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Open Access Highly Accessed Research article

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

Author Affiliations

1 School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK

2 Academic Unit of Primary Health Care, University of Bristol, Bristol, UK

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BMC Cancer 2011, 11:404  doi:10.1186/1471-2407-11-404


The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2407/11/404


Received:25 May 2011
Accepted:23 September 2011
Published:23 September 2011

© 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.

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

Neutropenia is the major dose-limiting toxicity of many chemotherapy regimens. Grade 3 and grade 4 neutropenia are defined as a neutrophil count < 1.0 × 109/L and < 0.5 × 109/L respectively. Febrile neutropenia (FN) is defined as neutropenia with fever, usually indicating infection, and is associated with substantial morbidity, mortality, and costs [1]. The direct risk of mortality associated with FN has been estimated as 9.5% (95% confidence interval [CI]: 9.2%, 9.8%) in a study of 41,779 cancer patients hospitalised with FN [1]. Management of FN often requires lengthy hospitalisation, [1] with associated costs and detrimental effects on quality of life [2,3]. In addition, an FN episode has been shown to increase the risk of chemotherapy dose reductions and delays [4]. Unplanned reductions in chemotherapy dose may cause further deaths from cancer in the long-term; in a retrospective analysis of breast cancer patients with a 30-year follow-up, the survival rate was 40% (95% CI: 26%, 55%) among patients receiving at least 85% of their planned dose, but only 21% (95% CI: 14%, 26%) among patients who received less than 85% [5].

Recombinant human granulocyte colony-stimulating factors (G-CSFs) stimulate production of mature, functional neutrophils [6]. G-CSFs have been shown to reduce the incidence of FN when used as prophylaxis following chemotherapy. Three G-CSFs are currently in common usage: filgrastim, pegfilgrastim, and lenograstim. Filgrastim and lenograstim are administered as a series of daily injections; clinical studies suggest an average of 11 injections per chemotherapy cycle are required to achieve recovery of the absolute neutrophil count (ANC) to within the normal range [7-10]. Pegfilgrastim is administered as a single injection per chemotherapy cycle [11,12]. G-CSFs may be administered as primary prophylaxis (in every chemotherapy cycle from cycle 1) or as secondary prophylaxis (in all remaining cycles following a neutropenic event such as FN or prolonged severe neutropenia). The overall FN risk is dependent on chemotherapy regimen as well as individual patient risk factors such as age, performance status and disease stage [13]. Guidelines from the European Organisation for Research and Treatment of Cancer (EORTC), [13] the American Society of Clinical Oncology (ASCO) [14] and the National Comprehensive Cancer Network (NCCN) [15] recommend that prophylactic G-CSFs should be used where the risk of FN associated with the chemotherapy regimen is greater than or equal to 20%, and may be considered where the risk is 10-20%, particularly where additional patient risk factors are present.

This paper reports a systematic review and meta-analysis of the effect of primary G-CSF prophylaxis (with pegfilgrastim, filgrastim or lenograstim) on incidence of FN. The effect of each G-CSF is assessed in comparison with no primary G-CSF prophylaxis and in comparison with other G-CSFs.

Methods

Search strategy

The systematic review followed the recommendations in the PRISMA statement [16,17]. A systematic search was undertaken to identify randomised controlled trials (RCTs) of pegfilgrastim, filgrastim or lenograstim, compared with no primary G-CSF or with one another, for the reduction of FN following chemotherapy. A previous systematic review by Kuderer et al. [18] presented a meta-analysis of FN incidence within RCTs of primary G-CSF prophylaxis versus no primary G-CSF prophylaxis, while a systematic review by Pinto et al. [19] meta-analysed RCTs of primary prophylaxis using pegfilgrastim versus filgrastim. The literature searches within these previous reviews were conducted during 2006. Therefore, databases were searched from 2006 onwards, whereas studies published prior to 2006 were identified from the two existing reviews. Searches were undertaken in December 2009. The following databases were searched: Medline, Medline in Process, EMBASE, Science Citation Index, Cochrane Database of Systematic Reviews, Cochrane CENTRAL Register of Controlled Trials, Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database and NHS Economic Evaluation Database (NHS-EED). The Medline search strategy was designed with reference to the previous two reviews, and comprised subject headings and text words for G-CSFs combined with a search filter to identify RCTs (Appendix 1). Searches were not restricted by language. Bibliographies of retrieved papers were searched for any additional relevant studies.

