipation or headache exists when compared with standard antiemetic control regimens. The authors concluded that rolapitant is a valid addition to other available standard antiemetic regimens for highly and moderately antiemetic chemotherapy.

• Limited number of studies included
• Low sample sizes
• Limited information on patient age, sex, diagnosis, and treatment regimens

Rolapitant is associated with higher CR rates, no significant nausea, and no emesis compared to other control regimens in highly and moderately emetogenic chemotherapy without increased toxicity. Rolapitant should be a recommended addition to control regimens that do not include a neurokinin inhibitor.

To assess the efficacy of available strategies to reduce the risk and severity of leg lymphedema

Databases searched were MEDLINE (from January 1966 to April 2009), EMBASE (from January 1980 to April 2009), and the Cochrane Colorectal Cancer Group Specialized Register (January 2009).

Search keywords were inguinal node dissection, lymphedema, malignant melanoma, squamous cell carcinoma, saphenous vein, prevention, and combinations of these words.

Studies were included in the review if they

• Evaluated patients who underwent inguinal node dissection for metastatic malignant disease from the genitalia, lower trunk, or lower limbs.
• Used a comparison group (control) derived from the same population of patients who suffered the same condition.
• Included a cohort of patients with matching demographics, gender, comorbidities, and other forms of treatment, such as radiation therapy.
• Used the same surgical technique for prevention of lymphedema and other complications.
• Included a sufficient follow-up period to evaluate the development of chronic complications.
• Lymphedema has been defined clearly based on limb girth measurements.

The authors did not list the exclusion criteria. However, in the results section, the authors mentioned that two studies were excluded from the meta-analysis because they did not focus on the effect of saphenous vein preservation.

Suitable studies were assessed using the Newcastle-Ottawa scale for evaluation of the quality of nonrandomized cohort studies. This scale uses a star system for evaluation of nonrandomized studies. The grading is based on three criteria: patient selection, comparability of study groups, and outcome assessment. The analysis included studies that scored 6 stars or higher and were considered suitable for inclusion in the meta-analysis. The total number of studies initially reviewed was 14. Of these, 12 were included in the report and 4 in the meta-analysis.

Meta-analysis was conducted with the studies that reported on saphenous vein preservation. The rest were individual reports and were not pooled. The primary outcome was the rates of leg lymphedema. Other outcomes, such as cellulitis, flap necrosis, lymphocele, the number of harvested nodes, and rate of cancer recurrence, were considered secondary endpoints. Studies deemed suitable according to the Newcastle-Ottawa scale were pooled, and the data was entered in ‘‘Metaview’’, which is used by the Cochrane methods for systematic reviews. All of the results were analyzed as dichotomous variables. Statistical heterogeneity in the results of the meta-analysis was assessed by graphical presentations of the confidence intervals (CI) on forest plots and by performing a χ2 test for heterogeneity, in which p = 0.1 was regarded as significant heterogeneity.

Data were analyzed using a random effect model and expressed in odds ratios and a Forest plot. Heterogeneity among the included studies was tested using the Cochrane Q test, with p values < 0.01 to ensure that odd ratios from separate studies were homogenously distributed. A funnel plot then was constructed to visually test for the presence of publication bias.

• The total sample size included in the meta-analysis was 262.
• Sample ranges across all studies in the meta-analysis was 10–139.
• Sample characteristics of the studies in the meta-analysis were patients with vulval malignancies, inguinal lymphadenectomy, and saphenous vein preserved or sacrificed.

The search result defined few studies that reported results of saphenous vein sparing technique; some of those studies were found suitable for meta-analysis based on the Newcastle-Ottawa scale for nonrandomized studies. The meta-analysis showed significant reduction of lymphedema (odds ratio 0.24; 95% CI, 0.11–0.53) and other complications of inguinal node dissection. No randomized studies addressed this problem. Isolated studies reported on the benefits of other techniques, but none of them was suitable for meta-analysis.

Meta-analysis of the reported studies on sparing the long saphenous vein in inguinal node dissection suggests a reduced rate of lymphedema and other postoperative complications.

Other methods that may be beneficial are fascia preserving dissection, pedicledomental flap, and microsurgery. Sartorius transposition has not been shown to reduce the rate of complications. Randomized controlled trials are needed to prove the benefits of various technical modifications.

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

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.

• 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.

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

• PHASE OF CARE: Active antitumor treatment

• Randomized, parallel-group, noninferiority trial

• Blood cell counts

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.

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

• Risk of bias (no blinding)

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.

