The risk of febrile neutropenia (FN) in cancer patients receiving chemotherapy is mainly due to the type of chemotherapy regimen and the presence of specific risk factors in patients. The recent trend of using a dose-dense treatment schedule has enhanced the risk of FN. In the present prospective study, we evaluated the feasibility of a reduction of duration of therapy with colony-stimulating factor (G-CSF) in a dose-dense regimen.
Between June 2002 and December 2011, 107 patients with a new diagnosis of non-Hodgkin lymphoma (NHL) receiving dose-dense chemotherapy, every 14 days, were included in the study. The primary endpoint was defined as the completion of planned chemotherapy cycles as scheduled. Secondary endpoints were median number of administered G-CSF doses (vials), incidence of FN, hospitalization and toxicity.
The planned chemotherapy cycles (primary endpoint) were completed by 84.1 % of patients. The median number of G-CSF (lenograstim) doses administered for each patient was 24 (range 10–35), which corresponds to a median of five vials (range 0–10) for each cycle. Grades 3–4 toxicities, related to G-CSF administration, included neutropenia and thrombocytopenia (14.0 and 1.9 %, respectively). No grades 3–4 bone pain was detected. The incidence of FN and hospitalization was 9.3 % (10/107) and 4.5 % (5/107), respectively.
Reduced dosage of G-CSF allows dose-dense chemotherapy scheduling, limits exposure to G-CSF and also represents an opportunity for cost savings.
G-CSF; Lenograstim; Nadir; Neutropenia; NHL; Pegfilgrastim
Febrile neutropenia (FN) is a common complication among patients with chemotherapy-induced myelotoxicity and is associated with a number of negative outcomes including prolonged hospitalization, increased medical costs, increased risk of mortality, dose reductions, and delays. Granulocyte-colony-stimulating factor (G-CSF), granulocyte–macrophage-colony stimulating factor (GM-CSF), and pegylated G-CSF are effective at reducing risk and duration of neutropenia-related events. However, despite guidelines, the use of G-CSF and pegylated G-CSF in the United States has not been consistent and pattern of care studies have focused primarily on G-CSF. A number of studies found that G-CSF is underutilized in patients undergoing chemotherapy treatments associated with a high risk of FN, while being over utilized in patients with a low-risk FN. Wide variations in overuse, underuse, and misuse of G-CSF are associated with a number of physician and patient factors. Improved awareness of the guidelines, feedback to providers regarding proper usage, and understanding of chemotherapy regimens associated with very low risks as well as high risks (>20%) of FN is some of the approaches that could lead to improving care.
Granulocyte-colony-stimulating factor; mylosupressive chemotherapy; neutropenia
Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) are the two most commonly used cytokines for mobilization of stem cells in patients undergoing high dose chemotherapy with stem cell support. Both cytokines increase the peripheral blood white blood cell count and the stem cell count but there are other differences in the stem cell products mobilized by G-CSF versus those mobilized with GM-CSF. Generally higher numbers of dendritic cells are mobilized with GM-CSF than by G-CSF. The primary objective of this randomized study was to evaluate the safety and efficacy of chemotherapy plus G-CSF versus chemotherapy plus G-CSF and GM-CSF in patients with B-cell non-Hodgkin’s lymphoma (NHL) who were undergoing chemo-mobilization. Secondary objectives were to determine the expression of various dendritic cell subsets in the two groups and to determine the incidence of disease progression or relapse at 12 months.
We prospectively evaluated 84 patients with relapsed NHL who were candidates for high dose therapy (HDT). All patients underwent chemo-mobilization using ifosfamide, etoposide, and rituximab. All patients were randomized in an adaptive manner to receive either G-CSF or G-CSF plus GM-CSF (G+GM) starting 24 hours after completion of chemotherapy and continuing until completion of apheresis. The stem cell yield/kg, the number of apheresis procedures needed in the two groups, and the toxicity were recorded. We also enumerated dendritic cell subsets, myeloid DCs (mDC) and plasmacytoid DCs (pDC), in apheresis products and in peripheral blood (PB) samples collected pre-chemotherapy. The data were expressed as a percentage of peripheral blood mononuclear cells.
A total of 84 patients were treated. Forty-three patients received G-CSF and 41 received G+GM. Both regimens were well tolerated. The median CD34+ cell dose collected was similar in the two groups. A total of 54 (G-CSF N = 25 and G+GM N = 29) paired samples from baseline and post-apheresis were available for analysis of dendritic cell subsets. There was no significant difference in the percentages of mDC subsets between baseline and post-apheresis collected with G-CSF or G+GM mobilization. However, there was a significant increase in the percentage of pDC subsets in the G-CSF alone when compared to the G+GM arm (P = 0.002). Furthermore, the ratio of mDC and pDC was significantly lower after mobilization with G-CSF versus G+GM (P = 0.029).
Addition of GM-CSF to G-CSF to the mobilization regimen resulted in lower percentages of pDC in the apheresis products when compared to those with G-CSF alone. This shifts the mDC/pDC ratio in the apheresis grafts in favor of mDC in the combination arm. However, these differences did not seem to impact the clinical outcomes in the two groups. (ClinicalTrials.gov Identifier: NCT00499343).
lymphoma; filgrastim; sargramostim; stem cell mobilization
Primary prophylaxis with granulocyte colony–stimulating factors (pp-g-csf) is recommended in patients undergoing chemotherapy carrying a febrile neutropenia (fn) risk of 20% or more. In the present study, we examined clinical practice patterns and the impact of pp-g-csf on fn incidence in women with early-stage breast cancer (ebc) treated with modern adjuvant chemotherapy (act).
