Optimal primary febrile neutropenia prophylaxis for patients receiving docetaxel–cyclophosphamide chemotherapy for breast cancer: a systematic review

Abstract

Background

Due to the high rate of febrile neutropenia (FN) with docetaxel–cyclophosphamide (DC) chemotherapy, primary FN prophylaxis is recommended. However, the optimal choice of prophylaxis [i.e., granulocyte-colony stimulating factors (G-CSF) or antibiotics] is unknown. A systematic review was performed to address this knowledge gap.

Methods

Embase, Ovid Medline, Pubmed, the Cochrane database of systematic reviews, and Cochrane register of controlled trials were searched from 1946 to April 2016 for studies evaluating primary prophylactic FN treatments in breast cancer patients receiving DC chemotherapy. Outcome measures evaluated included: incidence of FN and treatment-related hospitalizations, chemotherapy dose reduction/delays/discontinuations, and adverse events. Screening and data collection were performed by two independent reviewers.

Results

Of 2105 identified records, 7 studies (n = 2535) met the pre-specified eligibility criteria. Seven additional studies (n = 621) were identified from prior systematic reviews. There were 3 randomized controlled trials (RCTs) (n = 2256) and 11 retrospective studies (n = 900). Study sample sizes ranged from 30 to 982 patients (median 99.5), evaluating pegfilgrastim (n = 1274), filgrastim (n = 1758), and oral ciprofloxacin (n = 108). Given the heterogeneity of patients and study design, a narrative synthesis of results was performed. Median FN rates with and without primary prophylaxis were 6.6 % (IQR 3.9–10.6 %) and 31.3 % (IQR 25–33 %), respectively. No FN-related deaths were reported. No RCT directly compared G-CSF with antibiotic interventions.

Conclusions

Primary FN prophylaxis reduces the incidence of FN. Despite considerable cost and toxicity differences between G-CSF and antibiotics, there is insufficient data to make a recommendation of one strategy over another.

Appendices

Appendix 1: Systematic review supplement: electronic literature search strategy

Database: Embase Classic + Embase <1947 to 2016 April 13>, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) <1946 to Present>.

Search Strategy:

1	exp Breast Neoplasms/
2	(breast adj2 (cancer$ or neoplasm$ or carcinoma$)).tw.
3	1 or 2
4	Granulocyte Colony-Stimulating Factor/
5	Granulocyte-colony stimulating factor$.tw.
6	gcsf.tw.
7	g csf.tw.
8	Neupogen.tw.
9	Neulasta.tw.
10	PegFilgrastim.tw.
11	Filgrastim/ or Filgrastim.tw.
12	colony-stimulating factor 3.tw.
13	or/4–12
14	3 and 13
15	exp Anti-Bacterial Agents/ and pc.fs.
16	exp Anti-Bacterial Agents/ and (prevention or prophyla$).tw.
17	Antibiotic Prophylaxis/
18	(antibiotic$ or antibacterial$) adj5 (prevent$ or prophyla$)).tw.
19	(septra or Trimethoprim-Sulfamethoxazole or cipro or Ciprofloxacin or Moxifloxacin) adj5 (prophyla$ or prevent$)).tw.
20	or/15–19
21	3 and 20
22	14 or 21
23	exp antineoplastic agents/
24	Antineoplastic Combined Chemotherapy Protocols/
25	Neoadjuvant Therapy/
26	Cyclophosphamide.tw.
27	Fluorouracil.tw.
28	Epirubicin.tw.
29	Docetaxel.tw.
30	(Paclitaxel or Taxol).tw.
31	(Adriamycin or doxorubicin).tw.
32	Cytoxan.tw.
33	Methotrexate.tw.
34	(chemotherap$ or antineoplastic agent$).tw.
35	Chemotherapy, Adjuvant/
36	or/23–35
37	22 and 36

PRESS EBC search submission

AMED	□
C2-SPCTRE	□
CINAHL	□
Cochrane Database of Systematic Reviews (CDSR; Cochrane Reviews)	□
Cochrane Central Register of Controlled Trials (CENTRAL; Clinical Trials)	□
Cochrane Methodology Register (CMR; Methods Studies)	□
Cochrane Library (all databases)	□
Database of Abstracts of Reviews of Effects (DARE; Other Reviews)	□
Embase	□
ERIC	□
ICTRP (International Clinical Trials Registry Platform)	□
LILACS (Latin American and Caribbean Health Sciences Literature)	□
MEDLINE	□
PreMEDLINE	□
PsycINFO	□
Other	□
Other	□

1. Translation of the research question	x
2. Boolean and proximity operators	x
3. Subject headings	x
4. Natural language/free-text	x
5. Spelling, syntax and line numbers	x
6. Limits and filters	x
7. Search strategy adaptations	x

Appendix 2: Risk of bias assessment of Included Randomized Trials

Trials at low risk of bias (green), high risk of bias (red) or unclear risk of bias (yellow)

Green (−) = low risk bias

Red (+) = high risk bias

Yellow (?) = unclear risk of bias

Appendix 3: PRISMA Checklist

Section/topic	#	Checklist item	Reported on page #
Title
Title	1	Identify the report as a systematic review, meta-analysis, or both	1
Abstract
Structured summary	2	Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number	2,3
Introduction
Rationale	3	Describe the rationale for the review in the context of what is already known	4,5
Objectives	4	Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS)	5
Methods
Protocol and registration	5	Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number	N/A
Eligibility criteria	6	Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale	6,7
Information sources	7	Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched	6,7
Search	8	Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated	18-22
Study selection	9	State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis)	6,7
Data collection process	10	Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators	6,7
Data items	11	List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made	6,7
Risk of bias in individual studies	12	Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis	7,28
Summary measures	13	State the principal summary measures (e.g., risk ratio, difference in means)	N/A
Synthesis of results	14	Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis	N/A
Risk of bias across studies	15	Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies)	7, 28
Additional analyses	16	Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified	N/A
Results
Study selection	17	Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram	6-7,18
Study characteristics	18	For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations	6-9
Risk of bias within studies	19	Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12)	7,28
Results of individual studies	20	For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot	6-110
Synthesis of results	21	Present results of each meta-analysis done, including confidence intervals and measures of consistency	N/A
Risk of bias across studies	22	Present results of any assessment of risk of bias across studies (see Item 15)	7,28
Additional analysis	23	Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16])	N/A
Discussion
Summary of evidence	24	Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers)	6-10
Limitations	25	Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias)	10-13
Conclusions	26	Provide a general interpretation of the results in the context of other evidence, and implications for future research	10-13
Funding
Funding	27	Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review	N/A