Closed‐system drug‐transfer devices plus safe handling of hazardous drugs versus safe handling alone for reducing exposure to infusional hazardous drugs in healthcare staff

Kurinchi Selvan Gurusamy; Lawrence MJ Best; Cynthia Tanguay; Elaine Lennan; Mika Korva; Jean‐François Bussières

doi:10.1002/14651858.CD012860.pub2

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Figure 1

PRISMA study flow diagram. CSTD: closed‐system transfer device

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Green +: Low risk of bias. Yellow ?: Moderate risk of bias or 'No information'. Red ‐: Serious or critical risk of bias.

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Figure 3

Funnel plot of comparison: 1 Closed‐system transfer device plus safe handling versus safe handling alone, outcome: 1.2 Proportion of surfaces contaminated.

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Figure 4

Funnel plot of comparison: 1 Closed‐system transfer device plus safe handling versus safe handling alone, outcome: 1.3 Quantity of surface contamination (pg/cm²).

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Analysis 1.1

Comparison 1 Closed‐system transfer device plus safe handling versus safe handling alone, Outcome 1 Urine tests for exposure.

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Analysis 1.2

Comparison 1 Closed‐system transfer device plus safe handling versus safe handling alone, Outcome 2 Proportion of surfaces contaminated.

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Analysis 1.3

Comparison 1 Closed‐system transfer device plus safe handling versus safe handling alone, Outcome 3 Quantity of surface contamination (pg/cm²).

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Analysis 2.1

Comparison 2 Subgroup analysis (based on study design and device), Outcome 1 Urine tests for exposure (PhaSeal only).

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Analysis 2.2

Comparison 2 Subgroup analysis (based on study design and device), Outcome 2 Proportion of surfaces contaminated with cyclophosphamide in pharmacy areas: stratified by study design.

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Analysis 2.3

Comparison 2 Subgroup analysis (based on study design and device), Outcome 3 Proportion of surfaces contaminated with ifosfamide in pharmacy areas: stratified by study design.

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Analysis 2.4

Comparison 2 Subgroup analysis (based on study design and device), Outcome 4 Proportion of surfaces contaminated with methotrexate in pharmacy areas: stratified by study design.

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Analysis 2.5

Comparison 2 Subgroup analysis (based on study design and device), Outcome 5 Proportion of surfaces contaminated with 5‐fluorouracil in pharmacy areas: stratified by study design.

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Analysis 2.6

Comparison 2 Subgroup analysis (based on study design and device), Outcome 6 Proportion of surfaces contaminated (PhaSeal only).

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Analysis 2.7

Comparison 2 Subgroup analysis (based on study design and device), Outcome 7 Proportion of surfaces contaminated (Tevadaptor only).

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Analysis 2.8

Comparison 2 Subgroup analysis (based on study design and device), Outcome 8 Quantity of surface contamination with cyclophosphamide in pharmacy areas (pg/cm²): stratified by study design.

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Analysis 2.9

Comparison 2 Subgroup analysis (based on study design and device), Outcome 9 Quantity of surface contamination with ifosfamide in pharmacy areas (pg/cm²): stratified by study design.

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Analysis 2.10

Comparison 2 Subgroup analysis (based on study design and device), Outcome 10 Quantity of surface contamination with methotrexate in pharmacy areas (pg/cm²): stratified by study design.

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Analysis 2.11

Comparison 2 Subgroup analysis (based on study design and device), Outcome 11 Quantity of surface contamination with 5‐fluorouracil in pharmacy areas (pg/cm²): stratified by devices.

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Analysis 2.12

Comparison 2 Subgroup analysis (based on study design and device), Outcome 12 Quantity of surface contamination with 5‐fluorouracil in pharmacy areas (pg/cm²): stratified by study design.

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Analysis 2.13

Comparison 2 Subgroup analysis (based on study design and device), Outcome 13 Quantity of surface contamination (pg/cm²): stratified by devices.

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Analysis 3.1

Comparison 3 Sensitivity analysis, Outcome 1 Urine tests for exposure (ICC = 0.05).

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Analysis 3.2

Comparison 3 Sensitivity analysis, Outcome 2 Urine tests for exposure (ICC = 0.01).

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Analysis 3.3

Comparison 3 Sensitivity analysis, Outcome 3 Urine tests for exposure (ICC = 0.00).

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Analysis 3.4

Comparison 3 Sensitivity analysis, Outcome 4 Proportion of surfaces contaminated (ICC = 0.05).

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Analysis 3.5

Comparison 3 Sensitivity analysis, Outcome 5 Proportion of surfaces contaminated (ICC = 0.01).

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Analysis 3.6

Comparison 3 Sensitivity analysis, Outcome 6 Proportion of surfaces contaminated (ICC = 0.00).

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Analysis 3.7

Comparison 3 Sensitivity analysis, Outcome 7 Quantity of surface contamination (pg/cm²) (ICC = 0.05).

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Analysis 3.8

Comparison 3 Sensitivity analysis, Outcome 8 Quantity of surface contamination (pg/cm²) (ICC = 0.01).

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Analysis 3.9

Comparison 3 Sensitivity analysis, Outcome 9 Quantity of surface contamination (pg/cm²) (ICC = 0.00).

