Primary Prophylaxis Of Febrile Neutropenia Research Articles

Lecture: management of chemotherapy-induced febrile neutropenia; guidelines and colony stimulating factors

Chemotherapy-induced febrile neutropenia (FN) is a major risk factor for severe infections potentially fatal, and also a dose-limiting toxicity, so causing dose reductions and/or delays in scheduled chemotherapy. This lecture provides recommendations for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. If expected risk of FN is equal or superior to 20%, a primary prophylaxis of FN with G-CSF is recommended. Primary prophylaxis can be considered in case of intermediate 10-20% risk of FN, in presence of factors that increase the frequency/risk of FN, such as age >65, advanced disease, prior episode of FN, poor performance status, radiotherapy to a wide body area (>20%). In case of low risk of FN (<10%), primary prophylaxis is not recommended. We also described the differences in potency and efficacy between two G-CSF, lenograstim (glycosylated) and filgrastim (non-glycosylated), which should be considered when deciding the G-CSF for each patient, particularly in high risk settings for FN.

Abstract P3-14-18: Result of Phase I Part of a Phase I/II Study of Lapatinib (L) Plus Oral Vinorelbine (oVNR) in Metastatic Breast Cancer (MBC) Patients Overexpressing ErbB2

Abstract Background: Lapatinib(L) is effective in overexpressing ErbB2 MBC patients. Oral vinorelbine (oVNR) has similar efficacy to that of the injection formulation and has demonstrated generally favorable tolerability. Oral medications provide convenient treatment and satisfactory life quality. We investigated the combination of L + VNR, seeking the recommended dose for further phase II studies. Methods: This open-label, single-center, single-arm phase I study aimed to determine the maximum tolerated dose (MTD) and recommended dose of L+oVNR to women with ErbB2+ MBC, in progression after trastuzumab-taxane based treatment. Patients refractory to any line of anticancer treatment including vinorelbin was allowed to join in this study, except lapatinib. Cohorts of 3 patients received oral vinorelbine at escalating doses of 30-80 mg/day on day 1 and day 8 every 3 weeks (q3w) combined with lapatinib at escalating doses of 1000-1250 mg/day given po continuously, with each successive cohort until the MTD (2/3, 2/6 patients experiencing dose-limiting toxicity [DLT]) was reached. Additional patients received repeated administration at the recommended dose. G-CSF as primary prophylaxis of febrile neutropenia was not permitted. Results: 15 patients have been enrolled. During dose escalation, 2 of 3 experienced DLT at dose level of oral vinorelbine 60mg/kg day 1 and day 8 q3w plus lapatinib 1000mg/day. One with grade 3 diarrhea and the other with prolonged grade 3 neutropenia. This dose level was declared as MTD. Therefore we stop recruiting patient into next dose level of oral vinorelbine 60mg/kg plus lapatinib 1250mg/day. Recommended dose was lapatinib 1000mg/day with oral vinorelbine 50mg/kg day 1, day 8 q3w. There is no DLT experienced in 12 patients with the dose level below MTD. The most frequent treatment-related adverse events included diarrhea, skin rash, and fatigue, mostly grade 1-2. As of June 2010, 6 patients are still on treatment. Efficacy signals in other 9 patients included 2 maintained stable disease (SD) &amp;gt; 6 months (both of them had unconfirmed PR during treatment), 1 unconfirmed partial response (PR), 1 SD &amp;lt; 6 months, and 4 progressive disease (3 of them had refractory to vinorelbine before). Phase II study with the recommended dose was just starting. Final result of the efficacy signal in phase I part and the toxicity profile of more patients receiving recommended dose will be presented at the meeting. Conclusions: The combination of lapatinib and oral vinorelbine is tolerable and has antitumor activity in heavily pretreated ErbB2+ MBC. Further phase II study is underway. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-18.

Pharmacokinetic (PK) Interactions between Lapatinib (L) and Vinorelbine (VNR) in a Phase I Study in Locally Advanced or Metastatic Breast Cancer (LAMBC) Patients(Pts) Overexpressing HER2. GEP-01 – A Study of the FNCLCC-Group of Early Phase Trials.