This single-centre retrospective cohort study of women with ebc, who were identified from the pharmacy database and who received at least 1 cycle of modern act from January 2009 to December 2011, was conducted at the Cancer Centre of Southeastern Ontario. Data on patient demographics, pathology, stage distribution, chemotherapy, pp-g-csf use, dose reductions, chemotherapy delays, treatment discontinuation, relative dose intensity, and fn events were collected. Chi-square tests, t-tests, univariate and multivariate logistic regression analyses, and nonparametric Mann–Whitney U-tests were used for data analysis.
Of the 239 women eligible for analysis, 145 (61%) received pp-g-csf, and 50 (21%) developed at least 1 episode of fn. Use of pp-g-csf was associated with a significantly lower rate of fn (14% vs. 31%, p = 0.002) and trends to fewer dose delays (17% vs. 27%, p = 0.060) and dose reductions (19% vs. 25%, p = 0.28). Among women receiving pp-g-csf, higher fn rates were associated with an age of 65 years or older, taxane-based chemotherapy, and prophylaxis with filgrastim
Clinical practice patterns at our institution showed that more than 50% of ebc patients treated with modern act received pp-g-csf, which led to fewer fn episodes and increased delivery of planned act. The observed high fn risk despite pp-g-csf was linked to older age, taxane-based chemotherapy, and filgrastim.
Adjuvant chemotherapy; early-stage breast cancer; febrile neutropenia; filgrastim; pegfilgrastim; practice patterns; primary prophylaxis with granulocyte colony-stimulating factors
Febrile neutropenia (FN) occurs following myelosuppressive chemotherapy and is associated with morbidity, mortality, costs, and chemotherapy reductions and delays. Granulocyte colony-stimulating factors (G-CSFs) stimulate neutrophil production and may reduce FN incidence when given prophylactically following chemotherapy.
A systematic review and meta-analysis assessed the effectiveness of G-CSFs (pegfilgrastim, filgrastim or lenograstim) in reducing FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. G-CSFs were compared with no primary G-CSF prophylaxis and with one another. Nine databases were searched in December 2009. Meta-analysis used a random effects model due to heterogeneity.
Twenty studies compared primary G-CSF prophylaxis with no primary G-CSF prophylaxis: five studies of pegfilgrastim; ten of filgrastim; and five of lenograstim. All three G-CSFs significantly reduced FN incidence, with relative risks of 0.30 (95% CI: 0.14 to 0.65) for pegfilgrastim, 0.57 (95% CI: 0.48 to 0.69) for filgrastim, and 0.62 (95% CI: 0.44 to 0.88) for lenograstim. Overall, the relative risk of FN for any primary G-CSF prophylaxis versus no primary G-CSF prophylaxis was 0.51 (95% CI: 0.41 to 0.62). In terms of comparisons between different G-CSFs, five studies compared pegfilgrastim with filgrastim. FN incidence was significantly lower for pegfilgrastim than filgrastim, with a relative risk of 0.66 (95% CI: 0.44 to 0.98).
Primary prophylaxis with G-CSFs significantly reduces FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. Pegfilgrastim reduces FN incidence to a significantly greater extent than filgrastim.
Updated international guidelines published in 2006 have broadened the scope for the use of granulocyte colony-stimulating factor (G-CSF) in supporting delivery of myelosuppressive chemotherapy. G-CSF prophylaxis is now recommended when the overall risk of febrile neutropenia (FN) due to regimen and individual patient factors is ≥20%, for supporting dose-dense and dose-intense chemotherapy and to help maintain dose density where dose reductions have been shown to compromise outcomes. Indeed, there is now a large body of evidence for the efficacy of G-CSFs in supporting dose-dense chemotherapy. Predictive tools that can help target those patients who are most at risk of FN are now becoming available. Recent analyses have shown that, by reducing the risk of FN and chemotherapy dose delays and reductions, G-CSF prophylaxis can potentially enhance survival benefits in patients receiving chemotherapy in curative settings. Accumulating data from ‘real-world’ clinical practice settings indicate that patients often receive abbreviated courses of daily G-CSF and consequently obtain a reduced level of FN protection. A single dose of PEGylated G-CSF (pegfilgrastim) may provide a more effective, as well as a more convenient, alternative to daily G-CSF. Prospective studies are needed to validate the importance of delivering the full dose intensity of standard chemotherapy regimens, with G-CSF support where appropriate, across a range of settings. These studies should also incorporate prospective evaluation of risk stratification for neutropenia and its complications.