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Summary of findings for the main comparison. Closed‐system transfer device plus safe handling versus safe handling alone for reducing healthcare staff exposure to infusional hazardous drugs: exposure and surface contamination

Closed‐system transfer device safe handling versus safe handling alone for reducing healthcare staff exposure to infusional hazardous drugs: exposure and contamination
Patient or population: healthcare staff who handle infusional hazardous drugs Settings: hospitals Intervention: closed‐system transfer device plus safe handling Control: safe handling alone
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of hospitals (samples; studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Safe handling alone	Closed‐system transfer device plus safe handling
Exposure (urine tests for exposure)
Cyclophosphamide alone	917 per 1000	761 per 1000 (422 to 1393)	RR 0.83 (0.46 to 1.52)	2 hospitals (20 participants; 2 studies)	⊕⊝⊝⊝ Very low^a,b,c
Cyclophosphamide or ifosfamide	714 per 1000	64 per 1000 (0 to 1000)	RR 0.09 (0.00 to 2.79)	1 hospital (14 participants; 1 study)	⊕⊝⊝⊝ Very low^a,b,c
Cyclophosphamide, ifosfamide, or gemcitabine	There were no participants with exposure in either group.			4 hospitals (36 participants; 1 study)	⊕⊝⊝⊝ Very low^a,b,c
Other measures of exposure	None of the studies report on blood tests or other measures of exposure to infusional hazardous drugs such as urine mutagenicity, chromosomal aberrations, sister chromatid exchanges, or micronuclei induction.
Surface contamination (proportion of surfaces contaminated)
*Pharmacy areas*
Cyclophosphamide	507 per 1000	451 per 1000 (395 to 512)	RR 0.89 (0.78 to 1.01)	338 hospitals (2937 samples; 13 studies)	⊕⊝⊝⊝ Very low^a,b,d,e
Ifosfamide	267 per 1000	251 per 1000 (197 to 317)	RR 0.94 (0.74 to 1.19)	304 hospitals (2332 samples; 9 studies)	⊕⊝⊝⊝ Very low^a,b,d
Methotrexate	102 per 1000	85 per 1000 (59 to 124)	RR 0.84 (0.58 to 1.22)	280 hospitals (1781 samples; 6 studies)	⊕⊝⊝⊝ Very low^a,b,d
5‐fluorouracil	236 per 1000	149 per 1000 (99 to 222)	RR 0.63 (0.42 to 0.94)	107 hospitals (1068 samples; 4 studies)	⊕⊝⊝⊝ Very low^a,d,f
Cytarabine	267 per 1000	192 per 1000 (48 to 762)	RR 0.72 (0.18 to 2.86)	84 hospitals (780 samples; 2 studies)	⊕⊝⊝⊝ Very low^a,b,d
Gemcitabine	322 per 1000	309 per 1000 (193 to 496)	RR 0.96 (0.60 to 1.54)	84 hospitals (780 samples; 2 studies)	⊕⊝⊝⊝ Very low^a,b,d
Irinotecan, docetaxel, paclitaxel, vinorelbine, ganciclovir, epirubicin, multiple drugs^ϯ	There is no evidence of difference in the proportion of samples contaminated with 5‐fluorouracil, cytarabine, gemcitabine, irinotecan, docetaxel, paclitaxel, vinorelbine, ganciclovir, epirubicin, or multiple drugs in pharmacy areas between closed‐system transfer device plus safe handling versus safe handling alone			Irinotecan, docetaxel, paclitaxel, vinorelbine: 83 hospitals (493 samples; 1 study) Ganciclovir: 1 hospital (287 samples; 1 study) Epirubicin: 1 hospital (60 samples; 1 study) Multiple drugs: 4 hospitals (109 samples; 1 study)	⊕⊝⊝⊝ Very low^a,b,d
*Patient‐care areas*
Cyclophosphamide	440 per 1000	444 per 1000 (378 to 519)	RR 1.01 (0.86 to 1.18)	279 hospitals (1535 samples; 5 studies)	⊕⊝⊝⊝ Very low^a,b,d
Ifosfamide	71 per 1000	102 per 1000 (64 to 161)	RR 1.44 (0.91 to 2.28)	279 hospitals (1535 samples; 5 studies)	⊕⊝⊝⊝ Very low^a,b,d
Methotrexate	25 per 1000	25 per 1000 (14 to 46)	RR 1.00 (0.55 to 1.85)	279 hospitals (1535 samples; 5 studies)	⊕⊝⊝⊝ Very low^a,b,d
5‐fluorouracil, cytarabine, gemcitabine, irinotecan, docetaxel, paclitaxel, vinorelbine, multiple drugs^ϯ	There is no evidence of difference in the proportion of samples contaminated with 5‐fluorouracil, cytarabine, gemcitabine, irinotecan, docetaxel, paclitaxel, vinorelbine, multiple drugs in patient‐care areas between closed‐system transfer device plus safe handling and safe handling alone			5‐fluorouracil, cytarabine, gemcitabine, irinotecan, docetaxel, paclitaxel, vinorelbine: 83 hospitals (493 samples; 1 study) Multiple drugs: 4 hospitals (33 samples; 1 study)	⊕⊝⊝⊝ Very low^a,b,d
Surface contamination (quantity of surface contamination (pg/cm²))
*Pharmacy areas*
Cyclophosphamide^‡	The mean cyclophosphamide in the control group is 124.30 pg/cm²	The mean cyclophosphamide in the intervention group is 49.34 pg/cm² lower (84.11 lower to 14.56 lower)	MD −49.34 pg/cm² (−84.11 to −14.56)	282 hospitals (1793 samples; 7 studies)	⊕⊝⊝⊝ Very low^a,b,f
Ifosfamide	The mean ifosfamide in the control group is 10.8 pg/cm²	The mean ifosfamide in the intervention group is 0.32 pg/cm² lower (6.58 lower to 5.94 higher)	MD −0.32 pg/cm² (−6.58 to 5.94)	280 hospitals (1749 samples; 6 studies)	⊕⊝⊝⊝ Very low^a,b,d
Methotrexate	The mean methotrexate in the control group is 18.23 pg/cm²	The mean methotrexate in the intervention group is 3.09 pg/cm² lower (13.80 lower to 7.61 higher)	MD −3.09 pg/cm² (−13.80 to 7.61)	280 hospitals (1749 samples; 6 studies)	⊕⊝⊝⊝ Very low^a,b,d
5‐fluorouracil	The mean 5‐fluorouracil in the control group is 740 pg/cm²	The mean 5‐fluorouracil in the intervention group is 231.62 pg/cm² higher (460.52 lower to 923.76 higher)	MD 231.62 (−460.52 to 923.76)	85 hospitals (602 samples; 3 studies)	⊕⊝⊝⊝ Very low^a,b,d
Epirubicin	The mean epirubicin in the control group is 110 pg/cm²	The mean 5‐fluorouracil in the intervention group is 110.00 pg/cm² lower (112.93 lower to 107.07 lower)	MD −110.00 (−112.93 to −107.07)	1 hospital (60 samples; 1 study)	⊕⊝⊝⊝ Very low^a,c,d
Cytarabine, gemcitabine, and irinotecan	There is no evidence of difference in the amount of cytarabine, gemcitabine, and irinotecan in pharmacy areas between closed‐system transfer device plus safe handling and safe handling alone			83 hospitals (493 samples; 1 study)	⊕⊝⊝⊝ Very low^a,b,d
*Patient‐care areas*
Cyclophosphamide	The mean cyclophosphamide in the control groups is 168 pg/cm²	The mean cyclophosphamide in the intervention group is 13.34 pg/cm² lower (36.01 lower to 9.32 higher)	MD −13.34 pg/cm² (−36.01 to 9.32)	279 hospitals (1535 samples; 5 studies)	⊕⊝⊝⊝ Very low^a,b,d,e
Ifosfamide	The mean ifosfamide in the control group is 4.59 pg/cm²	The mean ifosfamide in the intervention group is 3.59 pg/cm² higher (3.45 lower to 10.63 higher)	MD 3.59 pg/cm² (−3.45 to 10.63)	279 hospitals (1535 samples; 5 studies)	⊕⊝⊝⊝ Very low^a,b,d
Methotrexate	The mean methotrexate in the control groups is 1.42 pg/cm²	The mean methotrexate in the intervention group is 0.10 pg/cm² higher (0.57 lower to 0.78 higher)	MD 0.10 pg/cm² (−0.57 to 0.78)	279 hospitals (1535 samples; 5 studies)	⊕⊝⊝⊝ Very low^a,b,d
5‐fluorouracil, cytarabine, gemcitabine, and irinotecan	There is no evidence of difference in the amount of 5‐fluorouracil, cytarabine, gemcitabine, and irinotecan in patient‐care areas between closed‐system transfer device plus safe handling and safe handling alone			83 hospitals (460 samples; 1 study)	⊕⊝⊝⊝ Very low^a,b,d
Other measures of contamination	None of the studies report on atmospheric contamination.
CI: confidence interval; MD: mean difference; RR: risk ratio The basis for the assumed risk* is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ^ϯReport contains multiple drugs with no outcome information on individual drugs. ^‡In addition, one interrupted time‐series study (three hospitals; 342 samples) provided data on the quantity of contamination with cyclophosphamide from surface samples in pharmacy areas during three phases, initial phase of no CSTD, followed by CSTD, and then by no CSTD, each phase lasting three weeks (Harrison 2006). The authors took biweekly measurements in all three phases. Between the first two phases, the change in the slope between pre‐CSTD and CSTD was 3.9439 pg/cm² (95% CI 1.2303 to 6.6576; P = 0.01). Between the second and third phases, the slope and level were expected to rise again but the change in the slope between CSTD and post‐CSTD withdrawal was −1.9331 pg/cm², 95% CI −5.126 to 1.2598 (P = 0.200) and the level was 14.167 pg/cm² (SD = 10.619).
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aThe study or studies was or were at serious risk of bias (downgraded one level for risk of bias). ^bThe confidence intervals were wide (downgraded one level for imprecision). ^cThe sample size was small (downgraded one level for imprecision). ^dThis is a surrogate measure of health benefit (downgraded one level for indirectness). ^eThere was possible evidence of publication bias (Egger's test P value < 0.05) (downgraded one level for publication bias). ^fThere is no evidence that this small difference in levels of cyclophosphamide leads to decreased exposure or tangible health benefits (downgraded one level for imprecision).