Abstract Background: Lapatinib is effective in overexpressing HER2 LAMBC pts. Following anthracyclines, taxanes and capecitabine, VNR is an active agent in metastatic setting. Both drugs use the same main metabolic pathway: Cytochrome P450 3A4. We investigated the combination of L + VNR, seeking the recommended dose for further phase II studies, and looking for the PK interactions between the 2 drugs.Methods: Women with HER2+ LAMBC, in progression after ≤ 2 lines of trastuzumab-based treatment were treated with a 7 day (D-7 to D0) loading dose of L before starting VNR on a D1 and D8 q3w iv regimen. L was given po continuously. G-CSF as primary prophylaxis of febrile neutropenia (FN) was not permitted. Dose levels (DL) (L mg/VNR mg/m²) ranged from 750/20 to 1250/30 with 3 patients per DL. PK samples were collected on 7 points on D1 of cycle 1 for L and VNR dosages. PK time points analysis was performed on plasma for L and whole blood for VNR. For both drugs the analytical method was Ultra Performance Liquid Chromatography (UPLC) coupled with tandem mass spectrometry (MS-MS) as detection. VNR PK parameters were estimated by nonlinear mixed effect modeling (NONMEM) and L PK parameters were estimated by non compartmental software (MicroPharm).Results: Seventeen pts and 68 PK time points were available for VNR analysis. VNR was ascribed to a tri-compartment model. When considering all VNR data together, VNR clearance (CL) was 37.8±16.7 L/h, while it showed a gradual decrease according to specific dose of L: 47.5±20.4 L/h for L 750 mg (3 patients) vs 35.6±4.3 L/h for pooled data for L 1000 and 1250 (14 patients). This trend was not significant likely due to low number of patients treated at lower dose of L, while no significant difference was observed between L 1000 and L 1250. The mean elimination half life time (t1/2) of VNR was 0.12 h. Six patients and 42 PK time points were analyzed for L. L CL were respectively 83.8 ± 41.3 and 57.1 ± 5.5 L/h for patients who received 750 mg (3 patients) and 1000 mg (3 patients) of L with 20 mg of VNR. The mean elimination half life time (t1/2) of L was 2.89 h.Conclusions: A potential PK interference occurred between VNR and L. When the dose of L increased, both VNR and L CL decreased, likely due to CYP450-3A4 interactions. This trend should be confirmed by the PK analysis of L and VNR in more patients, including an intermediate DL (1250/22.5) still ongoing. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5091.

GEP01: A phase I study of lapatinib (L) and vinorelbine (VNR) in HER2 overexpressing (HER2+) locally advanced or metastatic breast cancer (LAMBC) patients (pts): A FNCLCC Group of early phase trials study

1051 Background: Lapatinib is an effective anti-HER-2 therapy in LAMBC pts, currently investigated in the adjuvant setting. Following anthracyclines, taxanes and capecitabine, VNR is an active agent in metastatic setting. Its main toxicity consists of neutropenia and may challenge the standard weekly, day D1 and D8 regimen. We investigated the combination of L + VNR, seeking the recommended dose for further phase II studies and the potential pharmacokinetic (PK) interactions. Methods: Women with a HER-2+ LAMBC, in progression after ≤ 2 lines of trastuzumab-based treatment were treated with a 7D (D-7 to D0) loading dose of L before starting VNR on a D1 and D8 q3w IV regimen. L was given orally continuously. Primary prophylaxis of febrile neutropenia (FN) with G-CSF was not permitted. Dose levels (DL, L [mg]/VNR [mg/m2]) ranged from 750/20 to 1250/30 with 3 pts/DL (6 in case of dose-limiting toxicity [DLT]). DLT was defined on tolerance at cycle 1 and included grade (gr) 4 neutropenia (PN) ≥ 7D, FN, thrombocytopenia (gr4 or symptomatic gr3), omission of D8 for haematological toxicity, and any drug-related gr3–4 non-haematological toxicity. PK samples were collected on 7 points on D1 of cycle 1 for L and VNR dosages. Results: From August 2007 to December 2008, 15 evaluable pts were enrolled (median age 58 [46–75], 43% PS 0, 8 pts previously exposed to only 1 line of trastuzumab) and 65 cycles were administered. Toxicity is available for 13 pts. Of 3 pts treated at DL4 (1000/25), 2 developed a DLT: 1 FN and 1 gr4 PN &gt; 7D. Other significant toxicities (% pts) included gr2 anaemia 8%, gr4 PN 46%, gr1 diarrhoea 62%, gr2 nausea/vomiting 8%, gr1 skin rash 23%, gr2 transaminases 23%; no decrease of cardiac function occurred. From DL1 to DL3 (750/20, 1000/22.5), total body clearance of VNR decreased by 50% (32 ± 19 L/h vs 17 ± 7 L/h). Conclusions: Maximal tolerated dose has been reached at 1000/22.5 for the combination of L with VNR given on a D1 and D8 q3w schedule. Given a potential PK interference which would yield to higher exposure to VNR, an intermediate DL is going to be explored (1250/22.5) to allow an accurate definition of the recommanded dose of the combination for future phase II comparison studies. [Table: see text]

