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
Purpose of review
This review updates treatment of neutropenia from articles published from January 2008 through April 2009.
Chemotherapy-induced neutropenia occurs most commonly in the first cycle of treatment. Older patients, patients with multiple co-morbidities, and those receiving more myelotoxic drugs are prone to develop neutropenia and its complications. Current guidelines recommend use of the myeloid growth factors for the first cycle of chemotherapy for patients with more that a 20 % risk of febrile neutropenia. Meta-analysis from randomized trials shows that granulocyte colony-stimulating factor (G-CSF) prophylaxis is associated with patients receiving more intensive chemotherapy, having better survival, but also having a higher risk of secondary AML. Antibiotic remain the mainstay of treatment of febrile neutropenia and are increasingly used for prophylaxis in “low risk” patients. Diagnosis and treatment of other type of neutropenia is also steadily improving.
The myeloid growth factor G-CSF has radically changed our approach to the management of neutropenia. Antibiotics remain the mainstay of treatment of febrile neutropenia.
neutrophil; neutropenia; granulocyte colony-stimulating factor (G-CSF); chemotherapy-induced neutropenia
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
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
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
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
A 36-year-old woman was admitted to our hospital after modified radical mastectomy operation. Adjuvant chemotherapy was administered using TAC regimen. Severe neutropenia occurred after chemotherapy. Granulocyte colony stimulating factor (G-CSF) was given to treat neutropenia. On the second day of G-CSF use, the patient complained of swelling of her neck on the left side, which subsided spontaneously after discontinuation of G-CSF medication. However, the same symptom recurred following G-CSF use on the second cycle of chemotherapy. B-mode ultrasound showed swollen lymph nodes and biopsy revealed no evidence of metastasis. Therefore, the unilateral lymphadenopathy is considered to be the side effect of G-CSF, which is very rare.
Hematologic toxicities of cancer chemotherapy are common and often limit the ability to provide treatment in a timely and dose-intensive manner. These limitations may be of utmost importance in the adjuvant and curative intent settings. Hematologic toxicities may result in febrile neutropenia, infections, fatigue, and bleeding, all of which may lead to additional complications and prolonged hospitalization. The older cancer patient and patients with significant comorbidities may be at highest risk of neutropenic complications. Colony-stimulating factors (csfs) such as filgrastim and pegfilgrastim can effectively attenuate most of the neutropenic consequences of chemotherapy, improve the ability to continue chemotherapy on the planned schedule, and minimize the risk of febrile neutropenia and infectious morbidity and mortality. The present consensus statement reviews the use of csfs in the management of neutropenia in patients with cancer and sets out specific recommendations based on published international guidelines tailored to the specifics of the Canadian practice landscape. We review existing international guidelines, the indications for primary and secondary prophylaxis, the importance of maintaining dose intensity, and the use of csfs in leukemia, stem-cell transplantation, and radiotherapy. Specific disease-related recommendations are provided related to breast cancer, non-Hodgkin lymphoma, lung cancer, and gastrointestinal cancer. Finally, csf dosing and schedules, duration of therapy, and associated acute and potential chronic toxicities are examined.
Canadian recommendations; neutropenia; febrile neutropenia; supportive care; colony-stimulating factors; chemotherapy-induced neutropenia; safety
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
Current guidelines recommend prophylactic use of granulocyte-colony stimulating factors (G-CSF) when febrile neutropenia (FN) risk is greater than 20%. Advanced age is a risk factor for FN; however, little is known about the impact of other factors on the incidence of FN in an older population.
Patients and methods
We analyzed SEER-Medicare data (1994–2005) to develop and validate a prediction model for hospitalization with fever, infection, or neutropenia occurring after chemotherapy initiation for patients with breast, colorectal, prostate, and lung cancer.
In multivariate analysis (N = 58,053) independent predictors of FN included advanced stage at diagnosis [stage 2 (OR 1.29; 95% CI: 1.09–1.53), stage 3 (1.38; 95% CI: 1.19–1.60), and stage 4 (1.57; 95% CI: 1.35–1.83)], number of associated comorbid conditions [one condition (1.13; 95% CI: 1.02–1.28), two conditions (1.39; 95% CI: 1.22–1.57), and three or more conditions (1.81; 95% CI: 1.61–2.04)], receipt of myelosuppressive chemotherapy (1.11; 95% CI: 0.94–1.32), and receipt of chemotherapy within 1 month of diagnosis [1 to 3 months (0.70; 95% CI: 0.62–0.80) and greater than 3 months (0.63; 95% CI: 0.55–0.73)].