Cancer treatment; Colony-stimulating factors; Neutropenia; Guidelines
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is effective in countering chemotherapy-induced neutropenia. However, serum rhG-CSF levels cannot be maintained throughout the course of rhG-CSF therapy. The drop in serum rhG-CSF levels may vary with the duration of rhG-CSF administration or with the circulating neutrophil counts. We investigated the relationship between serum G-CSF levels and circulating neutrophil counts and the pharmacokinetics of rhG-CSF for patients with lung cancer who had been treated with myelosuppressive chemotherapy and then with subcutaneous rhG-CSF (lenograstim, 2 micrograms per kg of body weight per day). Twelve patients were randomly assigned to four groups with different rhG-CSF therapy schedules. Serum G-CSF levels were measured by an enzyme immunoassay method. Serum G-CSF levels during the rhG-CSF therapy greatly exceeded endogenous G-CSF levels and were mainly due to the presence of exogenous rhG-CSF rather than increased levels of endogenous G-CSF. Despite the duration of rhG-CSF administration, serum G-CSF levels during rhG-CSF therapy were inversely correlated with circulating neutrophil counts (r2 = 0.73, P < 0.0001). The value for the area under the concentration-time curve of rhG-CSF on the day of neutrophilia was lower than that on the day of neutropenia (P < 0.05). Our results suggest that the fall in serum G-CSF levels during rhG-CSF therapy may result from increased clearance and/or decreased absorption of rhG-CSF, two processes related to circulating neutrophil counts.
Prophylaxis with granulocyte colony-stimulating factor (G-CSF) reduces the severity of chemotherapy-induced neutropenia. Biosimilar G-CSF is now approved for use, based on comparable efficacy, safety and quality with the originator product.
We conducted a retrospective review of patients’ charts following the switch from originator G-CSF (Neupogen®) to biosimilar G-CSF (Zarzio®/Filgrastim Hexal®) in a large community oncology practice. A total of 77 consecutive patients with cancer who received biosimilar G-CSF were reviewed, as were 25 patients who received originator G-CSF at the same centre.
The median age of patients in the biosimilar G-CSF cohort was 67 years (range 20−83). In this cohort 48% had chemotherapy with a febrile neutropenia risk of >20%. Biosimilar G-CSF was given as primary prophylaxis in 52% and as secondary prophylaxis in 48% of patients. Age and febrile neutropenia in medical history or in previous chemotherapy were factors that triggered the use of G-CSF in patients with a febrile neutropenia risk of <20%. One patient developed febrile neutropenia. Neutropenia led to chemotherapy dose reductions in five patients (6.5%) and discontinuation in two patients (2.5%). No unexpected safety findings were observed. Patient characteristics were generally similar in the originator G-CSF cohort. Only 24% of patients had a febrile neutropenia risk >20% and 36% received primary prophylactic G-CSF. One patient developed febrile neutropenia. Neutropenia led to chemotherapy dose reductions in two patients (8%) and discontinuation in two patients (8%).
Biosimilar G-CSF was effective and prevented dose reductions/discontinuation in the majority of patients. Biosimilar G-CSF was considered clinically comparable to its reference product.
biosimilars; chemotherapy; granulocyte colony-stimulating factor; neutropenia
Daily granulocyte colony-stimulating factors [(G-CSFs); e.g. filgrastim, lenograstim] are frequently used to reduce the duration of chemotherapy-induced neutropenia (CIN) and the incidence of febrile neutropenia (FN) in cancer patients. A pegylated formulation of filgrastim, pegfilgrastim, which is administered once per cycle, was introduced in Spain in 2003. LEARN was a multi-centre, retrospective, observational study in Spain comparing patterns of use of daily G-CSF and pegfilgrastim, and CIN-related outcomes in adults with non-myeloid malignancies receiving myelosuppressive chemotherapy. Outcome measures were the percentage of patients receiving G-CSF for primary prophylaxis versus secondary prophylaxis/treatment, duration of treatment with G-CSF and incidence of CIN-related complications. Medical records from consecutive patients with documented pegfilgrastim (n = 75) or daily G-CSF (n = 111) use during 2003 were included. The proportion of patients receiving primary or secondary prophylaxis was comparable between the pegfilgrastim (39 and 48% respectively) and daily G-CSF (40 and 48% respectively) groups. However, there was a trend towards less frequent use to treat a neutropenic event such as FN or neutropenia in the pegfilgrastim group (17 versus 30% with daily G-CSF). Chemotherapy-induced neutropenia-related complications were less frequent in patients receiving pegfilgrastim (e.g. FN 11 versus 24% with daily G-CSF). This is the first study to show the potential benefits of pegfilgrastim over daily G-CSF in Spanish clinical practice.
pegfilgrastim; G-CSF; pattern of use; neutropenia; febrile neutropenia
Use of granulocyte colony-stimulating factor (g-csf) as primary prophylaxis against chemotherapy-induced neutropenia has significant cost implications. We examined use of g-csf for early-stage breast cancer patients at our centre. The study also examined the pattern of nurse-led patient teaching with respect to drug self-administration.
Patients who received g-csf between November 2009 and October 2010 were identified from pharmacy records. After consent had been obtained, electronic charts were examined to extract data on chemotherapy and use of g-csf. Patients were contacted by telephone to obtain information on the utilization of home-care nursing visits for g-csf administration.
The study analyzed 36 patients. Median age was 58 years (range: 31–78 years). Of the 36 patients, 30 (83%) had received adjuvant treatment, and 6 (17%), neoadjuvant treatment. Most patients (71%) received 10 days (range: 7–10 days) of filgrastim. Of the 36 patients, 29 (81%) received g-csf as primary prophylaxis. In 90% of those patients, primary prophylaxis commenced with the taxane component of treatment. Of the 36 patients, 7 (19%) received g-csf after neutropenia, including 2 who had febrile neutropenia. In 96% of the patients, injections were received at home with the help of a nurse; those patients were subsequently taught self-injection techniques. The median number of nursing visits was 2 (range: 1–3 visits). Most patients were satisfied with the home care and g-csf teaching they received.