Inclusion and exclusion criteria

Studies were considered suitable for inclusion if they assessed primary G-CSF prophylaxis (pegfilgrastim, filgrastim or lenograstim) administered 1-3 days after the completion of chemotherapy, versus a different G-CSF or versus no primary G-CSF prophylaxis. Studies were only included if they reported incidence of FN. For consistency with the two existing systematic reviews, [18,19] only studies of adult cancer patients with solid tumours or lymphoma were included. Studies allowing concomitant antibiotic prophylaxis were included if identical prophylaxis was administered in both study arms. The following study types were excluded: studies of G-CSFs for treatment of FN; studies in children; studies in patients with leukaemia, myeloid malignancies or myelodysplastic syndromes; studies of G-CSFs for stem cell mobilisation in bone marrow or peripheral blood stem cell transplantation; economic analyses; studies with differing drugs, doses or schedules of chemotherapy in each arm; studies with differing doses of the same G-CSF in each arm; and studies not published in English.

Outcome measures

The outcome measure assessed in this review was the incidence of FN over all cycles of chemotherapy within each study. FN was chosen as a key clinical outcome due to its direct bearing on morbidity, mortality and hospitalisation rates, and also because this review was undertaken alongside the development of an economic model which utilised FN rate as a key parameter.

Data extraction

Data was extracted by two reviewers using a form developed for this review and any discrepancies were resolved through discussion.

Data synthesis

Meta-analyses were undertaken to compare the effectiveness of G-CSFs versus no prophylaxis and versus each other for the reduction of FN. Analyses were undertaken using RevMan software (version 5, Cochrane Collaboration). Results for each comparison were presented as a pooled relative risk and 95% CIs. Although clinical and statistical heterogeneity existed between studies, there was insufficient data on individual populations to facilitate separate analyses. Therefore, for consistency with existing reviews, all studies were included in the analysis, and a random effects model was used. Heterogeneity was presented using the I2 statistic, which describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance) [20].

Results

Number and characteristics of included studies

The flow chart for study inclusion is shown in Figure 1 and the included studies are described in Table 1. Studies published from 2006 onwards were identified from the literature search, and studies published prior to 2006 were identified from two previous reviews [18,19]. In total, 23 citations relating to 25 studies satisfied the inclusion criteria: 5 studies of primary pegfilgrastim vs. no primary G-CSF (within 4 citations); [21-24] 10 studies of primary filgrastim vs. no primary G-CSF (within 9 citations); [25-33] 5 studies of primary lenograstim vs. no primary G-CSF; [9,10,34-36] and 5 studies of primary pegfilgrastim vs. primary filgrastim [7,8,37-39]. No studies were identified comparing lenograstim with either pegfilgrastim alone or filgrastim alone.

thumbnailFigure 1. Flow chart for identification of relevant studies.

Table 1. Description of trials of primary G-CSFs (vs. no primary G-CSF, or vs. each other)

A previous systematic review of prophylactic G-CSF use [18] included only a single study of pegfilgrastim versus no primary G-CSF [21]. Our literature search identified 4 additional RCTs of pegfilgrastim vs. no primary G-CSF, which were conducted in populations with colorectal cancer, [24] breast cancer, [23] non-Hodgkin's lymphoma, [22] and various solid tumours; [22] the latter three studies were restricted to elderly patients. Our review also identified an additional large RCT of filgrastim vs. no primary G-CSF in breast cancer [33].