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Summary of findings 2. Closed‐system transfer device plus safe handling versus safe handling alone for reducing healthcare staff exposure to infusional hazardous drugs: clinical outcomes

Closed‐system transfer device safe handling versus safe handling alone for reducing healthcare staff exposure to infusional hazardous drugs: clinical outcomes
Patient or population: healthcare staff who handle infusional hazardous drugs Settings: hospitals Intervention: closed‐system transfer device plus safe handling Control: safe handling alone
Outcomes	Illustrative comparative risks (95% CI)		Relative effect (95% CI)	No of hospitals (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Safe handling alone	Closed‐system transfer device plus safe handling
Health outcomes	None of the studies report health outcomes such as skin rashes, reproductive health effects (infertility or miscarriage), or development of any type of cancer.
Adverse events	None of the studies report this outcome.
Potential cost savings	The studies used different methods of calculating the costs and reported results in formats that could not be pooled via meta‐analysis. There is significant variability between the studies in terms of whether the use of CSTD results in cost savings (the point estimates of the average potential cost savings ranged between (2017) US D−642,656 and (2017) USD +221,818*.			6 hospitals (5 studies)	⊕⊝⊝⊝ Very low^a,b
Negative sign indicates cost savings and positive sign indicate increased costs due to the use of closed‐system transfer device. CI: confidence interval; CSTD*: closed‐system transfer device.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aThe studies are at serious risk of bias (downgraded one level for risk of bias). ^bThere is very serious inconsistency in magnitude and direction of effect (downgraded two levels for inconsistency).