Most of the g-csf used in breast cancer treatment during the study period was given for primary prophylaxis. A major reason for the decision to use g-csf appears to have been physician-perceived risk of febrile neutropenia. Delivery of g-csf by home-care nurses was well received by patients.
Growth factor; breast cancer; chemotherapy; neutropenia; febrile neutropenia; prophylaxis; drug administration
Granulocyte colony-stimulating factors (G-CSF) are high-cost agents recommended as prophylaxis of febrile neutropenia or as adjunctive treatment of severe neutropenic sepsis. Their use in high-risk situations such as acute myeloid leukaemia, acute lymphocytic leukaemia, myelodysplastic syndrome and stem cell transplantation is also indicated.
This audit assessed the use of G-CSF within the Oncology and Haematology Service Delivery Unit at Guy’s and St. Thomas’ hospital (London, United Kingdom).
Patients who received G-CSF in April-May 2008 were identified retrospectively from the pharmacy labelling system, and chemotherapy front sheets, clinic letters and transplantation protocols were reviewed. Patients on lenograstim, in clinical trials or under non-approved chemotherapy protocols were excluded.
A total of 104 G-CSF treatments were assessed. The most commonly treated malignancy was breast cancer (41.3%), with docetaxel 100 mg/m
(34.6%) being the most frequent chemotherapy regimen. The chemotherapy intent was curative in 66.3 % of cases. Pegfilgrastim was used in 73.1 % of cases and primary prophylaxis was the most common indication (54.8%). Stem cell transplantation was the first indication to meet the audit criterion (93.3%), followed by primary prophylaxis (89.5%). There was a considerable nonadherence for secondary prophylaxis (6.7%).
The overall level of compliance with the audit criteria was 72.1%. The results for primary and secondary prophylaxis would have been different if FEC100 (fluorouracil, epirubicin, cyclophosphamide) and docetaxel 100 mg/m
had been considered a single chemotherapy regimen. Also, the lack of access to medical notes may have affected the reliability of the results for ‘therapeutic’ use.
Hematopoietic Cell Growth Factors; Neutropenia; Clinical Audit; Drug Utilization Review; United Kingdom
Clinical practice adherence to current guidelines that recommend primary prophylaxis (PP) with granulocyte colony-stimulating factors (G-CSFs) for patients at high (≥20 %) overall risk of febrile neutropenia (FN) was evaluated.
Adult patients with breast cancer, non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), or ovarian cancer were enrolled if myelotoxic chemotherapy was planned, and they had an investigator-assessed overall FN risk ≥20 %. The primary outcome was FN incidence.
In total, 1,347 patients were analysed (breast cancer, n = 829; NSCLC, n = 224; SCLC, n = 137; ovarian cancer, n = 157). Patients with breast cancer exhibited fewer individual FN risk factors than patients with other cancers and were far more likely to have received a high-FN-risk chemotherapy regimen. However, a substantial proportion of all patients (45–80 % across tumour types) did not receive G-CSF PP in alignment with investigator risk assessment and guideline recommendations. FN occurred in 127 patients overall (9 %, 95% confidence interval (CI) 8–11 %), and incidence was higher in SCLC (15 %) than other tumour types (8 % in ovarian and NSCLC, 9 % in breast cancer). A post hoc analysis of G-CSF use indicated that G-CSF prophylaxis was not given within the recommended timeframe after chemotherapy (within 1–3 days) or was not continued across all cycles in 39 % of patients.
FN risk assessment was predominantly based on clinical judgement and individual risk factors, and guidelines regarding G-CSF PP for patients at high FN risk were not consistently followed. Improved education of physicians may enable more fully informed neutropenia management in patients with solid tumours.
Electronic supplementary material
The online version of this article (doi:10.1007/s00520-013-2021-2) contains supplementary material, which is available to authorized users.
Chemotherapy; Myelotoxicity; Febrile neutropenia; Risk assessment; Granulocyte colony-stimulating factor; Prophylaxis
Chemotherapy-induced neutropenia is a major cause of morbidity and mortality. It frequently causes dose reductions or treatment delay, which can be prevented or treated by the administration of granulocyte-colony-stimulating factor (G-CSF). However, a better knowledge of the incidence, day of onset after therapy, and duration of neutropenia is essential to optimize the use of G-CSF.
Design and methods
Six hundred and ninety-four patients from a single institution, affected by lympho-proliferative diseases, were retrospectively reviewed for the occurrence of grade 4 neutropenia and febrile neutropenia (FN). Duration of neutropenia and time of neutrophil nadir were also retrieved. The diagnoses included non-Hodgkin's lymphoma, Hodgkin's lymphoma, and multiple myeloma. Chemotherapy regimens were obviously different according to the diagnosis, disease stage, and first or subsequent lines of therapy.