There was heterogeneity among trials of all three G-CSFs in terms of cancer type, patient age, chemotherapy regimen, number of chemotherapy cycles and cycle length (Table 1). Filgrastim and lenograstim were generally given for 10-14 days where the chemotherapy cycle length was 3 weeks (and for fewer days in a small number of trials with shorter cycle lengths). The comparator arm in some of the studies included secondary G-CSFs for those patients having an FN event, and some trials allowed prophylactic antibiotics in both arms. Some studies were open-label rather than double-blind.

Effectiveness of G-CSFs in reducing febrile neutropenia incidence

The relative risks of FN incidence are shown in Figure 2 for trials of G-CSF versus no primary G-CSF, and in Figure 3 for trials of pegfilgrastim versus filgrastim. The pooled relative risks for each G-CSF comparison are summarised in Table 2. Primary prophylaxis with each of the G-CSFs significantly decreased the risk of FN compared with no primary G-CSF, 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 when using any primary G-CSF prophylaxis versus no primary G-CSF prophylaxis was 0.51 (95% CI: 0.41 to 0.62).

thumbnailFigure 2. Primary G-CSFs versus no primary G-CSF: FN incidence. Cancer types for each study are shown after the author and date. CHOP and CNOP = chemotherapy regimens for NHL (see Table 1 footnote); NHL = non-Hodgkin's lymphoma; SCLC = small-cell lung cancer; solid = solid tumours. *Indicates studies in patients aged ≥ 60 or ≥ 65 years.

thumbnailFigure 3. Pegfilgrastim versus filgrastim: FN incidence. Cancer types for each study are shown after the author and date. HL = Hodgkin's lymphoma; NHL = non-Hodgkin's lymphoma. *Indicates studies in patients aged ≥ 60 or ≥ 65 years. In the Holmes 2002 (phase II) study,[37] FN incidence in the filgrastim arm was reported as 2/25, which was incorrectly converted to 12%. The absolute numbers (2/25) have been used in this analysis. Therefore the resulting relative risk differs slightly from that reported in the previous systematic review by Pinto (2007),[19] which used the 12% figure.

Table 2. Summary of febrile neutropenia incidence based on meta-analyses of trials of G-CSFs

There was a relatively high level of statistical heterogeneity in the analyses as shown by the I2 statistic, which ranged from 50-76%; this is likely to reflect the variations between studies in factors such as cancer type, patient age, chemotherapy regimen, number of chemotherapy cycles and cycle length. Individual studies differed on too many variables for formal sub-analyses to be meaningful. However, Figures 2 and 3 illustrate the cancer type for each study (shown after the author and date) and highlight studies in populations aged ≥ 60 or ≥ 65 years (shown by asterisks). There was no clear difference in G-CSF effectiveness between cancer types, nor in studies restricting to an elderly population. As the majority of studies administered filgrastim and lenograstim for 10-14 days (for 3-week chemotherapy cycles), there was insufficient data to assess the effects of shorter durations of G-CSF treatment.

In terms of comparisons between different G-CSFs, the relative risk of FN for pegfilgrastim versus filgrastim was 0.66 (95% CI: 0.44 to 0.98). There were no head-to-head trials comparing lenograstim to either of the other two G-CSFs.

Discussion

Our systematic review and meta-analyses confirm and strengthen previous evidence that primary prophylaxis with each of the three G-CSFs is effective in reducing the risk of FN following chemotherapy. In particular, our systematic review identified 4 further RCTs of pegfilgrastim vs. no primary G-CSF, [22-24] whereas at the time of a previous systematic review [18] only a single RCT [21] making this comparison was available. Although these 5 RCTs comparing pegfilgrastim with no primary G-CSF were heterogeneous in terms of clinical population and chemotherapy regimen, the pooled relative risk indicated a significant effect of pegfilgrastim in reducing FN incidence. Filgrastim and lenograstim also significantly reduced FN incidence.