Summary of findings 2. Closed‐system transfer device plus safe handling versus safe handling alone for reducing healthcare staff exposure to infusional hazardous drugs: clinical outcomes

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Table 1. Potential cost savings

Study name	Country	Number of hospitals	Device used	Method of calculation	Cost difference in original currency^a	Cost difference in USD 2017 equivalent^a
Chan 2016	Malaysia	1	Not stated	Actual costs of drugs and CSTD used during the period	(2015) MYR +148,632	(2017) USD +221,818
Edwards 2013	USA	1	Phaseal	Actual costs for CSTD, actual costs for drug use in CSTD group and hypothetical calculation of drugs necessary if CSTD was not used	(2012) USD −596,491	(2017) USD −642,656
Juhasz 2016	Hungary	2	Tevadaptor	Simulation costs based on potential drug left behind in the vial; costs of CSTD were not included	(2014) EUR −70,913	(2017) USD −61,202
Mullot 2008	France	1	Phaseal/Tevadaptor	Actual costs of drugs and CSTD used during the period	(2006) EUR +160,680	(2017) USD +155,144
Ozyaman 2016	Turkey	1	Phaseal	Simulation costs based on potential drug left behind in the vial; costs of CSTD were not included	(2014) EUR −22,064	(2017) USD −23,370
CSTD: closed‐system transfer device. ^aNegative sign indicates cost savings and positive sign indicates increased costs due to the use of CSTD.

Table 1. Potential cost savings

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Comparison 1. Closed‐system transfer device plus safe handling versus safe handling alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Urine tests for exposure Show forest plot	4		Risk Ratio (Random, 95% CI)	Subtotals only

1.1 Cyclophoshamide	2		Risk Ratio (Random, 95% CI)	0.83 [0.46, 1.52]
1.2 Cyclophosphamide or ifosfamide	1		Risk Ratio (Random, 95% CI)	0.09 [0.00, 2.79]
1.3 Cyclophosphamide, ifosfamide, or gemcitabine	1		Risk Ratio (Random, 95% CI)	0.0 [0.0, 0.0]
2 Proportion of surfaces contaminated Show forest plot	15		Risk Ratio (Random, 95% CI)	Subtotals only

2.1 Cyclophosphamide (pharmacy areas)	13		Risk Ratio (Random, 95% CI)	0.89 [0.78, 1.01]
2.2 Ifosfamide (pharmacy areas)	9		Risk Ratio (Random, 95% CI)	0.94 [0.74, 1.19]
2.3 Methotrexate (pharmacy areas)	6		Risk Ratio (Random, 95% CI)	0.84 [0.58, 1.22]
2.4 5‐fluorouracil (pharmacy areas)	4		Risk Ratio (Random, 95% CI)	0.63 [0.42, 0.94]
2.5 Cytarabine (pharmacy areas)	2		Risk Ratio (Random, 95% CI)	0.72 [0.18, 2.86]
2.6 Gemcitabine (pharmacy areas)	2		Risk Ratio (Random, 95% CI)	0.96 [0.60, 1.54]
2.7 Irinotecan (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.36 [0.10, 1.33]
2.8 Docetaxel (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.0 [0.0, 0.0]
2.9 Paclitaxel (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.57 [0.04, 9.06]
2.10 Vinorelbine (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	1.72 [0.16, 18.73]
2.11 Ganciclovir (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.01 [0.00, 27.11]
2.12 Epirubicin (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.03 [0.00, 6.29]
2.13 Multiple drugs (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.87 [0.43, 1.77]
2.14 Cyclophosphamide (patient‐care areas)	5		Risk Ratio (Random, 95% CI)	1.01 [0.86, 1.18]
2.15 Ifosfamide (patient‐care areas)	5		Risk Ratio (Random, 95% CI)	1.44 [0.91, 2.28]
2.16 Methotrexate (patient‐care areas)	5		Risk Ratio (Random, 95% CI)	1.00 [0.55, 1.85]
2.17 5‐fluorouracil (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	1.09 [0.53, 2.23]
2.18 Cytarabine (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.59 [0.01, 24.53]
2.19 Gemcitabine (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	1.13 [0.55, 2.33]
2.20 Irinotecan (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.44 [0.03, 6.15]
2.21 Docetaxel (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.59 [0.01, 24.53]
2.22 Paclitaxel (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.59 [0.01, 24.53]
2.23 Vinorelbine (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.0 [0.0, 0.0]
2.24 Multiple drugs (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	2.38 [0.69, 8.23]
3 Quantity of surface contamination (pg/cm²) Show forest plot	9		Mean Difference (Random, 95% CI)	Subtotals only

3.1 Cyclophosphamide (pharmacy areas)	7		Mean Difference (Random, 95% CI)	‐49.34 [‐84.11, ‐14.56]
3.2 Ifosfamide (pharmacy areas)	6		Mean Difference (Random, 95% CI)	‐0.32 [‐6.58, 5.94]
3.3 Methotrexate (pharmacy areas)	6		Mean Difference (Random, 95% CI)	‐3.09 [‐13.80, 7.61]
3.4 5‐fluorouracil (pharmacy areas)	3		Mean Difference (Random, 95% CI)	231.62 [‐460.52, 923.76]
3.5 Cytarabine (pharmacy areas)	1		Mean Difference (Random, 95% CI)	‐0.6 [‐15.67, 14.47]
3.6 Gemcitabine (pharmacy areas)	1		Mean Difference (Random, 95% CI)	‐32.7 [‐102.43, 37.03]
3.7 Irinotecan (pharmacy areas)	1		Mean Difference (Random, 95% CI)	‐18.27 [‐56.89, 20.35]
3.8 Epirubicin (pharmacy areas)	1		Mean Difference (Random, 95% CI)	‐110.0 [‐112.93, ‐107.07]
3.9 Cyclophosphamide (patient‐care areas)	5		Mean Difference (Random, 95% CI)	‐13.34 [‐36.01, 9.32]
3.10 Ifosfamide (patient‐care areas)	5		Mean Difference (Random, 95% CI)	3.59 [‐3.45, 10.63]
3.11 Methotrexate (patient‐care areas)	5		Mean Difference (Random, 95% CI)	0.10 [‐0.57, 0.78]
3.12 5‐fluorouracil (patient‐care areas)	1		Mean Difference (Random, 95% CI)	‐43.9 [‐141.51, 53.71]
3.13 Cytarabine (patient‐care areas)	1		Mean Difference (Random, 95% CI)	‐0.20 [‐0.79, 0.39]
3.14 Gemcitabine (patient‐care areas)	1		Mean Difference (Random, 95% CI)	0.47 [‐1.77, 2.71]
3.15 Irinotecan (patient‐care areas)	1		Mean Difference (Random, 95% CI)	‐0.05 [‐0.15, 0.05]

