Comment and reply on: Pegfilgrastim is safe and effective in the prevention of neutropenia and treatment delays in biweekly regimens

Pegfilgrastim is regarded today as the standard therapy in the primary prophylaxis of febrile neutropenia induced by three-weekly chemotherapy regimens while its use with biweekly regimens is still controversial [1]. Pegfilgrastim clearance is mainly mediated by binding to granulocyte colony stimulating factor (G-CSF) receptors found on myeloid bone marrow elements and neutrophils and the recovery of neutrophils count to levels in excess of 1.000/ml is associated with subtherapeutic levels of pegfilgrastim [2]. Silvestris et al. confirmed that a single dose of pegfilgrastim in appropriate patients provides a more convenient and effective strategy for assisting neutrophil recovery [3].

Given these data, the authors designed a prospective study in which they administered one dose of pegfilgrastim (6 mg s.c. 48 h after treatment completion) to 20 consecutively enrolled patients affected by colorectal cancer (13), pancreas cancer (2), biliary tract cancer (2) and other type of cancers (3), who developed at least a grade 3 neutropenia during a biweekly regimen despite receiving filgrastim 30/0.6, 1 s.c. for 5 days. The study design was approved by internal ethical committee. Patients received Folfiri (7), Folfox (6), Folfoxiri (2) or other biweekly regimens (4). The basal value of white blood cells (WBCs) and polymorphonuclear leukocytes (PMNs) was recorded at days 14 and 28 as well as the incidence of treatment delays. The median basal value of WBCs and PMNs was 5.280/mmc (95% confidence interval (CI) 4.385 – 8.247) and 3.140/mmc (95% CI 2.183 – 5.820), respectively. After the chemotherapy cycle and the first pegfilgrastim injection, at day 14, median values were 6.400/mmc (95% CI 5.450 – 11.130) and 3.900/mmc (95% CI 3.294 – 8.283), respectively. At day 28, median values were 6.930/mmc (95% CI 6.154 – 9.779) and 4.760/mmc (95% CI 4.090 – 6.487), respectively. Interestingly, for both WBCs and PMNs the difference between the basal median value and day 14 median value was statistically significant (p = 0.034 and 0.036), while the difference between day 14 and 28 was not statistically significant (p = 0.56 and 0.39). No treatment delays were recorded. The principal side effect was bone pain, reported by eight patients (38%), mild in all cases (median visual-analog score (VAS): 5) and easily manageable with paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs).

The results, consistently with previous Phase II studies, confirmed the safety of pegfilgrastim in biweekly regimens and its efficacy in avoiding treatment delays [4,5]. The authors demonstrated how the increase in WBCs and PMNs levels, usually recorded after the first administration, is transient and settles with the second dose. On these bases, the authors believe that the use of pegfilgrastim in biweekly regimens should be considered. Further studies in larger cohort of patients are warranted.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.

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Author's reply

In their letter, the authors raised the point relating to the possible use of pegfilgrastim in biweekly regimens in a subset of patients who developed at least a grade 3 neutropenia despite daily use of filgrastim as secondary prophylaxis. According to granulopoiesis physiology, it is well established that pegfilgrastim should be administered 24 h after chemotherapy. The principal theoretical concern about its administration no sooner than 14 days before chemotherapy is based on the need to avoid ‘priming effect’ of G-CSF given before chemotherapy, since it renders the mitotic pool highly sensitive to cytotoxic drugs.

Data pooled from seven pegfilgrastim registrational clinical trials by Yang et al. considering patients affected by solid and hematological malignancies showed that serum concentrations of this drug were consistently cleared to subtherapeutic levels by 12 days after its administration [1]. Indeed, a single-institution Phase I trial to determine the feasibility of using filgrastim or pegfilgrastim to increase the dose intensity of biweekly docetaxel and gemcitabine in patients with metastatic solid tumors showed no significant differences in toxicity or effectiveness [2]. These data have been confirmed in several studies evaluating the administration of pegfilgrastim together with chemotherapy in patients receiving intensive chemotherapy regimens at 14 days intervals [3,4].

In conclusion, pegfilgrastim given 13 days before the next chemotherapy cycle may be substituted for daily G-CSF even if further studies are warranted.