This review also strengthens the evidence base regarding the comparative effectiveness of the three G-CSFs; in particular, comparison of the "once-per-cycle" G-CSF pegfilgrastim versus the "once-daily" G-CSF filgrastim. Meta-analysis of five RCTs indicated that FN incidence was significantly lower following primary prophylaxis with pegfilgrastim than with filgrastim. This is consistent with the fact that the reduction in FN risk for pegfilgrastim versus no primary G-CSF was greater than the reduction observed for filgrastim versus no primary G-CSF.

As discussed in previous reviews, [18,19] there was heterogeneity among the studies in terms of the clinical population (age, cancer type), chemotherapy regimen, and cycle length and number. Correspondingly, heterogeneity was observed among the study results. Since individual studies differed on too many variables for formal sub-analyses to be meaningful, all studies were included in the analysis. There was no clear difference in G-CSF effectiveness between cancer types, nor in studies restricting to elderly populations. However, the variation in clinical population, and the corresponding high levels of heterogeneity, indicate that caution should be used when applying the results to individual clinical settings. Conversely, the range of populations and treatment regimens covered by the included studies is likely to reflect the variations which would be observed in clinical practice.

Conclusions

This systematic review and meta-analysis demonstrate that primary G-CSF prophylaxis with pegfilgrastim, filgrastim and lenograstim is effective in reducing the risk of FN in adults undergoing chemotherapy for solid tumours or lymphoma. In addition, although heterogeneity existed between studies, a meta-analysis suggests that pegfilgrastim reduces the risk of FN to a greater extent than filgrastim.

List of abbreviations

ANC: Absolute neutrophil count; ASCO: American Society of Clinical Oncology; DARE: Database of Abstracts of Reviews of Effects; EORTC: European Organisation for Research and Treatment of Cancer; FN: Febrile neutropenia; G-CSF: Granulocyte colony-stimulating factor; NCCN: National Comprehensive Cancer Network; NHS-EED: NHS Economic Evaluation Database; RCT: Randomised controlled trial.

Competing interests

The research underlying this paper was funded by Amgen Ltd, and a research grant from Amgen (EUROPE) GmbH was provided to support the production of the manuscript. Amgen staff reviewed and made suggested edits to the manuscript, but final content, authorship and right to publication remained with the research team.

Authors' contributions

KC undertook the systematic review and drafted the manuscript. JM undertook the statistical analyses. SW contributed to study selection and interpretation. MS contributed to study selection and interpretation and to the statistical analyses. RA participated in the design and coordination of the study and contributed to the statistical analyses. All authors read and approved the final manuscript.

Appendix 1: Search strategy (Medline)

1 Granulocyte colony-stimulating factor/

2 Granulocyte colony-stimulating factor, recombinant/

3 Colony-stimulating factors, recombinant/

4 Filgrastim/

5 G-CSF$

6 granulocyte colony-stimulating factor$

7 filgrastim

8 Neupogen

9 pegfilgrastim

10 Neulasta

11 lenograstim

12 Granocyte

13 Euprotin

14 r-metHuG-CSF

15 SD-01

16 PEG-rmetHuG-CSF

17 XM02

18 Ratiograstim

19 or/1-18

20 randomized controlled trial.pt.

21 controlled clinical trial.pt.

22 randomized controlled trial/

23 random allocation/

24 double blind method/

25 single blind method/

26 clinical trial.pt.

27 exp clinical trial/

28 (clin$ adj25 trial$).ti,ab.

29 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab.

30 placebos/

31 placebos.ti,ab.

32 random.ti,ab.

33 research design/

34 randomised.ti,ab

35 randomized.ti,ab

36 or/20-35

37 19 and 36

("$" indicates truncations; "/" indicates medical subject headings)

Acknowledgements and funding

The research underlying this paper was funded by Amgen Ltd, and a research grant from Amgen (EUROPE) GmbH was provided to support the production of the manuscript. Amgen staff reviewed and made suggested edits to the manuscript, but final content, authorship and right to publication remained with the research team.

References

  1. Kuderer N, Dale D, Crawford J, Cosler L, Lyman G: Mortality, Morbidity, and Cost Associated with Febrile Neutropenia in Adult Cancer Patients.