We created a prediction model for febrile neutropenia with first cycle of chemotherapy in a large population of elderly patients with common malignancies.
Elderly patients; Febrile neutropenia; Prediction rule; SEER-Medicare dataset
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.
We evaluated risk factors for neutropenic fever and febrile prolonged neutropenia during vincristine-including chemotherapy to treat HIV-related lymphoma to investigate whether protease inhibitor (PI) treatment is associated with infectious complications due to drug interactions with chemotherapeutic agents. We included all HIV patients who received chemotherapy including vincristine for lymphoma at a single referral center in 1999-2010. Neutropenic fever was defined as absolute neutrophil count < 500 cells/µL with body temperature over 38℃; and prolonged neutropenia was defined if it persisted over 7 days. CODOX-M/IVAC and Stanford regimens were considered high-risk regimens for prolonged neutropenia. We analyzed 48 cycles of chemotherapy in 17 HIV patients with lymphoma. There were 22 neutropenic fever and 12 febrile prolonged neutropenia events. In multivariate analysis, neutropenic fever was associated with old age and low CD4 cell count, but not with PI use or ritonavir-boosted PI use. Low CD4 cell count and high-risk regimens were associated with febrile prolonged neutropenia. Neutropenic fever and febrile prolonged neutropenia is associated with old age, low CD4 cell count, and high-risk regimens, but not PI use, in HIV patients undergoing chemotherapy including vincristine for lymphoma.
Human Immunodeficiency Virus; Lymphoma; Neutropenia
The use of chemotherapy regimens with moderate or high risk of febrile neutropenia (defined as having a FN incidence of 10% or more) and the respective incidence and clinical management of FN in breast cancer and NHL has not been studied in Belgium. The existence of a medical need for G-CSF primary and secondary prophylaxis with these regimens was investigated in a real-life setting.
Nine oncologists and six hematologists from different Belgian general hospitals and university centers were surveyed to collect expert opinion and real-life data (year 2007) on the use of chemotherapy regimens with moderate or high risk of febrile neutropenia and the clinical management of FN in patients aged <65 years with breast cancer or NHL. Data were retrospectively obtained, over a 6-month observation period.
The most frequently used regimens in breast cancer patients (n = 161) were FEC (45%), FEC-T (37%) and docetaxel alone (6%). In NHL patients (n = 39), R-CHOP-21 (33%) and R-ACVBP-14 (15%) were mainly used. Without G-CSF primary prophylaxis (PP), FN occurred in 31% of breast cancer patients, and 13% had PSN. After G-CSF secondary prophylaxis (SP), 4% experienced further FN events. Only 1 breast cancer patient received PP, and did not experience a severe neutropenic event. Overall, 30% of chemotherapy cycles observed in breast cancer patients were protected by PP/SP. In 10 NHL patients receiving PP, 2 (20%) developed FN, whereas 13 (45%) of the 29 patients without PP developed FN and 3 (10%) PSN. Overall, 55% of chemotherapy cycles observed in NHL patients were protected by PP/SP. Impaired chemotherapy delivery (timing and/or dose) was reported in 40% (breast cancer) and 38% (NHL) of patients developing FN. Based on oncologist expert opinion, hospitalization rates for FN (average length of stay) without and with PP were, respectively, 48% (4.2 days) and 19% (1.5 days). Similar rates were obtained from hematologists.
Despite the studied chemotherapy regimens being known to be associated with a moderate or high risk of FN, upfront G-CSF prophylaxis was rarely used. The observed incidence of severe neutropenic events without G-CSF prophylaxis was higher than generally reported in the literature. The impact on medical resources used is sizeable.
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.