Comparison 1. Closed‐system transfer device plus safe handling versus safe handling alone

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Comparison 2. Subgroup analysis (based on study design and device)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Urine tests for exposure (PhaSeal only) Show forest plot	3		Risk Ratio (Random, 95% CI)	Subtotals only

1.1 Cyclophoshamide	2		Risk Ratio (Random, 95% CI)	0.83 [0.46, 1.52]
1.2 Cyclophosphamide or ifosfamide	1		Risk Ratio (Random, 95% CI)	0.09 [0.00, 2.79]
2 Proportion of surfaces contaminated with cyclophosphamide in pharmacy areas: stratified by study design Show forest plot	13		Risk Ratio (Random, 95% CI)	0.89 [0.78, 1.01]

2.1 Uncontrolled before‐after studies	7		Risk Ratio (Random, 95% CI)	0.87 [0.76, 0.99]
2.2 Cross‐sectional studies	6		Risk Ratio (Random, 95% CI)	0.92 [0.72, 1.19]
3 Proportion of surfaces contaminated with ifosfamide in pharmacy areas: stratified by study design Show forest plot	9		Risk Ratio (Random, 95% CI)	0.94 [0.74, 1.19]

3.1 Uncontrolled before‐after studies	3		Risk Ratio (Random, 95% CI)	0.85 [0.64, 1.14]
3.2 Cross‐sectional studies	6		Risk Ratio (Random, 95% CI)	1.00 [0.65, 1.53]
4 Proportion of surfaces contaminated with methotrexate in pharmacy areas: stratified by study design Show forest plot	6		Risk Ratio (Random, 95% CI)	0.84 [0.58, 1.22]

4.1 Uncontrolled before‐after studies	1		Risk Ratio (Random, 95% CI)	3.00 [0.01, 777.04]
4.2 Cross‐sectional studies	5		Risk Ratio (Random, 95% CI)	0.83 [0.57, 1.22]
5 Proportion of surfaces contaminated with 5‐fluorouracil in pharmacy areas: stratified by study design Show forest plot	4		Risk Ratio (Random, 95% CI)	0.63 [0.42, 0.94]

5.1 Uncontrolled before‐after studies	2		Risk Ratio (Random, 95% CI)	0.33 [0.04, 2.88]
5.2 Cross‐sectional studies	2		Risk Ratio (Random, 95% CI)	0.71 [0.38, 1.34]
6 Proportion of surfaces contaminated (PhaSeal only) Show forest plot	8		Risk Ratio (Random, 95% CI)	Subtotals only

6.1 Cyclophosphamide (pharmacy areas)	8		Risk Ratio (Random, 95% CI)	0.88 [0.78, 0.99]
6.2 Ifosfamide (pharmacy areas)	4		Risk Ratio (Random, 95% CI)	0.84 [0.63, 1.11]
6.3 Methotrexate (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	3.00 [0.01, 777.04]
6.4 5‐fluorouracil (pharmacy areas)	2		Risk Ratio (Random, 95% CI)	0.61 [0.36, 1.02]
6.5 Cytarabine (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.35 [0.08, 1.58]
6.6 Gemcitabine (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.88 [0.33, 2.33]
6.7 Ganciclovir (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.01 [0.00, 27.11]
7 Proportion of surfaces contaminated (Tevadaptor only) Show forest plot	1		Risk Ratio (Random, 95% CI)	Subtotals only

7.1 5‐fluorouracil (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.04 [0.00, 2.03]
7.2 Epirubicin (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.03 [0.00, 6.29]
8 Quantity of surface contamination with cyclophosphamide in pharmacy areas (pg/cm²): stratified by study design Show forest plot	7		Mean Difference (Random, 95% CI)	‐49.34 [‐84.11, ‐14.56]

8.1 Uncontrolled before‐after studies	2		Mean Difference (Random, 95% CI)	‐255.35 [‐1144.66, 633.96]
8.2 Cross‐sectional studies	5		Mean Difference (Random, 95% CI)	‐49.02 [‐83.82, ‐14.22]
9 Quantity of surface contamination with ifosfamide in pharmacy areas (pg/cm²): stratified by study design Show forest plot	6		Mean Difference (Random, 95% CI)	‐0.32 [‐6.58, 5.94]

9.1 Uncontrolled before‐after studies	1		Mean Difference (Random, 95% CI)	‐2.59 [‐26.75, 21.57]
9.2 Cross‐sectional studies	5		Mean Difference (Random, 95% CI)	‐0.78 [‐8.58, 7.03]
10 Quantity of surface contamination with methotrexate in pharmacy areas (pg/cm²): stratified by study design Show forest plot	6		Mean Difference (Random, 95% CI)	‐3.09 [‐13.80, 7.61]

10.1 Uncontrolled before‐after studies	1		Mean Difference (Random, 95% CI)	10.34 [‐34.01, 54.69]
10.2 Cross‐sectional studies	5		Mean Difference (Random, 95% CI)	‐3.92 [‐14.96, 7.11]
11 Quantity of surface contamination with 5‐fluorouracil in pharmacy areas (pg/cm²): stratified by devices Show forest plot	2		Mean Difference (Random, 95% CI)	Subtotals only

11.1 5‐fluorouracil (pharmacy areas; SpikeSwan)	1		Mean Difference (Random, 95% CI)	14300.0 [‐47951.46, 76551.46]
11.2 5‐fluorouracil (pharmacy areas; Tevadaptor)	1		Mean Difference (Random, 95% CI)	‐118.00 [‐2746.04, 2506.04]
12 Quantity of surface contamination with 5‐fluorouracil in pharmacy areas (pg/cm²): stratified by study design Show forest plot	3		Mean Difference (Random, 95% CI)	231.62 [‐460.52, 923.76]

