CIFN remains one of the serious adverse events of chemotherapeutic agents which is associated with significant morbidity and mortality. In Singapore surveys, the mortality in post chemotherapy FN ranged between 3% and 8.8%. [10]. Others have reported a hospitalization rate of 35% and mortality ranging from 2.6–22.4% depending on coexisting morbidities. (8,9, 10)
Primary prophylaxis has the potential to improve morbidity and even mortality.In geriatric cancer patients (≥ 65 years old), retrospective, observational cohort study for patients who had chemotherapy and primary prophylaxis using G-CSF from January 2008 to August 2011 concluded that FN is prevalent among geriatric cancer patients receiving adjuvant chemotherapy despite G-CSF support especially with comorbidities.
The median overall survival (OS) rate was 6-12-months, and hazard ratios [HRs; unadjusted Cox model with 95% confidence intervals (CIs)] were estimated for patients receiving ≥ 1 dose of filgrastim, Pegfilgrastim, or placebo. (11)
Comparisons were based on a log-rank test. A fixed-effect meta-analysis Filgrastim/Pegfilgrastim on OS in patients with lung cancer, the medium OS was 14.1 versus 11.1 months in patients receiving filgrastim (HR, 0.81; 95% CI 0.48–1.35; P = 0.412). (12)
Another meta-analysis result of 148 trials of primary CSF prophylaxis in patients with cancer also showed a significant decrease in the rates of documented neutropenic fever and infection. (4)
A different meta-analysis including 61 randomized controlled trials (RCTs) comparing chemotherapy with or without G-CSFs supportive therapy and reporting all-cause mortality with at least two years was significantly reduced. (relative risk [RR] 0.93, 95% CI 0.90–0.96). (13)
These data led to widespread exponential use of G-CSFs in the management of neutropenic complications. However, these medications are not without their own side-effects and also add significantly to cost of care if used inappropriately. (14)
Guidelines have been developed and updated periodically to optimize the use of G-CSFS based on evidence. These guidelines have been adapted by different practices to optimize the use of growth factors. Limited real world data address the inappropriate/overuse of these medications after implementing and adapting the guidelines by many practices.
Over and underutilization is common. Our study mainly addressed the overutilization of G-CSFs. The study confirmed G-CSFs are being over utilized in patients with solid tumors undergoing chemotherapy; in all clinical settings.
There was 51% compliance with prescribing of G-CSFs according to the ASCO guidelines for primary/secondary prophylaxis and therapy of FN. In other words, 49% (47%, 50% and 40%) of G-CSFs use was inappropriate as per ASCO guidelines according to the three indications. The study confirmed G-CSFs are being over utilized in patients with solid tumors undergoing chemotherapy in all clinical settings.
In primary prophylaxis, careful assessment of neutropenia risk can lead to avoidance of use G-CSF use in low risk and intermediate risk individuals with no comorbidities as per ASCO guidelines.
The MONITOR-GCSF, observational study of 1447 evaluable patients from 140 cancers centers in 12 European countries treated with myelosuppressive chemotherapy. Patients were under- (17.4%), correctly- (56.6%), or over-prophylactic (26.0%) of patients. (15)
With regards to secondary prophylaxis, we found inappropriate use is common. In a polish study this was also highlighted despite the knowledge among oncologists about the indication highlighting the need to adhere to guidelines. (16)
Alternative options to secondary prophylaxis, include options like dose reductions can potentially reduce the inappropriate utilization.
Our study indicates that overuse of G-CSFs is common in the setting of FN. G-CSFs was administered in 10 patients in our study due to chemotherapy-induced neutropenia; 6 (60%) of them inappropriately. These patients were stable and did not require addition of growth factors. Although the numbers were small however there is a low threshold for potential inappropriate use of G-CSFs in this setting as well. For treatment of neutropenia in solid cancer patients who received chemotherapy. Filgrastim is considered appropriate in the presence of severe neutropenic symptoms or in case of hypotension or multi-organ failure.
Previous studies showed that approximately 60%-65% of G-CSFs complied with prescribing guidelines for primary and secondary prophylaxis and management of Complicated FN. (17)
According to ASCO guideline, G-CSFS injection should continue until the neutrophil count has recovered to > 1000 cells/mm3 on two consecutive days. In our study, the average use of G-CSFs was 5 days and was not guided by neutrophils counts in most cases. The duration was not an issue for pegfilgrastim as it is used as a single dose. [6
Our study has several limitations. It was a retrospective review and patient included were those that already received growth factors. This potentially can impact on the underutilization or inappropriate omission of the growth factors in primary prophylaxis secondary of febrile neutropenia setting. This might have an impact of overall appropriate utilization of growth factors.
Our study also has a smaller number of patients included in the use of chemotherapy for curative intent and this can be partially explained by the study being carried in a tertiary care center that receives patient who have failed first- and second-line therapies at other centers. The study also had an abundance of breast cancer and colorectal cancers and this merely reflects the most common cancers seen in the studied population therefore, in a different practice these numbers may be different and therefore our results cannot be generalized to all community practices. Our study is also limited by the fact that it was a retrospective study, carried out at one institution. Other guidelines like EORTC and European guidelines exists and in our study ASCO guidelines was sued as a reference. The impact of under, over and appropriate utilizations remains a subject of debate.