    CANCER 2006, 106:2258-2266. PubMed Abstract | Publisher Full Text OpenURL

  2. Brown R, Hutton J, Burrell A: Cost Effectiveness of Treatment Options in Advanced Breast Cancer in the UK.

    Pharmacoeconomics 2001, 19:1091-1102. PubMed Abstract | Publisher Full Text OpenURL

  3. Brown RE, Hutton J: Cost-utility model comparing docetaxel and paclitaxel in advanced breast cancer patients.

    Anticancer Drugs 1998, 9:899-907. PubMed Abstract | Publisher Full Text OpenURL

  4. Shayne M, Crawford J, Dale D, Culakova E, Lyman G, for the ANC Study Group: Predictors of reduced dose intensity in patients with early-stage breast cancer receiving adjuvant chemotherapy.

    Breast Cancer Res Treat 2006, 100:255-262. PubMed Abstract | Publisher Full Text OpenURL

  5. Bonadonna G, Moliterni A, Zambetti M, Daidone M, Pilotti S, Gianni L, et al.: 30 years' follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study.

    BMJ 2005, 330:217-222. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  6. Welte K, Gabrilove J, Bronchud MH, Platzer E, Morstyn G: Filgrastim (r-metHuG-CSF): the first 10 years.

    Blood 1996, 88:1907-1929. PubMed Abstract | Publisher Full Text OpenURL

  7. Green M, Koelbl H, Baselga J, GAlid A, Guillem V, Gascon P, et al.: A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy.

    Annals of Oncology 2003, 14:29-35. PubMed Abstract | Publisher Full Text OpenURL

  8. Holmes F, O'Shaughnessy J, Vukelja S, Jones S, Shogan J, Savin M, et al.: Blinded, Randomized, Multicenter Study to Evaluate Single Administration Pegfilgrastim Once per Cycle Versus Daily Filgrastim as an Adjunct to Chemotherapy in Patients With High-Risk Stage II or Stage III/IV Breast Cancer.

    JOURNAL OF CLINICAL ONCOLOGY 2002, 20:727-731. PubMed Abstract | Publisher Full Text OpenURL

  9. Chevallier B, Chollet P, Merrouche Y, Roche H, Fumoleau P, Kerbrat P, et al.: Lenograstim prevents morbidity from intensive induction chemotherapy in the treatment of inflammatory breast cancer.

    J Clin Oncol 1995, 13:1564-1571. PubMed Abstract | Publisher Full Text OpenURL

  10. Bui BN, Chevallier B, Chevreau C, Krakowski I, Peny AM, Thyss A, et al.: Efficacy of lenograstim on hematologic tolerance to MAID chemotherapy in patients with advanced soft tissue sarcoma and consequences on treatment dose-intensity.

    J Clin Oncol 1995, 13:2629-2636. PubMed Abstract | Publisher Full Text OpenURL

  11. Molineux G: The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta).

    Curr Pharm Des 2004, 10:1235-1244. PubMed Abstract | Publisher Full Text OpenURL

  12. Molineux G: Pegfilgrastim: using pegylation technology to improve neutropenia support in cancer patients.

    Anticancer Drugs 2003, 14:259-264. PubMed Abstract | Publisher Full Text OpenURL

  13. Aapro MS, Bohlius J, Cameron DA, Dal LL, Donnelly JP, Kearney N, et al.: 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours.

    Eur J Cancer 2011, 47:8-32. PubMed Abstract | Publisher Full Text OpenURL

  14. Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al.: 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline.

    J Clin Oncol 2006, 24:3187-3205. PubMed Abstract | Publisher Full Text OpenURL

  15. National Comprehensive Cancer Network (NCCN): Clinical Practice Guidelines in Oncology: Myeloid Growth Factors.

    2011.

    1-5-2010

  16. Moher D, Liberati A, Tetzlaff J, Altman DG: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.

    Ann Intern Med 2009, 151:264-269. PubMed Abstract | Publisher Full Text OpenURL

  17. PRISMA statement website [http://www.prisma-statement.org] webcite

    2009.