No patient received G-CSF as primary prophylaxis. Median nadir did not significantly differ among patients treated with first or successive lines of therapy. The incidence of grade 4 neutropenia and FN ranged from 0 to 94%, depending on the chemotherapy regimen. Patients receiving a first-line chemotherapy regimen had a significantly lower incidence of febrile grade 4 neutropenia compared to patients treated with a second or subsequent line of therapy. The duration of grade 4 neutropenia was significantly longer in patients given second or subsequent lines.
The results of this study could be useful to define the nadir onset in the hematologic setting in order to correctly tailor timing and duration of G-CSF prophylaxis and to assess the lowest fully effective dose.
Chemotherapy; G-CSF; Neutropenia; Non-Hodgkin's lymphoma; Hodgkin's lymphoma; Multiple myeloma
Myelosuppressive chemotherapy can lead to dose-limiting febrile neutropenia. Prophylactic use of recombinant human G-CSF such as daily filgrastim and once-per-cycle pegfilgrastim may reduce the incidence of febrile neutropenia. This comparative study examined the effect of pegfilgrastim versus daily filgrastim on the risk of hospitalization.
This retrospective United States claims analysis utilized 2004–2009 data for filgrastim- and pegfilgrastim-treated patients receiving chemotherapy for non-Hodgkin’s lymphoma (NHL) or breast, lung, ovarian, or colorectal cancers. Cycles in which pegfilgrastim or filgrastim was administered within 5 days from initiation of chemotherapy (considered to represent prophylaxis) were pooled for analysis. Neutropenia-related hospitalization and other healthcare encounters were defined with a “narrow” criterion for claims with an ICD-9 code for neutropenia and with a “broad” criterion for claims with an ICD-9 code for neutropenia, fever, or infection. Odds ratios (OR) for hospitalization and 95% confidence intervals (CI) were estimated by generalized estimating equation (GEE) models and adjusted for patient, tumor, and treatment characteristics. Per-cycle healthcare utilization and costs were examined for cycles with pegfilgrastim or filgrastim prophylaxis.
We identified 3,535 patients receiving G-CSF prophylaxis, representing 12,056 chemotherapy cycles (11,683 pegfilgrastim, 373 filgrastim). The mean duration of filgrastim prophylaxis in the sample was 4.8 days. The mean duration of pegfilgrastim prophylaxis in the sample was 1.0 day, consistent with the recommended dosage of pegfilgrastim - a single injection once per chemotherapy cycle. Cycles with prophylactic pegfilgrastim were associated with a decreased risk of neutropenia-related hospitalization (narrow definition: OR = 0.43, 95% CI: 0.16–1.13; broad definition: OR = 0.38, 95% CI: 0.24–0.59) and all-cause hospitalization (OR = 0.50, 95% CI: 0.35–0.72) versus cycles with prophylactic filgrastim. For neutropenia-related utilization by setting of care, there were more ambulatory visits and hospitalizations per cycle associated with filgrastim prophylaxis than with pegfilgrastim prophylaxis. Mean per-cycle neutropenia-related costs were also higher with prophylactic filgrastim than with prophylactic pegfilgrastim.
In this comparative effectiveness study, pegfilgrastim prophylaxis was associated with a reduced risk of neutropenia-related or all-cause hospitalization relative to filgrastim prophylaxis.
To assess the use of colony-stimulating factors (CSFs) in patients with ovarian cancer who receive adjuvant paclitaxel and carboplatin chemotherapy in clinical practice and to assess whether the frequency of CSF use differs among hospitals in Japan.
CSF use in patients with ovarian cancer who received first-line paclitaxel and carboplatin was analyzed retrospectively using data from the Japanese hospitalization payment system.
A total of 1,050 patients at 104 hospitals were identified. The median age was 60 years (range, 22 to 88 years). Of these, 163 patients (15.5%) were diagnosed with neutropenia and 134 patients (12.8%) received CSFs. Among the patients who received CSFs, 125 (93%) received them for the treatment of neutropenia without fever and 1 received them for febrile neutropenia. In total, CSFs were administered for 272 cycles of chemotherapy. Among them, CSFs were used as treatment for neutropenia without fever in 259 cycles (95%), as prophylaxis (primary or secondary) in 12 cycles (4%), and as treatment for febrile neutropenia in 1 cycle. Among hospitals, a median of 4.0% of patients received CSFs with an interquartile range of 25% (Q1, 0%; Q3, 25%). A logistic random effects model showed that the variation in the proportion of patients receiving CSFs among the 104 hospitals was 2.0 (p<0.001), suggesting that the use of CSFs varied across hospitals.
Most patients received CSFs for neutropenia without fever. Standardized and evidence-based use of CSFs is critically required among hospitals in Japan.
Carboplatin; Colony-stimulating factor; Ovarian cancer; Paclitaxel
Objective: The aim of the present study was to investigate the differences
between therapeutic granulocyte-colony stimulating factor (G-CSF) cycles and prophylactic
G-CSF cycles in patients receiving paclitaxel and carboplatin combination chemotherapy for
Material and Method: Medical records of 15 women who received paclitaxel and
carboplatin combination chemotherapy for ovarian cancer between January 2003 and December
2012 were analyzed retrospectively. All 15 patients completed 6 cycles of paclitaxel and
carboplatin as the first-line chemotherapy. The complications were compared between
therapeutic G-CSF cycles and prophylactic G-CSF cycles.