12.1 Uncontrolled before‐after studies	1		Mean Difference (Random, 95% CI)	‐118.00 [‐2746.04, 2506.04]
12.2 Cross‐sectional studies	2		Mean Difference (Random, 95% CI)	257.87 [‐459.65, 975.38]
13 Quantity of surface contamination (pg/cm²): stratified by devices Show forest plot	4		Mean Difference (Random, 95% CI)	Subtotals only

13.1 Cyclophosphamide (pharmacy areas; PhaSeal)	2		Mean Difference (Random, 95% CI)	‐255.35 [‐1144.66, 633.96]
13.2 Ifosfamide (pharmacy areas; PhaSeal)	1		Mean Difference (Random, 95% CI)	‐2.59 [‐26.75, 21.57]
13.3 Methotrexate (pharmacy areas; PhaSeal)	1		Mean Difference (Random, 95% CI)	10.34 [‐34.01, 54.69]
13.4 5‐fluorouracil (pharmacy areas; SpikeSwan)	1		Mean Difference (Random, 95% CI)	14300.0 [‐47951.46, 76551.46]
13.5 5‐fluorouracil (pharmacy areas; Tevadaptor)	1		Mean Difference (Random, 95% CI)	‐118.00 [‐2746.04, 2506.04]

Comparison 2. Subgroup analysis (based on study design and device)

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Comparison 3. Sensitivity analysis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Urine tests for exposure (ICC = 0.05) Show forest plot	4		Risk Ratio (Random, 95% CI)	Subtotals only

1.1 Cyclophoshamide	2		Risk Ratio (Random, 95% CI)	0.82 [0.44, 1.52]
1.2 Cyclophosphamide or ifosfamide	1		Risk Ratio (Random, 95% CI)	0.09 [0.00, 1.99]
1.3 Cyclophosphamide, ifosfamide, or gemcitabine	1		Risk Ratio (Random, 95% CI)	0.0 [0.0, 0.0]
2 Urine tests for exposure (ICC = 0.01) Show forest plot	4		Risk Ratio (Random, 95% CI)	Subtotals only

2.1 Cyclophoshamide	2		Risk Ratio (Random, 95% CI)	0.81 [0.43, 1.51]
2.2 Cyclophosphamide or ifosfamide	1		Risk Ratio (Random, 95% CI)	0.09 [0.01, 1.48]
2.3 Cyclophosphamide, ifosfamide, or gemcitabine	1		Risk Ratio (Random, 95% CI)	0.0 [0.0, 0.0]
3 Urine tests for exposure (ICC = 0.00) Show forest plot	4		Risk Ratio (Random, 95% CI)	Subtotals only

3.1 Cyclophoshamide	2		Risk Ratio (Random, 95% CI)	0.81 [0.43, 1.51]
3.2 Cyclophosphamide or ifosfamide	1		Risk Ratio (Random, 95% CI)	0.09 [0.01, 1.36]
3.3 Cyclophosphamide, ifosfamide, or gemcitabine	1		Risk Ratio (Random, 95% CI)	0.0 [0.0, 0.0]
4 Proportion of surfaces contaminated (ICC = 0.05) Show forest plot	15		Risk Ratio (Random, 95% CI)	Subtotals only

4.1 Cyclophosphamide (pharmacy areas)	13		Risk Ratio (Random, 95% CI)	0.87 [0.76, 0.99]
4.2 Ifosfamide (pharmacy areas)	9		Risk Ratio (Random, 95% CI)	0.94 [0.73, 1.23]
4.3 Methotrexate (pharmacy areas)	6		Risk Ratio (Random, 95% CI)	0.84 [0.60, 1.19]
4.4 5‐fluorouracil (pharmacy areas)	4		Risk Ratio (Random, 95% CI)	0.62 [0.42, 0.92]
4.5 Cytarabine (pharmacy areas)	2		Risk Ratio (Random, 95% CI)	0.68 [0.17, 2.67]
4.6 Gemcitabine (pharmacy areas)	2		Risk Ratio (Random, 95% CI)	0.95 [0.64, 1.43]
4.7 Irinotecan (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.36 [0.11, 1.19]
4.8 Docetaxel (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.0 [0.0, 0.0]
4.9 Paclitaxel (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.57 [0.05, 7.13]
4.10 Vinorelbine (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	1.72 [0.20, 15.25]
4.11 Ganciclovir (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.01 [0.00, 3.43]
4.12 Epirubicin (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.03 [0.00, 2.02]
4.13 Multiple drugs (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.87 [0.49, 1.53]
4.14 Cyclophosphamide (patient‐care areas)	5		Risk Ratio (Random, 95% CI)	1.00 [0.86, 1.17]
4.15 Ifosfamide (patient‐care areas)	5		Risk Ratio (Random, 95% CI)	1.46 [0.91, 2.34]
4.16 Methotrexate (patient‐care areas)	5		Risk Ratio (Random, 95% CI)	1.01 [0.57, 1.76]
4.17 5‐fluorouracil (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	1.09 [0.57, 2.10]
4.18 Cytarabine (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.59 [0.02, 18.10]
4.19 Gemcitabine (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	1.13 [0.58, 2.20]
4.20 Irinotecan (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.44 [0.04, 4.97]
4.21 Docetaxel (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.59 [0.02, 18.10]
4.22 Paclitaxel (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.59 [0.02, 18.10]
4.23 Vinorelbine (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.0 [0.0, 0.0]
4.24 Multiple drugs (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	2.38 [0.79, 7.17]
5 Proportion of surfaces contaminated (ICC = 0.01) Show forest plot	15		Risk Ratio (Random, 95% CI)	Subtotals only