Cost-effectiveness of pegfilgrastim versus 6-day filgrastim primary prophylaxis in patients with non-Hodgkin's lymphoma receiving CHOP-21 in United States

ABSTRACTObjectives: Prophylaxis with granulocyte-colony stimulating factor (G-CSF) reduces the risk of febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy. Randomized clinical trials have shown that pegfilgrastim, a 2nd-generation G-CSF, is at least as effective as the 1st-generation G-CSF filgrastim. In the meta-analysis of trials pegfilgrastim performed better than filgrastim with respect to FN risk. The incremental cost-effectiveness of primary prophylaxis (starting in cycle 1 and continuing in subsequent cycles of chemotherapy) with pegfilgrastim versus filgrastim used for 6 days (as is often used in clinical practice) was estimated in patients with aggressive non-Hodgkin's lymphoma (NHL) receiving myelosuppressive chemotherapy in the United States.Methods: A decision-analytic model was constructed from a health insurer's perspective with a life-time study horizon. The model considered direct medical costs and outcomes related to reduced FN and potential survival benefits due to reduced FN-related mortality. Inputs for the model were obtained from the medical literature. Sensitivity analyses were conducted across plausible ranges in parameter values.Results: The incremental cost-effectiveness (ICER) of pegfilgrastim versus 6-day filgrastim primary prophylaxis was $2167/FN episode avoided. Adding survival benefit from avoiding FN mortality yielded an ICER of $5532/LY gained or $6190/QALY gained. When the potential benefit of optimized chemotherapy was included, the ICER was $1494/LY gained or $1677/QALY gained. The most influential factors included cost of pegfilgrastim, relative risk of FN between pegfilgrastim and filgrastim, FN case-fatality rate, cost of filgrastim and baseline FN risk.Conclusions: Pegfilgrastim is cost-effective in primary prophylaxis of FN compared to 6 days per cycle of filgrastim, in patients with NHL receiving myelosuppressive chemotherapy (e.g., cyclophosphamide + doxorubicin + vincristine + prednisolone [CHOP-21]) chemotherapy. Study limitations included lack of direct evidence linking G-CSF use with a reduction in FN-related mortality and limited data that show a relationship between relative dose intensity (RDI) and cancer-specific patient survival.

Pegfilgrastim ± ciprofloxacin for primary prophylaxis with TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy for breast cancer. Results from the GEPARTRIO study

BackgroundTAC (docetaxel/doxorubicin/cyclophosphamide) is associated with high incidences of grade 4 neutropenia and febrile neutropenia (FN). This analysis compared the efficacies of four regimens for primary prophylaxis of FN and related toxic effects in breast cancer patients receiving neoadjuvant TAC. Patients and methodsPatients with stage T2–T4 primary breast cancer were scheduled to receive 6–8 cycles of TAC. Primary prophylaxis was: ciprofloxacin 500 mg orally twice daily on days 5–14 (n=253 patients; 1478 cycles), daily granulocyte colony-stimulating factor (G-CSF) (filgrastim 5 μg/kg/day or lenograstim 150 μg/m2/day) on days 5–10 (n=377; 2400 cycles), pegfilgrastim 6 mg on day 2 (n=305; 1930 cycles), or pegfilgrastim plus ciprofloxacin (n=321; 1890 cycles). ResultsPegfilgrastim with/without ciprofloxacin was significantly more effective than daily G-CSF or ciprofloxacin in preventing FN (5% and 7% versus 18% and 22% of patients; all P<0.001), grade 4 neutropenia, and leukopenia. Pegfilgrastim plus ciprofloxacin completely prevented first cycle FN (P<0.01 versus pegfilgrastim alone) and fatal neutropenic events. ConclusionCiprofloxacin alone, or daily G-CSF from day 5–10 (as in common practice), provided suboptimal protection against FN and related toxic effects in patients receiving TAC. Pegfilgrastim was significantly more effective in this setting, especially if given with ciprofloxacin.

Pegfilgrastim Provides Effective Primary Prophylaxis Against Febrile Neutropenia in Patients with NHL Undergoing Chemotherapy: Initial Results from an Integrated Analysis - The Neulasta Versus Current Neutropenia Management Practice (Neucup) Project.