Results: The number of chemotherapy cycles correlated with the ratio of
prophylactic G-CSF cycles. It was considered that earlier prophylactic G-CSF injections
were chosen due to a gradual decrease in WBC and neutrophil counts. The WBC and neutrophil
counts were significantly higher in prophylactic G-CSF cycles than in therapeutic G-CSF
cycles. However, there were no significant differences in the intervals of chemotherapy,
delay of chemotherapy, and incidence of febrile neutropenia between the therapeutic G-CSF
and prophylactic G-CSF cycles.
Conclusion: Prophylactic G-CSF injections were not effective in preventing
the incidence of febrile neutropenia in patients receiving paclitaxel and carboplatin
combination chemotherapy for ovarian cancer.
granulocyte-colony stimulating factor (G-CSF); ovarian cancer; paclitaxel and carboplatin combination chemotherapy
We conducted a multicentre, retrospective, observational study including patients with solid tumours (excluding breast cancer) that received granulocyte colony-stimulating factors (G-CSF) and chemotherapy. We investigated the effectiveness of daily vs. non-daily G-CSFs (pegfilgrastim) adjusting by potential confounders. The study included 391 patients (211 daily G-CSF; 180 pegfilgrastim), from whom 47.3% received primary prophylaxis (PP) (57.8% pegfilgrastim), 26.3% secondary prophylaxis (SP: initiation after cycle 1 and no reactive treatment in any cycle) (51.5% pegfilgrastim) and 26.3% reactive treatment (19.4% pegfilgrastim). Only 42.2% of patients with daily G-CSF and 46.2% with pegfilgrastim initiated prophylaxis within 72 h after chemotherapy, and only 10.5% of patients with daily G-CSF received it for ≥7 days. In the multivariate models, daily G-CSF was associated with higher risk of grade 3-4 neutropenia (G3-4N) vs. pegfilgrastim [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.004–2.97]. Relative to SP, PP protected against G3-4N (OR for SP vs. PP: 6.0, 95%CI: 3.2–11.4) and febrile neutropenia (OR: 3.1, 95%CI: 1.1–8.8), and was associated to less chemotherapy dose delays and reductions (OR for relative dose intensity <85% for SP vs. PP: 3.1, 95%CI: 1.7–5.4) and higher response rate (OR: 2.1, 95%CI: 1.2–3.7). Data suggest that pegfilgrastim, compared with a daily G-CSF, and PP, compared with SP, could be more effective in preventing neutropenia and its related events in the clinical practice.
neutropenia; granulocyte-colony stimulating factors; multi-cycle chemotherapy; pegfilgrastim; filgrastim; lenograstim
Myelosuppression, particularly febrile neutropenia (FN), are serious dose-limiting toxicities that occur frequently during the first cycle of chemotherapy. Identifying patients most at risk of developing FN might help physicians to target prophylactic treatment with colony-stimulating factor (CSF), in order to decrease the incidence, or duration, of myelosuppression and facilitate delivery of chemotherapy as planned. We present a risk model for FN occurrence in the first cycle of chemotherapy, based on a subgroup of 240 patients with non-Hodgkin lymphoma (NHL) enroled in our European prospective observational study. Eligible patients had an International Prognostic Index of 0–3, and were scheduled to receive a new myelosuppressive chemotherapy regimen with at least four cycles. Clinically relevant factors significantly associated with cycle 1 FN were older age, increasing planned cyclophosphamide dose, a history of previous chemotherapy, a history of recent infection, and low baseline albumin (<35 g/l). Prophylactic CSF use and higher weight were associated with a significant protective effect. The model had high sensitivity (81%) and specificity (80%). Our model, together with treatment guidelines, may rationalise the clinical decision of whether to support patients with CSF primary prophylaxis based on their risk factor profile. Further validation is required.
Non-Hodgkin lymphoma; neutropenia; chemotherapy; risk factors
Elderly breast cancer patients are underrepresented in clinical trials and this leads to a lack of knowledge regarding the tolerance and side effects of modern chemotherapy regimens, especially in dose-dense (dd) or dose-intensified combination.
Patients and Methods
In this analysis, data from 4 German, randomized (neo-)adjuvant trials, including anthracycline-based chemotherapy, were evaluated for toxicity, compliance and feasibility. Patients were grouped according to age.
Of the 4,775 patients, 73.6% were < 60 years, 15.8% were 60–64 years and 10.6% were > 64 years. The patients’ compliance decreased with increasing age, the rate of therapy discontinuations was 10.3%; 16.0% were > 64 years old (p < 0.001). The rate of dose reductions also increased with increasing age in the docetaxel/doxorubicin/cyclophosphamide (TAC) (p overall = 0.02) and 5-fluorouracil/epirubicin-cyclophosphamide (FE120C) (p overall < 0.001) treatment groups. Neutropenia grade 3 + 4 in patients of > 64 years was 77% in FE120C- compared to 55% in TAC-treated patients (with primary granulocyte colony-stimulating factors (G-CSFs)). The incidence of febrile neutropenia (FN) was lowest in the regimens without additional taxanes. FN in patients aged > 64 years was lower in the FE120C- than in TAC-and dd-doxorubicin/docetaxel-treated groups.
The range and intensity of toxicity increased with age. Neutropenia did not increase significantly in the dd groups; the highest rate was seen in FE120C-treated patients. FE120C without G-CSFs is not an option in patients older than 64 years.