To compare the efficacy and safety of netupitant plus palonosetron (NEPA) compared to palonosetron alone in preventing chemotherapy-induced nausea and vomiting (CINV)

Chemotherapy-naïve patients receiving anthracycline- or cyclophosphamide-based chemotherapy were randomized to receive a single dose of PO NEPA (300 mg netupitant plus 0.50 mg palonosetron) and 12 mg dexamethasone or a single dose of 0.5 mg PO palonosetron and 20 mg dexamethasone on day 1, cycle 1, of their chemotherapy. Delayed (25-120 hours post chemotherapy) CINV was evaluated as the primary end point.

• N = 1,455 (participated in a total of 5,969 chemotherapy cycle extension)   
• MEDIAN AGE = 54 years
• MALES: 2%, FEMALES: 98%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Solid tumor cancer, 98% with breast cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Aged older than 18 years; chemotherapy-naïve; anthracycline- or cyclophosphamide-based chemotherapy; European Cooperative Oncology Group (ECOG) score of 0, 1, or 2; not receiving prolonged chemotherapy from day 1-5; not receiving abdominal radiotherapy; no bone marrow transplantation; did not received any antiemetics 24 hours before chemotherapy and did not experience anticipatory nausea and vomiting

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

PHASE OF CARE: Active antitumor treatment

Double-blind, randomized

• Diary: Emesis episodes and rescue medications used from 0-120 hour each cycle
• Visual analog scale (VAS) for nausea from 0 (no nausea) to 100 (nausea as bad as it could be)
• Proportion of patients with complete response (0-120 hours)
• Review treatment emergent adverse effects, ECG, troponin levels

Participants who received NEPA and dexamethasone reported complete remission (no emesis or rescue antiemetics) significantly more than participants who received palonosetron and dexamethasone (p ≤ 0.001).

NEPA and dexamethasone may offer more control over CINV compared to palonosetron and dexamethasone.

• Measurement validity/reliability questionable
• Using VAS for nausea and vomiting

Combination antiemetic therapies have been shown to provide more relief from CINV compared to single agents. The results of this study demonstrated that NEPA given with dexamethasone did prevent CINV better than palonosetron and dexamethasone.

To compare two treatments (palonosetron plus dexamethasone for 1 day with or without dexamethasone on days 2 and 3) for the management of chemotherapy-induced nausea and vomiting (CINV) in the overall study period (days 1–5) and to show comparison between the two treatments in complete response (CR) rates

• At the first cycle of chemotherapy, patients were randomly assigned to receive one of two treatment regimens. Group one received 0.25 mg palonosetron plus 8 mg IV dexamethasone on day 1 and placebo on days 2 and 3, and group two received 0.25 mg palonosetron plus 8 mg dexamethasone on day 1 and 4 mg oral dexamethasone twice a day on days 2 and 3.
• Patients recorded emetic episodes, use of rescue medication, and daily nausea ratings of nausea in diaries.
• Patients were allowed to take rescue medication, and the choice of rescue medication was at the discretion of the individual physician, except that no phenothiazines were allowed.

• The study consisted of 300 participants.
• Mean age was 51.6 years old (SD = 10.11 years).
• The sample was 100% female.
• Participants were chemotherapy-naïve patients with breast cancer receiving moderately emetogenic chemotherapy (MEC).

The study was conducted at multiple outpatient settings in Austria, Germany, Italy, and Spain.

This was a double-blind, randomized, controlled study.

• Patients used diaries to record date and time of emetic episodes, use of rescue medication, daily nausea ratings on a 0-10 visual analogue scale (VAS). 
• CR rate, defined as no emesis and no rescue medication during overall period (days 1–5), was recorded for acute phase (day 1) and delayed periods (days 2–5).
• Maximum severity of nausea (MSN) was recorded in daily and overall phases.
• Time-to-treatment failure (time to first emetic episode or time to first use of rescue medication) was recorded.
• Functional Living Index—Emesis (FLIE) was used in the screening phase and on day 6.
• Adverse events were recorded.

• More than 70% of patients had no emesis.
• CR was not significantly different in the overall, acute, and delayed phases between study groups. However on day 3, patients who received palonosetron plus dexamethasone on days 1–3 experienced less emesis (p = 0.004) and lower MSN (p = 0.028).
• Time-to-treatment failure and use of rescue medication was similar between groups.
• FLIE score and percentage of adverse events was not significantly different between groups.