In patients with severe congenital neutropenia (SCN), long-term therapy with granulocyte colony-stimulating factor (G-CSF) has reduced mortality from sepsis, revealing an underlying predisposition to myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML). We have reported the early pattern of evolution to MDS/AML, but the long-term risk remains uncertain. We updated a prospective study of 374 SCN patients on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry (SCNIR) with longer follow-up. After 10 years on G-CSF, the annual risk of MDS/AML was 2.3%/year. After 15 years on G-CSF, the cumulative incidence was 10% for death from sepsis and 22% for MDS/AML. The data continue to support the hypothesis that SCN patients with high G-CSF requirements are also at high risk of MDS/AML. The risk per year of MDS/AML in SCN now appears similar to, rather than higher than, the reported risk of AML in Fanconi anemia and dyskeratosis congenita.
severe congenital neutropenia; acute myeloid leukaemia; myelodysplastic syndromes; granulocyte colony-stimulating factor
Chemotherapy Induced neutropenia is a frequent and serious complication of cytotoxic cancer treatment.
Granulocyte colony stimulating factors (G-CSF) are frequently used to counter neutropenia, attempt rapid recovery of patients and allow for continuation of treatment without compromise on dose, especially in curative malignancies. Generally regarded as safe, G-CSF use has been very rarely reported to have resulted in serious side effects, such as, splenic rupture.
We are reporting a case of a twenty years old man, who was being treated for T cell acute lymphoblastic leukemia and received colony stimulating factors for treatment of severe neutropenia and suffered from splenic rupture, He was treated with splenectomy.
Although extremely rare, splenic rupture can be a serious and sometimes life threatening complication of high dose colony stimulating factors therapy.
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
Fever during neutropenia may be a symptom of severe life threatening infection, which must be treated immediately with antibiotics. If signs of infection persist, therapy must be modified. Diagnostic measures should not delay treatment. If the risk of febrile neutropenia after chemotherapy is ≥20%, then prophylactic therapy with G-CSF is standard of care. After protocols with a risk of febrile neutropenia of 10–20%, G-CSF is necessary, in patients older than 65 years or with severe comorbidity, open wounds, reduced general condition. Anemia in cancer patients must be diagnosed carefully, even preoperatively. Transfusions of red blood cells are indicated in Hb levels below 7–8 g/dl. Erythropoiesis stimulating agents (ESA) are recommended after chemotherapy only when hemoglobin levels are below 11 g/dl. The Hb-level must not be increased above 12 g/dl. Anemia with functional iron deficiency (transferrin saturation <20%) should be treated with intravenous iron, as oral iron is ineffective being not absorbed. Nausea or emesis following chemotherapy can be classified as minimal, low, moderate and high. The antiemetic prophylaxis should be escalated accordingly. In chemotherapy with low emetogenic potential steroids are sufficient, in the moderate level 5-HT3 receptor antagonists (setrons) are added, and in the highest level Aprepitant as third drug.
neutropenia; febrile neutropenia; documented infection; antibiotic therapy; G-CSF; anemia; erythropoiesis stimulating agents; nausea and emesis after chemotherapy; diarrhea
This study was aimed to develop a new method for personalising chemotherapeutic and granulocyte colony-stimulating factor (G-CSF) combined schedules, and use it for suggesting efficacious chemotherapy with reduced neutropenia.
Clinical data from 38 docetaxel (Doc)-treated metastatic breast cancer patients were employed for validating a new pharmacokinetic/pharmacodynamics model for Doc, combined with a mathematical model for granulopoiesis. An optimisation procedure was constructed and used for selecting improved treatment schedules.
The combined model accurately predicted observed nadir timing (r=0.99), grade 3 or 4 neutropenia (86% success) and neutrophil counts over time in individual patients (r=0.63), and showed robustness to CYP3A-induced variability in Doc clearance. For average patients, the predicted optimal support for the standard chemotherapy regimen, Doc 100 μg m−2 tri-weekly, is G-CSF, 300 μg, Q1D × 3, starting day 7 post-Doc. This regimen largely moderates chemotherapy-induced neutrophil nadir and neutropenia duration. The more intensive Doc dose, 150 mg m−2, is optimally supported by the slightly less cost-effective G-CSF 300 μg, Q1D × 4, 5 days post-Doc. The latter regimen is optimal for borderline patients (2000 neutrophils per μl) under Doc, 100–150 mg m−2 tri-weekly.
The new computational method can serve for tailoring efficacious cytotoxic and supportive treatments, minimising side effects to individual patients. Prospective clinical validation is warranted.
granulocyte colony-stimulating factor; neutropenia; Doc; mechanistic PK/PD; mathematical modelling; optimisation
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used to treat neutropenia during cytotoxic chemotherapy. The optimal scheduling of rhG-CSF is unknown and can hardly be tested in clinical studies due to numerous therapy parameters affecting outcome (chemotherapeutic regimen, rhG-CSF schedules, individual covariables). Motivated by biomathematical model simulations, we aim to investigate different rhG-CSF schedules in a preclinical chemotherapy mouse model.