Elderly; Chemotherapy; Side effect; Tolerability; Breast cancer
Granulocyte colony-stimulating factor (G-CSF) is effective in accelerating neutrophil recovery after intensive chemotherapy for acute myeloid leukemia (AML). However, the optimal G-CSF dosage for patients with AML has not been determined. To our knowledge, G-CSF dosages have not been compared in a randomized AML study.
Patients enrolled on the St. Jude AML97 protocol who remained on study after window therapy were eligible to participate. The effect of the dosage of G-CSF given after induction chemotherapy courses 1 and 2 was analyzed in 46 patients randomly assigned in a double-blinded manner to receive 5 or 10 μg/kg/day of G-CSF. The number of days of G-CSF treatment, neutropenia (absolute neutrophil count < 0.5 × 109/L), and hospitalization; the number of episodes of febrile neutropenia, grade 2-4 infection, and antimicrobial therapy; transfusion requirements; the cost of supportive care; and survival were compared between the two study arms.
We found no statistically significant difference between the two arms in any of the endpoints measured.
The higher G-CSF dosage (10 μg/kg/day) offers no greater benefit than the lower dosage (5 μg/kg/day) in patients undergoing intensive chemotherapy for AML.
acute myeloid leukemia; granulocyte colony-stimulating factor; dosage; children; randomized trial
No published data are available concerning the activity and tolerability of intramuscularly administered granulocyte colony-stimulating factor (G-CSF) in humans. To fill this gap, 19 patients with advanced ovarian cancer previously treated with at least one first-line chemotherapy cycle received the following myelosuppressive regimen: mitoxantrone (DHAD) 12 mg m-2 i.v. on day 1; ifosfamide (IFO) 4 g m-2 i.v. on days 1 and 2; mesna 800 mg m-2 i.v. t.i.d. on days 1 and 2. G-CSF (Filgrastim) was given at a dose of 5 micrograms/kg/day i.m. from day 6 to day 19, its pharmacokinetics being assessed in five patients. The neutrophil nadir was observed after a mean period of 8 days, and the neutrophil count was < 1.0 x 10(3) mm-3 for a mean of 6 days during the cycle of chemotherapy. The neutrophil count fell after the withdrawal of G-CSF on the 19th day of treatment. The difference in absolute neutrophil count between day 19 and day 21 was statistically significant (P = 0.0001); nevertheless, at day 21 no WHO grade 3-4 neutropenia was reported. DHAD and IFO were respectively given at 95% and 93% of the planned dose. The pharmacokinetics of G-CSF i.m. seems to be similar to that of the drug given subcutaneously. No evidence of cumulative myelosuppression was observed. G-CSF was well tolerated and no complications were observed at the injection sites. In conclusion, if the results obtained in this pilot study regarding the activity of i.m. G-CSF are confirmed by a randomised trial, the intramuscular administration of G-CSF could become a valid alternative for patients who dislike the subcutaneous route and who are being treated with chemotherapy that does not induce profound thrombocytopenia.
We investigated the reconstitutive potential of haematopoietic progenitor cells collected in autologous whole blood during multicycle dose-intensified chemotherapy. Forty patients with metastatic solid tumours were treated with up to six cycles of cisplatin and escalating doses of ifosfamide every 14 days. Cisplatin was administered in 3% sodium chloride over 3 h, followed by ifosfamide over 24 h and mesna over 36 h. The first cohort of patients received granulocyte colony-stimulating factor (G-CSF) days 4-14. Once dose-limiting toxicity was reached in cohort 1, the study continued with a second cohort of patients, in whom, in addition to G-CSF on days 4-14, 500 ml of G-CSF and chemotherapy-'primed' whole blood was collected on day 15, i.e. on day 1 of treatment cycles two to six, before cisplatin administration. This volume of blood was kept unprocessed at 4 degrees C and reinfused 20-24 h after the completion of ifosfamide. In cohort 1, dose-limiting toxicity (DLT) was reached at ifosfamide 6.0 g m(-2) with two out of six of the patients developing neutropenic fever. Although in cohort 2 no neutropenic fever was encountered, neither the frequency nor the duration of grade 4 neutropenia and thrombocytopenia were reduced. Cumulative asthenia resulted in DLT at 7.0 g m(-2). The median number of CD34+ cells in 500 ml of whole blood after the first cycle (i.e. at start of cycle 2) was 1.15 x 10(6) kg(-1). This number was significantly greater after the second cycle (2.06 x 10(6) kg(-1), P = 0.01) and then gradually decreased after cycles three to six. After storing whole blood, the number of CD34+ cells had not decreased (median + 10%). We conclude that the method of combined bone marrow support by G-CSF and haematopoietic progenitor cells in autologous whole blood collected before each cycle of a 2-weekly regimen of cisplatin-ifosfamide does not result in clinically measurable reduced bone marrow toxicity compared with what can be expected by the use of G-CSF alone.
The study was designed to assess prospectively the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the management of chemotherapy-induced oral mucositis in non-neutropenic cancer patients.
Material and Methods:
In a prospective open study, adult cancer patients with chemotherapy-induced, neutropenia-independent oral mucositis were treated with GM-CSF (Schering Plough Corporation, Kenilworth, NJ) prepared as mouthwash solution (5 to 10 μgm /ml). GM-CSF was administered within 24 hours of occurrence of oral mucositis at a frequency of 4 to 6 times daily. Systemic GM-CSF was not permissible. Oral mucositis was graded according to the modified Radiation Therapy Oncology Group criteria.
