Granulocyte Colony-Stimulating Factors for Febrile

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Granulocyte Colony-Stimulating Factors for Febrile Cooper et al. BMC Cancer 2011, 11:404 http://www.biomedcentral.com/1471-2407/11/404 RESEARCHARTICLE Open Access Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis Katy L Cooper1*, Jason Madan2, Sophie Whyte1, Matt D Stevenson1 and Ron L Akehurst1 Abstract Background: 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. Methods: 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. Results: 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). Conclusions: 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. Background associated costs and detrimental effects on quality of Neutropenia is the major dose-limiting toxicity of many life [2,3]. In addition, an FN episode has been shown to chemotherapy regimens. Grade 3 and grade 4 neutrope- increase the risk of chemotherapy dose reductions and nia are defined as a neutrophil count < 1.0 × 109/L and delays [4]. Unplanned reductions in chemotherapy dose <0.5×109/L respectively. Febrile neutropenia (FN) is may cause further deaths from cancer in the long-term; defined as neutropenia with fever, usually indicating in a retrospective analysis of breast cancer patients with infection, and is associated with substantial morbidity, a 30-year follow-up, the survival rate was 40% (95% CI: mortality, and costs [1]. The direct risk of mortality 26%, 55%) among patients receiving at least 85% of their associated with FN has been estimated as 9.5% (95% planned dose, but only 21% (95% CI: 14%, 26%) among confidence interval [CI]: 9.2%, 9.8%) in a study of 41,779 patients who received less than 85% [5]. cancer patients hospitalised with FN [1]. Management Recombinant human granulocyte colony-stimulating of FN often requires lengthy hospitalisation, [1] with factors (G-CSFs) stimulate production of mature, func- tionalneutrophils[6].G-CSFshavebeenshownto * Correspondence: [email protected] reduce the incidence of FN when used as prophylaxis 1 School of Health and Related Research (ScHARR), University of Sheffield, following chemotherapy. Three G-CSFs are currently in Sheffield, UK Full list of author information is available at the end of the article common usage: filgrastim, pegfilgrastim, and © 2011 Cooper et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cooper et al. BMC Cancer 2011, 11:404 Page 2 of 11 http://www.biomedcentral.com/1471-2407/11/404 lenograstim. Filgrastim and lenograstim are administered NHS Economic Evaluation Database (NHS-EED). The as a series of daily injections; clinical studies suggest an Medline search strategy was designed with reference to average of 11 injections per chemotherapy cycle are the previous two reviews, and comprised subject head- required to achieve recovery of the absolute neutrophil ings and text words for G-CSFs combined with a search count (ANC) to within the normal range [7-10]. Pegfil- filter to identify RCTs (Appendix 1). Searches were not grastim is administered as a single injection per che- restricted by language. Bibliographies of retrieved papers motherapy cycle [11,12]. G-CSFs may be administered were searched for any additional relevant studies. as primary prophylaxis (in every chemotherapy cycle from cycle 1) or as secondary prophylaxis (in all remain- Inclusion and exclusion criteria ing cycles following a neutropenic event such as FN or Studies were considered suitable for inclusion if they prolonged severe neutropenia). The overall FN risk is assessed primary G-CSF prophylaxis (pegfilgrastim, fil- dependent on chemotherapy regimen as well as indivi- grastim or lenograstim) administered 1-3 days after the dual patient risk factors such as age, performance status completion of chemotherapy, versus a different G-CSF and disease stage [13]. Guidelines from the European or versus no primary G-CSF prophylaxis. Studies were Organisation for Research and Treatment of Cancer only included if they reported incidence of FN. For con- (EORTC), [13] the American Society of Clinical Oncol- sistency with the two existing systematic reviews, [18,19] ogy (ASCO) [14] and the National Comprehensive Can- only studies of adult cancer patients with solid tumours cer Network (NCCN) [15] recommend that prophylactic or lymphoma were included. Studies allowing concomi- G-CSFs should be used where the risk of FN associated tant antibiotic prophylaxis were included if identical with the chemotherapy regimen is greater than or equal prophylaxis was administered in both study arms. The to 20%, and may be considered where the risk is 10- following study types were excluded: studies of G-CSFs 20%, particularly where additional patient risk factors for treatment of FN; studies in children; studies in are present. patients with leukaemia, myeloid malignancies or myelo- This paper reports a systematic review and meta-ana- dysplastic syndromes; studies of G-CSFs for stem cell lysis of the effect of primary G-CSF prophylaxis (with mobilisation in bone marrow or peripheral blood stem pegfilgrastim, filgrastim or lenograstim) on incidence of cell transplantation; economic analyses; studies with dif- FN. The effect of each G-CSF is assessed in comparison fering drugs, doses or schedules of chemotherapy in with no primary G-CSF prophylaxis and in comparison each arm; studies with differing doses of the same G- with other G-CSFs. CSF in each arm; and studies not published in English. Methods Outcome measures Search strategy The outcome measure assessed in this review was the The systematic review followed the recommendations in incidence of FN over all cycles of chemotherapy within the PRISMA statement [16,17]. A systematic search was each study. FN was chosen as a key clinical outcome undertaken to identify randomised controlled trials due to its direct bearing on morbidity, mortality and (RCTs) of pegfilgrastim, filgrastim or lenograstim, com- hospitalisation rates, and also because this review was pared with no primary G-CSF or with one another, for undertaken alongside the development of an economic the reduction of FN following chemotherapy. A previous model which utilised FN rate as a key parameter. systematic review by Kuderer et al. [18] presented a meta-analysis of FN incidence within RCTs of primary Data extraction G-CSF prophylaxis versus no primary G-CSF prophy- Data was extracted by two reviewers using a form devel- laxis, while a systematic review by Pinto et al. [19] oped for this review and any discrepancies were resolved meta-analysed RCTs of primary prophylaxis using pegfil- through discussion. grastim versus filgrastim. The literature searches within these previous reviews were conducted during 2006. Data synthesis Therefore, databases were searched from 2006 onwards, Meta-analyses were undertaken to compare the effec- whereas studies published prior to 2006 were identified tiveness of G-CSFs versus no prophylaxis and versus from the two existing reviews. Searches were undertaken each other for the reduction of FN. Analyses were in December 2009. The following databases were undertaken using RevMan software (version 5, Cochrane searched: Medline, Medline in Process, EMBASE, Collaboration). Results for each comparison were pre- Science Citation Index, Cochrane Database of Systema- sented as a pooled relative risk and 95% CIs. Although tic Reviews, Cochrane CENTRAL Register of Controlled clinical and statistical heterogeneity existed between stu- Trials, Database of Abstracts of Reviews of Effects dies, there was insufficient data on individual popula- (DARE), Health Technology Assessment Database and tions to facilitate separate analyses. Therefore, for Cooper et al. BMC Cancer 2011, 11:404 Page 3 of 11 http://www.biomedcentral.com/1471-2407/11/404 consistency with existing reviews, all studies were A previous systematic review of prophylactic G-CSF included in the analysis,
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