  18. Kuderer N, Dale D, Crawford J, Lyman G: Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review.

    JOURNAL OF CLINICAL ONCOLOGY 2007, 25:3158-6731. PubMed Abstract | Publisher Full Text OpenURL

  19. Pinto L, Liu Z, Doan Q: Comparison of pegfilgrastim with filgrastim on febrile neutropenia, grade IV neutropenia and bone pain: a meta-analysis of randomized controlled trials.

    Curr Med Res Opin 2007, 23:2283-2295. PubMed Abstract | Publisher Full Text OpenURL

  20. The Cochrane Collaboration, Higgins JPT, Green S:

    Cochrane Handbook for Systematic Reviews of Interventions. 2009. OpenURL

  21. Vogel C, Wojtukiewicz M, Carroll R, Tjulandin S, Barajas-Figueroa L, Wiens B, et al.: First and Subsequent Cycle Use of Pegfilgrastim Prevents Febrile Neutropenia in Patients With Breast Cancer: A Multicenter, Double-Blind, Placebo-Controlled Phase III Study.

    J Clin Oncol 2005, 23:1178-1184. PubMed Abstract | Publisher Full Text OpenURL

  22. Balducci L, Al-Halawani H, Charu V, Tam J, Shahin S, Dreiling L, et al.: Elderly cancer patients receiving chemotherapy benefit from first-cycle pegfilgrastim.

    Oncologist 2007, 12:1416-1424. PubMed Abstract | Publisher Full Text OpenURL

  23. Romieu G, Clemens M, Mahlberg R: Pegfilgrastim supports delivery of FEC-100 chemotherapy in elderly patients with high risk breast cancer: A randomized phase 2 trial.

    Critical Reviews in Oncology/Hematology 2007, 64:64-72. PubMed Abstract | Publisher Full Text OpenURL

  24. Hecht JR, Pillai M, Gollard R, Dreiling L, Mo M, Malik I: Pegfilgrastim in colorectal cancer (CRC) patients (pts) receiving every-two-week (Q2W) chemotherapy (CT): Long-term results from a phase II, randomized, controlled study.

    JOURNAL OF CLINICAL ONCOLOGY 2009, 27:Abstract 4072. OpenURL

  25. Doorduijn JK, van der HB, van Imhoff GW, van der Hem KG, Kramer MH, van Oers MH, et al.: CHOP compared with CHOP plus granulocyte colony-stimulating factor in elderly patients with aggressive non-Hodgkin's lymphoma.

    J Clin Oncol 2003, 21:3041-3050. PubMed Abstract | Publisher Full Text OpenURL

  26. Osby E, Hagberg H, Kvaloy S, Teerenhovi L, Anderson H, Cavallin-Stahl E, et al.: CHOP is superior to CNOP in elderly patients with aggressive lymphoma while outcome is unaffected by filgrastim treatment: results of a Nordic Lymphoma Group randomized trial.

    Blood 2003, 101:3840-3848. PubMed Abstract | Publisher Full Text OpenURL

  27. Zinzani PL, Pavone E, Storti S, Moretti L, Fattori PP, Guardigni L, et al.: Randomized trial with or without granulocyte colony-stimulating factor as adjunct to induction VNCOP-B treatment of elderly high-grade non-Hodgkin's lymphoma.

    Blood 1997, 89:3974-3979. PubMed Abstract | Publisher Full Text OpenURL

  28. Pettengell R, Gurney H, Radford J, Deakin D: Granulocyte Colony-Stimulating Factor to Prevent Dose-Limiting Neutropenia in Non-Hodgkin's Lymphoma: A Randomized Controlled Trial.