Forty-nine patients were recruited but nine were subsequently excluded as they experienced neutropenia during GM-CSF therapy. The remaining 40 patients were all evaluable. Most patients had either Grade 3 or 4 gross (71%) or functional (70%) mucositis. The mean ± SEM gross oral mucositis scores for all 40 patients combined decreased from 3.3 ± 0.11 at baseline to 2.1 ± 0.12 (p<0.0001) after 2 days, 0.95 ± 0.11 (p<0.0001) after 5 days and 0.23 ± 0.07 (p <0.0001) after 10 days of therapy. Likewise, the mean ± SEM functional oral mucositis scores decreased from 3.03 ± 0.13 at baseline to 1.58 ± 0.13 (p<0.0001) after 2 days, 0.68 ± 0.11 (p<0.0001) after 5 days, and 0.15 ± 0.06 (p<0.0001) after 10 days of therapy. The duration of severe oral mucositis was also shortened as Grade 0 or 1 (gross mucositis grading score) was evident in 12 (30%), 29 (73%), and 40 (100%) patients by the 2nd, 5th and 10th day of therapy, respectively. Similarly, Grade 0 or 1 (functional mucositis grading score) reported in 19 (48%), 31 (78%), and 40 (100%) patients by the 2nd, 5th and 10th day of therapy, respectively. The use of GM-CSF mouthwash was not associated with any apparent ill effect.
GM-CSF mouthwash as used in this study has a significant recuperative efficacy on the severity, morbidity, and duration of chemotherapy-induced oral mucositis. A large randomized, placebo-controlled study is warranted to ascertain that benefit and determine the optimal dosage and schedule.
Chemotherapy; mucositis; G-CSF; GM-CSF
The timed-sequential chemotherapy regimen consisting of etoposide, mitoxantrone and cytarabine (EMA) is an effective therapy for relapsed or refractory acute myelogenous leukemia (AML). We postulated that granulocyte colony-stimulating factor (G-CSF) might enhance the cytotoxicity of EMA by increasing the proportion of leukemic blasts in S-phase. We added G-CSF to EMA (EMA-G) for therapy of advanced high-risk AML patients.
High-risk AML was defined as refractory, relapsed or secondary to either an antecedent hematologic disorder or exposure to cytotoxic agents. The patients were treated with one course of EMA-G consisting of mitoxantrone and cytarabine on days 1–3, and etoposide and cytarabine on days 8–10. G-CSF was started on day 4 and continued until absolute neutrophil count recovered.
Thirty patients were enrolled. The median age was 51 years (range, 25–75). Seventeen (61%) patients had unfavorable cytogenetic karyotypes. Twenty (69%) patients had secondary AML. Ten (34%) had relapsed disease. Four (14%) had refractory AML. Three (10%) patients died from febrile neutropenia and sepsis. Major non-hematologic toxicity included hyperbilirubimenia, renal insufficiency, mucositis, diarrhea, nausea and vomiting, skin rash. A complete remission was achieved in 13 (46%) patients. Median overall survival was 9 months (range, 0.5–66). Median relapse-free survival (RFS) for those who had a CR was 3 months (range, 0.5–63) with RFS censored at the time of allogeneic bone marrow transplantation or peripheral stem cell transplantation for 6 of the patients.
EMA-G is a safe and efficacious option for induction chemotherapy in advanced, high-risk AML patients. The activity of EMA may be increased if applied in patients with less advanced disease.
Metastatic melanoma patients have a poor prognosis. No chemotherapy regimen has improved overall survival. More effective treatments are needed. Docetaxel has clinical activity in melanoma and may be more active when combined with vinorelbine. Granulocyte–macrophage colony-stimulating factor (GM-CSF) has shown activity as an adjuvant melanoma therapy. We carried out a phase II study of these agents in patients with stage IV melanoma.
Patients had documented stage IV melanoma and may have had prior immuno or chemotherapy. Previously treated brain metastases were allowed. Docetaxel (40 mg/m2 IV) and vinorelbine (30 mg/m2 IV) were administered every 14 days, followed by GM-CSF (250 mg/m2 SC on days 2 to 12). The primary endpoint of the study was 1-year overall survival (OS). Secondary objectives were median overall survival, response rate (per RECIST criteria), and the toxicity profiles.
Fifty-two patients were enrolled; 80% had stage M1c disease. Brain metastases were present in 21%. Fifty-two percent of patients had received prior chemotherapy, including 35% who received prior biochemotherapy. Toxicity was manageable. Grade III/IV toxicities included neutropenia (31%), anemia (14%), febrile neutropenia (11.5%), and thrombocytopenia (9%). DVS chemotherapy demonstrated clinical activity, with a partial response in 15%, and disease stabilization in 37%. Six-month PFS was 37%. Median OS was 11.4 months and 1-year OS rate was 48.1%.
The DVS regimen was active in patients with advanced, previously treated melanoma, with manageable toxicity. The favorable 1-year overall survival and median survival rates suggest that further evaluation of the DVS regimen is warranted.
Melanoma; Phase II; Docetaxel; Vinorelbine; Sargramostim