EORTC/ASCO guidelines recommend primary prophylaxis (PP) with granulocyte colony stimulating factor (G-CSF) when the risk of chemotherapy (CT)-induced febrile neutropenia (FN) is ≥20%. Without G-CSF prophylaxis, FN risk in patients with non-Hodgkin's lymphoma (NHL) receiving CHOP is up to 50%, and over 50% of FN occurs in cycle 1. Physicians often delay/reduce dose to manage neutropenia, potentially compromising CT efficacy.We identified 3 prospective clinical trials that assessed PP of neutropenia with pegfilgrastim (Neulasta®) 6 mg once per cycle in NHL patients receiving CHOP or CHOP-like regimens ± rituximab. In a retrospective integrated analysis, data from the 3 trials were combined to evaluate the efficacy and safety of PP with pegfilgrastim in a large NHL population. The primary outcome measure was the proportion of patients developing FN.In all, 280 patients started the first cycle of CT, of whom 275 (98%) received pegfilgrastim as PP and were included in the present analyses. The proportion of patients experiencing FN over all cycles was relatively low (15%), and approximately half of FN cases occurred during cycle 1 (Table). WHO grade 3/4 hematological toxicities occurred in the following proportions of patients: white blood cell count (WBC) <2.0×109/L, 63%; absolute neutrophil count (ANC) <1.0×109/L, 67%; hemoglobin <8.0 g/dL, 8%; and platelets <50×109/L, 21%. Grade 4 WBC <1.0×109/L and ANC <0.5×109/L were observed in 39% and 55% of patients. Fifteen percent of patients were hospitalized due to a neutropenic event and 11% were hospitalized due to FN. Anti-infectives were prescribed for 59% of patients. Across all CT cycles, relative dose intensity (RDI) ≥85% was achieved by 88% of patients and RDI ≥90% by 83% of patients. Pegfilgrastim was also effective as PP against FN in the subgroup aged ≥65 years (n=167), who are more susceptible to neutropenia. FN occurred in 17% of these patients (vs 12% of those aged <65 years). Hospitalization due to neutropenic events and FN occurred in 19% and 14% of patients ≥65 years old compared with 9% and 6% of those aged <65 years.To conclude, in this population, PP of FN with pegfilgrastim was associated with a relatively low occurrence of FN (15%) and a high proportion of patients achieving RDI ≥90%. These data support the use of pegfilgrastim 6 mg as PP against FN and neutropenic complications in NHL patients receiving CHOP-like CT, particularly the elderly for whom risk of FN and hospitalization is greatest. These findings support current ASCO/EORTC guideline recommendations.Patients starting each cycle, n (%)Patients with, n (%) [95% CI]FNRDI ≥90%Cycle 1275 (100)20 (7) [4, 10]250 (91) [88, 94]Cycle 2259 (94)7 (3) [1, 5]225 (87) [83, 91]Cycle 3244 (89)7 (3) [1, 5]202 (83) [78, 88]Cycle 4221 (80)8 (4) [1, 6]174 (79) [73, 84]Cycle 5173 (63)2 (1) [0, 3]132 (76) [70, 83]Cycle 6158 (57)5 (3) [0, 6]132 (84) [78, 89]Cycle 7*23 (13)018 (78) [61, 95]Cycle 8*19 (11)015 (79) [61, 97]All cycles275 (100)41 (15) [11, 19]228 (83) [78, 87]*Data from one study only