• The palonosetron with single-day dexamethasone dosing regimen offered high and similar protection as palonosetron with 3-day dosing of dexamethasone in terms of CR rates and patient performance.
• In some cases, the protection was insufficient on day 3, and the benefits of dexamethasone needed to be weighed against the increased risk of potential side effects.

• The sample was only women who were chemotherapy naïve receiving MEC regimens. These findings may not be generalizable to other groups, particularly as some research has shown differences in antiemetic results between men and women.
• Patient compliance with daily diary recordings was not discussed.

• With chemotherapy-naïve patients with breast cancer receiving chemotherapy, palonosetron plus dexamethasone provides fairly good control over CINV.
• In patients whose antiemetic-related side effects have been bothersome, a palonosetron plus single-dose dexamethasone regimen could be an option.
• In both groups, more than half of patients still had nausea on day 1 and about one-third still had nausea in the delayed period, pointing to the need for individualization of ongoing management.

To determine if the granulocyte–colony-stimulating factor (G-CSF) biosimilar filgrastim had similar outcomes for adults and older adult patients actively undergoing treatment for cancer

This was a prospective observational study of patients prescribed biosimilar filgrastim in 140 centers in 12 European countries.

• N = 1,447 patients; 41% were older than age 65 years (cut-off at age 65 years) and put into the older adult category   
• AGE = Adults aged 18 years or older
• MALES: 49.8% older adult, 31% adult
• FEMALES: 50.2% older adult, 69% adult
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Stage III–IV breast, ovarian, bladder, and lung cancer; metastatic prostate cancer as well as stage III–IV large B-cell lymphoma and multiple myeloma

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: 12 European countries

• PHASE OF CARE:  Active antitumor treatment
• APPLICATIONS: Elder care

Prospective observational

Comparative analysis of various components outlined by the authors

No statistically significant differences existed in the rates of chemotherapy-induced neutropenia and febrile neutropenia episodes between either groups. G-CSF support is equally important in both groups. Older adult patients with underlying chronic conditions may be at higher risk for febrile neutropenia; in both groups, it is important to provide timely prophylaxis.

Timely G-CSF support is important in both older adult and adult patients receiving myelotoxic chemotherapy.

Nurses need to be aware of G-CSF administration for patients after chemotherapy. Independent of age group, it is important that patients receiving specific regimens get timely G-CSF treatment to prevent neutropenia duration.

The purpose of this article was to update existing guidelines for prophylactic granulocytye–colony-stimulating factor (G-CSF). The article focuses on patients receiving chemotherapy, not limited to one definition of febrile neutropenia (FN). No studies with pediatric patients or patients with leukemia were included.

This guideline resource used a process where articles were rated using the table listing below.

Level                Type of Evidence
A                        Evidence of type I or consistent findings from multiple studies of types II, III, or IV
B                       Evidence of types Ii, II, or IV and findings are generally consistent
C                       Evidence of types Ii, II, or IV, but findings are inconsistent
D                       Little or no systematic empirical evidence 

Information from papers included in meta-analyses were only used to answer questions not included in the meta-analyses. Publications available from Congress presentations previously included as abstracts were only used is they provided answers not yet presented. Authors were contacted if their abstracts were relevant and publications noted as missing or “in press” were included.

Regarding a search strategy, the MEDLINE, PreMEDLINE, EMBASE, and Cochrane Library databases were used.

Key words included antineoplastic agents, filgrastim, granulocyte–colony-stimulating factor, lenograstim, neoplasms, neutropenia, pegfilgrastim, and guideline

Articles were included if they were recent reviews, any primary papers deemed relevant, and meta-analyses subject to manual review. In addition to filgrastim and pegfilgrastim, two filgrastim biosimilar molicules, XMO2 and EP2006, daily G-CSFs have been approved in Europe. 

Articles were excluded if their studies included patients younger than age 18 years or patients with a diagnosis of leukemia.
 

• The phase of care is active chemotherapy treatment
• Applications is adult patients receiving chemotherapy.
   

Recommendations  Primary prophylactic G-CSF is recommended for patients at risk and should be started 24–72 hours following completion of the first cycle.

Step I:

• Assess frequency of FN associated with planned chemotherapy regimen, and reassess with each cycle.
• If FN risk is less than10%, G-CSF prophylaxis is not recommended. If FN risk is greater than 20%, prophylactic G-CSF is recommended.
• If FN risk 10%–20%,  proceed to step 2.