5.1 Cyclophosphamide (pharmacy areas)	13		Risk Ratio (Random, 95% CI)	0.83 [0.73, 0.96]
5.2 Ifosfamide (pharmacy areas)	9		Risk Ratio (Random, 95% CI)	0.89 [0.66, 1.21]
5.3 Methotrexate (pharmacy areas)	6		Risk Ratio (Random, 95% CI)	0.85 [0.62, 1.16]
5.4 5‐fluorouracil (pharmacy areas)	4		Risk Ratio (Random, 95% CI)	0.57 [0.33, 0.97]
5.5 Cytarabine (pharmacy areas)	2		Risk Ratio (Random, 95% CI)	0.64 [0.17, 2.51]
5.6 Gemcitabine (pharmacy areas)	2		Risk Ratio (Random, 95% CI)	0.93 [0.69, 1.24]
5.7 Irinotecan (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.36 [0.12, 1.08]
5.8 Docetaxel (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.0 [0.0, 0.0]
5.9 Paclitaxel (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.57 [0.06, 5.79]
5.10 Vinorelbine (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	1.72 [0.23, 12.73]
5.11 Ganciclovir (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.01 [0.00, 0.27]
5.12 Epirubicin (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.03 [0.00, 0.62]
5.13 Multiple drugs (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.87 [0.57, 1.32]
5.14 Cyclophosphamide (patient‐care areas)	5		Risk Ratio (Random, 95% CI)	1.00 [0.85, 1.17]
5.15 Ifosfamide (patient‐care areas)	5		Risk Ratio (Random, 95% CI)	1.47 [0.91, 2.38]
5.16 Methotrexate (patient‐care areas)	5		Risk Ratio (Random, 95% CI)	1.01 [0.60, 1.69]
5.17 5‐fluorouracil (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	1.09 [0.59, 2.00]
5.18 Cytarabine (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.59 [0.02, 13.92]
5.19 Gemcitabine (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	1.13 [0.61, 2.09]
5.20 Irinotecan (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.44 [0.05, 4.13]
5.21 Docetaxel (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.59 [0.02, 13.92]
5.22 Paclitaxel (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.59 [0.02, 13.92]
5.23 Vinorelbine (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.0 [0.0, 0.0]
5.24 Multiple drugs (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	2.38 [0.89, 6.33]
6 Proportion of surfaces contaminated (ICC = 0.00) Show forest plot	15		Risk Ratio (Random, 95% CI)	Subtotals only

6.1 Cyclophosphamide (pharmacy areas)	13		Risk Ratio (Random, 95% CI)	0.82 [0.72, 0.94]
6.2 Ifosfamide (pharmacy areas)	9		Risk Ratio (Random, 95% CI)	0.85 [0.59, 1.21]
6.3 Methotrexate (pharmacy areas)	6		Risk Ratio (Random, 95% CI)	0.86 [0.63, 1.16]
6.4 5‐fluorouracil (pharmacy areas)	4		Risk Ratio (Random, 95% CI)	0.55 [0.32, 0.94]
6.5 Cytarabine (pharmacy areas)	2		Risk Ratio (Random, 95% CI)	0.64 [0.16, 2.46]
6.6 Gemcitabine (pharmacy areas)	2		Risk Ratio (Random, 95% CI)	0.91 [0.73, 1.13]
6.7 Irinotecan (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.36 [0.13, 1.05]
6.8 Docetaxel (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.0 [0.0, 0.0]
6.9 Paclitaxel (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.57 [0.06, 5.48]
6.10 Vinorelbine (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	1.72 [0.24, 12.15]
6.11 Ganciclovir (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.01 [0.00, 0.09]
6.12 Epirubicin (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.03 [0.00, 0.42]
6.13 Multiple drugs (pharmacy areas)	1		Risk Ratio (Random, 95% CI)	0.87 [0.60, 1.26]
6.14 Cyclophosphamide (patient‐care areas)	5		Risk Ratio (Random, 95% CI)	1.00 [0.85, 1.17]
6.15 Ifosfamide (patient‐care areas)	5		Risk Ratio (Random, 95% CI)	1.48 [0.91, 2.38]
6.16 Methotrexate (patient‐care areas)	5		Risk Ratio (Random, 95% CI)	1.01 [0.61, 1.67]
6.17 5‐fluorouracil (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	1.09 [0.60, 1.97]
6.18 Cytarabine (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.59 [0.02, 14.36]
6.19 Gemcitabine (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	1.13 [0.62, 2.06]
6.20 Irinotecan (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.44 [0.05, 3.93]
6.21 Docetaxel (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.59 [0.02, 14.36]
6.22 Paclitaxel (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.59 [0.02, 14.36]
6.23 Vinorelbine (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	0.0 [0.0, 0.0]
6.24 Multiple drugs (patient‐care areas)	1		Risk Ratio (Random, 95% CI)	2.38 [0.92, 6.12]
7 Quantity of surface contamination (pg/cm²) (ICC = 0.05) Show forest plot	9		Mean Difference (Random, 95% CI)	Subtotals only