A Predictive Model for Neutropenia Associated with Cancer Chemotherapy

Studies of primary prophylaxis of febrile neutropenia (FN) with recombinant human granulocyte colony-stimulating factor (rHu-G-CSF, filgrastim) administered to all patients starting their initial course of chemotherapy have demonstrated clinical effectiveness and an economic advantage in a wide range of settings. A recent meta-analysis confirmed the ability of filgrastim to reduce the risk of FN and documented infection in a variety of malignancies in both adults and children. The threshold risk for FN at which a cost saving is achieved by using filgrastim is inversely related to the daily cost of the drug and duration of hospitalization. Clinical practice guidelines for the use of filgrastim were developed based on these observations. Recent studies incorporating indirect institutional costs demonstrated that a cost saving can be achieved at substantially lower FN risk thresholds than previously estimated. Despite the demonstrated efficacy of filgrastim in primary prophylaxis, its value may be further increased by appropriately selecting patients and better understanding the importance of sustaining dose intensity in specific malignancies. Clinical prediction models capable of identifying individuals at high risk for neutropenic complications yield further reductions in FN risk thresholds and treatment costs in patients receiving cancer chemotherapy. These models also may be used to evaluate the cost-effectiveness or cost-efficiency of filgrastim. A clinical prediction model recently was presented and validated incorporating both baseline clinical characteristics as well as the results of the first cycle of chemotherapy in patients with early-stage breast cancer. A cost-effectiveness ratio of $34,297/year of life saved was estimated based on dose-response assumptions derived from a previously reported adjuvant breast cancer trial studying the impact of dose reduction on disease-free survival. The cost-effectiveness of filgrastim was evident over a wide range of clinical and cost assumptions. Clinical prediction models permit the rational and cost-effective identification of patients for filgrastim support. Existing clinical practice guidelines should be reevaluated in light of new information available on both the total costs associated with FN as well as the cost-effectiveness of these agents in patients receiving chemotherapy for sensitive and potentially curable malignancies.

A novel approach to maintain planned dose chemotherapy on time: a decision-making tool to improve patient care

Studies of primary prophylaxis of febrile neutropenia with recombinant granulocyte colony-stimulating factor (r-metHuG-CSF, filgrastim), administered to all patients starting with the initial course of chemotherapy, have demonstrated an economic advantage over a wide range of settings. In these analyses, the threshold risk for febrile neutropenia at which a cost saving is realised is inversely related to the direct medical costs of hospitalisation. Clinical practice guidelines for the use of filgrastim have been developed based on these observations. Recent studies incorporating indirect institutional costs have demonstrated that cost savings can be achieved at substantially lower febrile neutropenia risk thresholds than previously estimated. Despite the demonstrated efficacy of filgrastim in primary prophylaxis, its value may be further enhanced through the appropriate selection of patients for such therapy and a better understanding of the importance of sustaining dose intensity in specific malignancies. Clinical prediction models capable of identifying individuals at high risk for neutropenic complications yield further reductions in febrile neutropenia risk thresholds and treatment costs in patients receiving cancer chemotherapy. Prediction models can also be used to evaluate the cost-effectiveness or cost-efficiency of filgrastim use. Such a model has recently been developed and validated and is described here which incorporates both baseline clinical characteristics as well as the results of the first cycle of chemotherapy in patients with early-stage breast cancer. A cost-effectiveness ratio of US$ 34 297 (Euro 32 002) † † An exchange rate of US$ 1 equivalent to Euro 1.0717 was used in this paper (30 March 1999). per year of life saved (YLS) was calculated based on dose–response assumptions derived from a previously reported adjuvant breast cancer trial studying the impact of dose reduction on disease-free survival. This figure is comparable with accepted cost-effectiveness ratios for other interventions, e.g. US$ 45 000/LYS (Euro 41 989) for renal dialysis for patients with end-stage renal disease. The cost-effectiveness of filgrastim was evident over a wide range of clinical and cost assumptions. Clinical prediction models permit rational and cost-effective selection of patients for filgrastim support. Current guidelines should be re-evaluated in light of new information available on both the total cost of febrile neutropenia, as well as the cost-effectiveness of these agents in specific clinical situations.

Economic analysis of the clinical uses of the colony-stimulating factors.

Colony-stimulating factors can reduce the morbidity and possibly the mortality from some types of cancer treatment. Reductions in hospitalization and supportive care, eg, transfusion requirements and antibiotics, have been documented in several clinical trials and can lead to lower total care costs. However, the high cost of colony-stimulating factors and the necessity to treat large numbers of patients who do not benefit can offset the economic gains, unless the savings in hospitalization and supportive care are substantial. Primary prophylaxis with colony-stimulating factors is cost-saving only if the rate of hospitalization for febrile neutropenia is 40% or more; no current standard regimens are near that figure. In general, the American Society of Clinical Oncology clinical practice guide-lines for the use of colony-stimulating factors lead to effective and cost-conscious use of these expensive growth factors. Colony-stimulating factors are not recommended for primary prophylaxis of febrile neutropenia, are recommended for secondary prophylaxis if dose-reduction is not appropriate, and are recommended for stimulation of hematopoietic progenitor cells and reconstitution after high-dose chemotherapy. Further expansion of use based on economic factors will depend on documented survival benefit, major improvements in supportive care due to colony-stimulating factors, or markedly lower costs of colony-stimulating factors.