Bokemeyer, C., Gascon, P., Aapro, M., Ludwig, H., Boccadoro, M., Denhaerynck, K., . . . MacDonald, K. (2017). Over- and under-prophylaxis for chemotherapy-induced (febrile) neutropenia relative to evidence-based guidelines is associated with differences in outcomes: Findings from the MONITOR-GCSF study. Supportive Care in Cancer, 25, 1819–1828.

This study used the amended EORTC algorithm (that classified patients based on prophylaxis intensity levels, for myelotoxic chemotherapy regimen and patient risk factors associated with CIN/FN) to explore the impact of prophylaxis intensity using biosimilar filgrastim comparing these outcomes with dosing for under, correctly, or over prophylaxis guideline-recommended levels.

This was a real-world observational study evaluating patients as they received myelosuppressive chemotherapy and CIN/FN prophylaxis with biosimilar filgrastim. The evaluation of data for the study stratified patients into groups with biosimilar GCSF by prophylaxis intensity levels (under, correctly, or over-prophylaxis). Patient outcomes were compared first on demographics and clinical status at the start of chemotherapy to identify prophylaxis patterns, clinical, and safety outcomes. Data for patient-level evaluations were collected as patients progressed through chemotherapy treatments to isolate outcomes experienced at any time during the whole period of chemotherapy. The study collected ongoing data for a cycle-level analyses to evaluate outcomes during a particular cycle and from one cycle to the next, to evaluate outcomes as patients progressed through their cycles of chemotherapy. 

Of note: 

• Sample groups had different types of prophylaxis (primary/secondary) and time to initiation of biosimilar GCSF for prophylaxes 
• 100% under-prophylacted received secondary prophylaxis, 92.4% correctly prophylacted received primary prophylaxis, 76.6% over-prophylacted given primary, and 23.4% secondary prophylaxis 
• Mean day of initiation biosimilar GCSF different for groups: 2.7 over, 2.99 for under, and 3.26 mean days for correctly prophylacted
• 19.5% over-prophylacted initiated on day one after chemotherapy; 12.1% under-prophylacted initiated on day one after chemotherapy; 11.2% initiated on day one after chemotherapy for correctly-prophylacted
• Median prophylaxis duration same for all cohorts; mean duration of prophylaxis shortest for over-prophylacted

• N = 1,444  (251 under-prophylacted; 817 correct prophylacted; 376 over-prophylacted)
• AGE: 61.56  (65.2 under-prophylaxes; 61.8 correct prophylaxes; 57.7 over-prophylaxes averaged)
• MALES: 40% (45.0% under-prophylaxes; 37.2% correct prophylaxes; 37.8% over-prophylaxes averaged)  
• FEMALES: 60% (55% under-prophylaxes; 62.8% correct prophylaxes; 62.2% over-prophylaxes averaged)
• CURRENT TREATMENT: Chemotherapy, combination radiation, and chemotherapy
• KEY DISEASE CHARACTERISTICS: Adults (aged 18 years or older) stages III or IV breast, ovarian, bladder, or lung cancer; metastatic prostate cancer; stage III or IV diffuse large B cell lymphoma or multiple myeloma
• OTHER KEY SAMPLE CHARACTERISTICS: Patients were treated with myelosuppressive chemotherapy for up to six cycles receiving biosimilar filgrastim GCSF prophylaxis; cohort groups had baseline differences for age, FN risk factors; advanced disease, Hx of FN, ECOG performance status, poor nutritional status, HGB less than 12, presence of renal, CV, or liver disease, prior chemotherapy, presence of renal cardiovascular or liver disease, prior treatments, chemotoxicity

• SITE: Multi-site   
• SETTING TYPE: Inpatient    
• LOCATION: 140 cancers centers in 12 European countries

• PHASE OF CARE: Active anti-tumor treatment
• APPLICATIONS: Elder care, palliative care

Non-experimental prospective longitudinal observational cohort study (real-world observational study)

Chemotherapy associated FN risk was established using an author developed tool, Patient Risk Score (PRS), for a weighted sum of eight patient risk factors associated with CIN/FN specified in EORTC guidelines; prophylaxis patterns collected for GCSF decisions for primary or secondary prophylaxis and duration of prophylaxis; CIN/FN prior cycle; ECOG performance status; history of repeated infections; cancer tumor type, prior treatments chemotherapy/radiation therapy; and chemotoxicity. Data was collected (patient and cycle levels) for number  of episodes of CIN and grade (CIN1/4), number of episodes of FN; number of episodes of CIN/FN related to a hospitalization or chemotherapy disturbance (dose reduction, delay in administration of chemotherapy, cancellation of administration of chemotherapy); and a (worst-case) composite index of occurrence for any of the previous outcomes.

Different rates of CIN, grades 1-4, and CIN/FN-related hospitalization (all p ≤ 0.001)

There was no significant difference for proportions of patients with CIN/FN chemotherapy disturbances. 

The proportion of cycles of chemotherapy interruptions due to CIN/FN was significantly higher for under prophylaxes (p = 0.32) 

Patient level pairwise analysis: No difference between groups for the likelihood of CIN/FN. 

• Over-prophylacted less likely for ever experiencing compared to correctly prophylacted during chemotherapy; CIN/FN (all p ≤ 0.001) or in any given cycle (p < 0.001 for CIN, p = 0.004 for FN) 
• Under-prophylacted CIN more likely (p = 0.044) FN (p ≤ 0.001) at any time during chemotherapy 

Cycle-level pairwise analysis: likelihood of CIN/FN in any one cycle between under and correctly prophylacted no significant difference

• Over-prophylacted significantly less likely than correctly prophylacted for CIN/FN in any one cycle (p < 0.001 for all CIN, p = 0.004 for FN)
• Under-prophylacted more likely for CIN/FN in any one cycle compared to over-prophylacted (p = 0.025 to p < 0.001)
• In patients over-prophylacted, rates of chemotherapy-induced neutropenia (CIN) (all grades), FN, and CIN-related hospitalizations were consistently lower compared to under- and correctly prophylacted

Patients CIN/no GCSF safety differences between groups (except for headaches, p = 0.027, correct and over had higher percentage compared to under)

Comparing biosimilar GCSF prophylaxis intensity groups (under, correct, and over-prophylacted), GCSF support at levels above current guideline recommendations may reduce CIN, FN, and CIN/FN-related hospitalization. Patients who are under-prophylacted with biosimilar GCSF are at higher risk for disturbances to their chemotherapy regimens.

• Baseline sample/group differences of import        
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Risk of bias (no appropriate attentional control condition)
• Risk of bias (sample characteristics)
• Unintended interventions or applicable interventions not described that would influence results
• Key sample group differences that could influence results
• Measurement validity/reliability questionable
• Use on non-validated PRS tool developed by authors
• Findings not generalizable
• Other limitations/explanation: Cycle data were nested under patients and patients under centers, violating the assumption of statistical independence; statistical adjustments were required; there were more under-prophylaxes patients aged 65 and older who also had a history of FN, a Hb less than 12 g/dl, and renal, cardiovascular, or liver disease; the study design was not an experimental/RCT design, limiting its rigor and control for bias; issues concerning reliability and intervention fidelity, reduced rigor for internal and external validity; no effect sizes reported

Oncology nurses must evaluate patients for CIN/FN risk each cycle and adhere to current guideline recommendations for CIN/FN prophylaxis with GCSF to reduce risk of CIN/FN and chemotherapy interruptions. Large RCTs are necessary to evaluate if changing current recommended GCSF dosing schedule improves patient-related outcomes, to evaluate patient risk stratification and potential side effects of a different dosing schedule.