    Blood 1992, 80:1430-1436. PubMed Abstract | Publisher Full Text OpenURL

  29. Timmer-Bonte J, de Boo T, Smit H, Biesma B, Wilschut F, Cheragwandi S, et al.: Prevention of Chemotherapy-Induced Febrile Neutropenia by Prophylactic Antibiotics Plus or Minus Granulocyte Colony-Stimulating Factor in Small-Cell Lung Cancer: A Dutch Randomized Phase III Study.

    J Clin Oncol 2005, 23:7974-7984. PubMed Abstract | Publisher Full Text OpenURL

  30. Trillet-Lenoir V, Green J, Manegold C, Von Pawel J, Gatzemeier U, Lebeau B, et al.: Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy.

    European Journal of Cancer 1993, 29:319-324. Publisher Full Text OpenURL

  31. Crawford J, Ozer H, Stoller R, Johnson D, Lyman G, Tabbara I, et al.: Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer.

    N Engl J Med 1991, 325:164-170. PubMed Abstract | Publisher Full Text OpenURL

  32. Fossa SD, Kaye SB, Mead GM, Cullen M, de WR, Bodrogi I, et al.: Filgrastim during combination chemotherapy of patients with poor-prognosis metastatic germ cell malignancy. European Organization for Research and Treatment of Cancer, Genito-Urinary Group, and the Medical Research Council Testicular Cancer Working Party, Cambridge, United Kingdom.

    J Clin Oncol 1998, 16:716-724. PubMed Abstract | Publisher Full Text OpenURL

  33. del Giglio A, Eniu A, Ganea-Motan D, Topuzov E, Lubenau H: XM02 is superior to placebo and equivalent to Neupogen in reducing the duration of severe neutropenia and the incidence of febrile neutropenia in cycle 1 in breast cancer patients receiving docetaxel/doxorubicin chemotherapy.

    BMC Cancer 2008, 8:332. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  34. Gisselbrecht C, Haioun C, Lepage E, Bastion Y, Tilly H, Bosly A, et al.: Placebo-controlled phase III study of lenograstim (glycosylated recombinant human granulocyte colony-stimulating factor) in aggressive non-Hodgkin's lymphoma: factors influencing chemotherapy administration. Groupe d'Etude des Lymphomes de l'Adulte.

    Leuk Lymphoma 1997, 25:289-300. PubMed Abstract | Publisher Full Text OpenURL

  35. Gebbia V, Valenza R, Testa A, Cannata G, Borsellino N, Gebbia N: A prospective randomized trial of thymopentin versus granulocyte--colony stimulating factor with or without thymopentin in the prevention of febrile episodes in cancer patients undergoing highly cytotoxic chemotherapy.

    Anticancer Res 1994, 14:731-734. PubMed Abstract OpenURL

  36. Gebbia V, Testa A, Valenza R, Borsellino N, Cipolla C, Cannata G, et al.: A prospective evaluation of the activity of human granulocyte-colony stimulating factor on the prevention of chemotherapy-related neutropenia in patients with advanced carcinoma.

    J Chemother 1993, 5:186-190. PubMed Abstract OpenURL

  37. Holmes F, Jones S, O'Shaughnessy J, Vukelja S, George T, Savin M, et al.: Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer.

    Annals of Oncology 2002, 13:903-909. PubMed Abstract | Publisher Full Text OpenURL

  38. Grigg A, Solal-Celigny P, Hoskin P, Taylor K, McMillan A, Forstpointner R, et al.: Open-label, randomized study of pegfilgrastim vs. daily filgrastim as an adjunct to chemotherapy in elderly patients with non-Hodgkin's lymphoma.

    Leuk Lymphoma 2003, 44:1503-1508. PubMed Abstract | Publisher Full Text OpenURL

  39. Vose J, Crump M, Lazarus H, Emmanouilides C, Schenkein D, Moore J, et al.: Randomized, Multicenter, Open-Label Study of Pegfilgrastim Compared With Daily Filgrastim After Chemotherapy for Lymphoma.

    JOURNAL OF CLINICAL ONCOLOGY 2003, 21:514-519. PubMed Abstract | Publisher Full Text OpenURL

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-2407/11/404/prepub