Step 2: 

• Assess for high risk: age older than 65 years.  
• Increased risk (level I, II evidence): Advanced disease, history of prior FN, no antibiotic prophylaxis, no G-CSF use
• Other factors (level III, IV evidence): Poor performance/nutritional status, female, Hgb < 12 g/dl, liver, renal, cardiovascular disease
• and then proceed to step 3

Step 3: 

• Define the patient’s overall FN risk for planned chemotherapy regimen.
• If overall FN risk is greater than 20%
• Secondary prophylaxis: Start G-CSF if neutropenic event occurred in previous cycle.

Provides percent risk for development of FN for some tumor types based on chemotherapy regimen. Identifies additional risk factors, but provides little guidance on how to use these to calculate an increase in risk that would warrant prophylactic G-CSF.
 

The article included results from an updated literature search to identify patient and chemotherapy regimen risk factors for developing FN, use of prophylactic G-CSF, G-CSF with existing FN, impact of overall FN risk on G-CSF use, and choice of G-CSF formulation. It was difficult to identify new information as recommendations were combined with existing recommendations.

To evaluate the safety and efficacy of palonosetron at two different doses (0.25 mg versus 0.75 mg) compared with a single dose of 32 mg ondansetron in preventing chemotherapy-induced nausea and vomiting (CINV) after highly-emetogenic chemotherapy

Patients were assigned to one of three treatment arms: palonosetron 0.25 mg, palonosetron 0.75 mg, and ondansetron 32 mg.

The  study consisted of 673 patients, and final data were reported on 667 patients.

This was a phase III, multinational, randomized, double-blind, double-dummy, stratified, parallel-group, active-comparator trial.

• Patient diaries were used to record emetic episodes, nausea, and use of rescue medications.
• The Functional Living Index-Emesis (FLIE) was used.

Equal results were reported for palonosetron and ondansetron in the first 24 hours. In the delayed and overall phases, palonosetron (regardless of dose) was associated with higher complete response (CR) rates compared with ondansetron.

To evaluate the safety and efficacy of NEPA (a combination of netupitant plus palonosetron) compared to palonosetron (PALO) alone

During cycle 1 of moderately emetogenic chemotherapy, patients received either a single dose of NEPA (a combination of 300 mg netupitant and 0.50 mg palonosetron) plus 12 mg dexamethasone, or a single dose of 0.50 mg palonosetron (PALO) plus 20 mg dexamethasone. Patients were randomized and stratified by region. Matching placebos were used for blinding in all groups. Metoclopramide tablets were provided for breakthrough, though treating physicians could select another medication. Data were collected daily on days 1–6 after chemotherapy (0–120 hours).

• N = 1449  
• MEDIAN AGE = 54 years
• MALES: 1.9%, FEMALES: 98.1%
• KEY DISEASE CHARACTERISTICS: Primarily breast cancer (97.5%)
• OTHER KEY SAMPLE CHARACTERISTICS: Chemotherapy-naïve patients receiving moderately emetogenic chemotherapy with an ECOG performance status ≤ 2

• SITE: Multi-site    
• SETTING TYPE: Not specified    
• LOCATION: Multinational

PHASE OF CARE: Active antitumor treatment

Phase 3 trial, multicenter, randomized, double-blind, double-dummy, parallel group design

• Patient diary (timing and duration of emetic episode, severity of nausea, rescue medications needed)
• Visual analog scale (VAS) of pain
• The Functional Living Index-Emesis (FLIE) 
• Primary endpoint: Complete response (CR)

A significant number of patients in the NEPA group achieved CR when compared to patients in the PALO group overall (p = 0.001), in the delayed phase of treatment (p = 0.001), and during the acute phase of treatment (p = 0.047).

NEPA, the combination of netupitant and palonosetron, was demonstrated to be safe and more effective than palonosetron alone in producing CR during the acute, delayed, and overall phases of treatment in patients receiving cycle 1 of moderately emetogenic therapy.

• Risk of bias (sample characteristics)
• Other limitations/explanation: More than 98% of the participants in the study were women. Of those, more than 97% were diagnosed with breast cancer.

Chemotherapy-induced nausea and vomiting (CINV) guidelines recommend antiemetic therapies targeting multiple pathways involved in emesis. NEPA, the novel combination of netupitant and palonosetron, uses an NK1 receptor antagonist and a 5-HT3 receptor antagonist to maximize CINV control. NEPA was shown to be more effective than palonosetron alone in producing CR during the acute, delayed, and overall phases of cycle 1 of moderately emetogenic therapy. The majority of this sample, however, were women diagnosed with breast cancer. The findings may not be generalizable to males or to other types of cancer.

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