The time course of hematotoxicity was studied in CD-1 mice after cyclophosphamide (CP) administration. Filgrastim was applied concomitantly in a 2 × 3-factorial design of two dosing options (2 × 20 μg and 4 × 10 μg) and three timing options (directly, one, and two days after CP). Alternatively, a single dose of 40 μg pegfilgrastim was applied at the three timing options. The resulting cytopenia was compared among the schedules.
Dosing and timing had a significant influence on the effectiveness of filgrastim schedules whereas for pegfilgrastim the timing effect was irrelevant. The best filgrastim and pegfilgrastim schedules exhibited equivalent toxicity. Monocytes dynamics performed analogously to granulocytes. All schedules showed roughly the same lymphotoxicity.
We conclude that effectiveness of filgrastim application depends heavily on its scheduling during chemotherapy. There is an optimum of timing. Dose splitting is better than concentrated applications. Effectiveness of pegfilgrastim is less dependent on timing.
rhG-CSF; chemotherapy toxicity; mice; cyclophosphamide; cytopenia; neutropenia
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
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.
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.
Colony-stimulating factors (CSFs) are commonly used for the treatment of neutropenia following chemotherapy and for the mobilization of peripheral blood stem cells (PBSC). We recently experienced a rare case of a new onset of psoriasiform eruption by GM-CSF (granulocyte-macrophage colony-stimulating factor) which was exacerbated by G-CSF (granulocyte colony-stimulating factor) in a patient with breast cancer. A 36-year-old woman had received neoadjuvant chemotherapy (cyclophosphamide, epirubicin and 5-fluorouracil), modified radical mastectomy and adjuvant chemotherapy with paclitaxel and mitoxantrone followed by GM-CSF administration for the treatment of locally advanced breast cancer. She had developed a psoriatic skin lesion on face and both upper arms during leukocyte recovery in spite of no previous history of psoriasis. Next, the chemotherapy course was complicated by a flare of mild psoriatic skin lesion, although CSF was changed into G-CSF due to GM-CSF-associated psoriasis. Subsequently, she had had high-dose chemotherapy and autologous peripheral blood stem cell transplantation for consolidation therapy. GM-CSF was administered for the mobilization of PBSC and post-transplant period, but psoriatic skin lesion did not appear. During 6 months after PBSCT, psoriasiform eruption did not appear.
To determine the dose of trabectedin plus doxorubicin with granulocyte colony stimulating factor (G-CSF) support associated with manageable neutropenia and acceptable dose-limiting toxicities (DLTs) in patients with recurrent or persistent soft tissue sarcoma (STS).
In this phase I, open-label, multicenter trial, patients previously treated with 0–1 prior chemotherapy regimens excluding doxorubicin, an ECOG performance status 0–1, and adequate organ function received a 10–15-minute intravenous (IV) infusion of doxorubicin 60 mg/m2 immediately followed by a 3-hour IV infusion of trabectedin 0.9–1.3 mg/m2 on day 1 of a 3-week cycle. Because four of the first six patients experienced DLT-defining neutropenia during cycle 1, all subsequent patients received primary prophylactic G-CSF. The maximum tolerated dose (MTD) was the highest dose level with ≥6 patients in which less than one third of the patients experienced severe neutropenia or DLT. Blood was collected during cycle 1 for pharmacokinetic analyses. Adverse events (AEs), tumor response, and survival were assessed.
Patients (N = 41) received a median of six cycles of treatment (range, 2–13). The MTD was trabectedin 1.1 mg/m2 and doxorubicin 60 mg/m2. Common grade 3/4 treatment-emergent AEs were neutropenia (71%), ALT increase (46%), and thrombocytopenia (37%). Overall, five (12%) patients achieved a partial response, and 34 (83%) maintained stable disease. Median progression-free survival was 9.2 months. Doxorubicin and trabectedin pharmacokinetics were not altered substantially with concomitant administration.
The combination of doxorubicin 60 mg/m2 followed by trabectedin 1.1 mg/m2 every 21 days is safe and active in patients with STS.
trabectedin; ET-743; doxorubicin; sarcoma; pharmacokinetics; YONDELIS