7.1 Cyclophosphamide (pharmacy areas)	7		Mean Difference (Random, 95% CI)	‐49.47 [‐81.21, ‐17.73]
7.2 Ifosfamide (pharmacy areas)	6		Mean Difference (Random, 95% CI)	‐0.95 [‐7.63, 5.72]
7.3 Methotrexate (pharmacy areas)	6		Mean Difference (Random, 95% CI)	‐2.78 [‐12.45, 6.89]
7.4 5‐fluorouracil (pharmacy areas)	3		Mean Difference (Random, 95% CI)	224.25 [‐400.98, 849.49]
7.5 Cytarabine (pharmacy areas)	1		Mean Difference (Random, 95% CI)	‐0.6 [‐14.37, 13.17]
7.6 Gemcitabine (pharmacy areas)	1		Mean Difference (Random, 95% CI)	‐32.7 [‐96.40, 31.00]
7.7 Irinotecan (pharmacy areas)	1		Mean Difference (Random, 95% CI)	‐18.27 [‐53.55, 17.01]
7.8 Epirubicin (pharmacy areas)	1		Mean Difference (Random, 95% CI)	‐110.0 [‐112.32, ‐107.68]
7.9 Cyclophosphamide (patient‐care areas)	5		Mean Difference (Random, 95% CI)	‐30.44 [‐90.78, 29.90]
7.10 Ifosfamide (patient‐care areas)	5		Mean Difference (Random, 95% CI)	3.59 [‐2.88, 10.07]
7.11 Methotrexate (patient‐care areas)	5		Mean Difference (Random, 95% CI)	0.10 [‐0.51, 0.72]
7.12 5‐fluorouracil (patient‐care areas)	1		Mean Difference (Random, 95% CI)	‐43.9 [‐133.57, 45.77]
7.13 Cytarabine (patient‐care areas)	1		Mean Difference (Random, 95% CI)	‐0.20 [‐0.74, 0.34]
7.14 Gemcitabine (patient‐care areas)	1		Mean Difference (Random, 95% CI)	0.47 [‐1.59, 2.53]
7.15 Irinotecan (patient‐care areas)	1		Mean Difference (Random, 95% CI)	‐0.05 [‐0.14, 0.04]
8 Quantity of surface contamination (pg/cm²) (ICC = 0.01) Show forest plot	9		Mean Difference (Random, 95% CI)	Subtotals only

8.1 Cyclophosphamide (pharmacy areas)	7		Mean Difference (Random, 95% CI)	‐49.85 [‐78.93, ‐20.77]
8.2 Ifosfamide (pharmacy areas)	6		Mean Difference (Random, 95% CI)	‐1.29 [‐7.89, 5.32]
8.3 Methotrexate (pharmacy areas)	6		Mean Difference (Random, 95% CI)	‐1.93 [‐10.50, 6.64]
8.4 5‐fluorouracil (pharmacy areas)	3		Mean Difference (Random, 95% CI)	207.62 [‐351.04, 766.28]
8.5 Cytarabine (pharmacy areas)	1		Mean Difference (Random, 95% CI)	‐0.6 [‐13.23, 12.03]
8.6 Gemcitabine (pharmacy areas)	1		Mean Difference (Random, 95% CI)	‐32.7 [‐91.14, 25.74]
8.7 Irinotecan (pharmacy areas)	1		Mean Difference (Random, 95% CI)	‐18.27 [‐50.63, 14.09]
8.8 Epirubicin (pharmacy areas)	1		Mean Difference (Random, 95% CI)	‐110.0 [‐111.68, ‐108.32]
8.9 Cyclophosphamide (patient‐care areas)	5		Mean Difference (Random, 95% CI)	‐49.62 [‐133.49, 34.25]
8.10 Ifosfamide (patient‐care areas)	5		Mean Difference (Random, 95% CI)	3.59 [‐2.39, 9.58]
8.11 Methotrexate (patient‐care areas)	5		Mean Difference (Random, 95% CI)	0.06 [‐0.81, 0.94]
8.12 5‐fluorouracil (patient‐care areas)	1		Mean Difference (Random, 95% CI)	‐43.9 [‐126.66, 38.86]
8.13 Cytarabine (patient‐care areas)	1		Mean Difference (Random, 95% CI)	‐0.2 [‐0.70, 0.30]
8.14 Gemcitabine (patient‐care areas)	1		Mean Difference (Random, 95% CI)	0.47 [‐1.43, 2.37]
8.15 Irinotecan (patient‐care areas)	1		Mean Difference (Random, 95% CI)	‐0.05 [‐0.13, 0.03]
9 Quantity of surface contamination (pg/cm²) (ICC = 0.00) Show forest plot	9		Mean Difference (Random, 95% CI)	Subtotals only

9.1 Cyclophosphamide (pharmacy areas)	7		Mean Difference (Random, 95% CI)	‐50.15 [‐78.51, ‐21.79]
9.2 Ifosfamide (pharmacy areas)	6		Mean Difference (Random, 95% CI)	‐1.36 [‐7.81, 5.09]
9.3 Methotrexate (pharmacy areas)	6		Mean Difference (Random, 95% CI)	‐1.32 [‐9.47, 6.84]
9.4 5‐fluorouracil (pharmacy areas)	3		Mean Difference (Random, 95% CI)	198.18 [‐338.80, 735.17]
9.5 Cytarabine (pharmacy areas)	1		Mean Difference (Random, 95% CI)	‐0.6 [‐12.93, 11.73]
9.6 Gemcitabine (pharmacy areas)	1		Mean Difference (Random, 95% CI)	‐32.7 [‐89.74, 24.34]
9.7 Irinotecan (pharmacy areas)	1		Mean Difference (Random, 95% CI)	‐18.27 [‐49.86, 13.32]
9.8 Epirubicin (pharmacy areas)	1		Mean Difference (Random, 95% CI)	‐110.0 [‐111.48, ‐108.52]
9.9 Cyclophosphamide (patient‐care areas)	5		Mean Difference (Random, 95% CI)	‐53.61 [‐141.33, 34.10]
9.10 Ifosfamide (patient‐care areas)	5		Mean Difference (Random, 95% CI)	3.60 [‐2.27, 9.46]
9.11 Methotrexate (patient‐care areas)	5		Mean Difference (Random, 95% CI)	0.03 [‐1.02, 1.08]
9.12 5‐fluorouracil (patient‐care areas)	1		Mean Difference (Random, 95% CI)	‐43.9 [‐124.84, 37.04]
9.13 Cytarabine (patient‐care areas)	1		Mean Difference (Random, 95% CI)	‐0.2 [‐0.69, 0.29]
9.14 Gemcitabine (patient‐care areas)	1		Mean Difference (Random, 95% CI)	0.47 [‐1.39, 2.33]
9.15 Irinotecan (patient‐care areas)	1		Mean Difference (Random, 95% CI)	‐0.05 [‐0.13, 0.03]

Comparison 3. Sensitivity analysis

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