Cytotoxic agents are the major part of current therapeutic arsenal in
pediatric oncology. Recently, small molecules have been combined in the
standard regimen for targeted cancer therapy. Both drugs provoke adverse
effects on the living cells via the specific and non-specific actions to
neoplastic cells. Considering genetic and epigenetic events, the late
effect rather than acute toxicity is a matter of concern for healthy
subjects at risk of exposure to anticancer drugs. To reduce the risk, a
list of hazardous drugs (HDs) has been updated by the National Institute
for Occupational Safety and Health (NIOSH) including commonly used
cytotoxic agents. HDs are defined by their association with
genotoxicity, carcinogenicity, teratogenicity, impaired fertility,
reproductive toxicity, and/or serious organ toxicity even at a lower
dose.1 The American Society of Clinical Oncology
(ASCO) standard promotes the safety of professional staff of
pharmacists, physicians, nurses, and other collaborators in oncology
care.2 It recommends the preventive measures to avoid
the toxic products, incorporating the latest evidence of the deleterious
late effects after exposure, and the benefits of control measures, along
with expert consensus. United States Pharmacopeia Chapter
<800> requires an appropriate list of HDs in
healthcare settings, providing concrete information regarding the
articles of personal protective equipment, as well as where and how they
should be donned, used, and removed is prescribed.3
Several guidelines for the occupational exposure to HDs have been
established for the health of hospital workers,1-5 but
not the family members of childhood cancer. We thus investigated the
exposure of caregiver and medical staff to anticancer drugs and the
environmental contamination. Fifteen inpatients with pediatric cancer
were recruited who received high-dose cyclophosphamide (CPM) from 2017
to 2018. Seven infants and 8 adolescents had 4 leukemias and 11 solid
tumors. The median age at the time of this study was 78 months ranging
from 13 to 200 months. The infants and adolescents received CPM of 1g
/m2 or more; median 640 (range
620~1300) mg, and 1230 (range 780~1230)
mg, respectively. Six hours after the first administration, the
concentration of CPM was measured in the urine and saliva from attending
mothers, nurses, doctors, nursery teachers, child-life specialists, and
housekeeping staff members in the ward, using the liquid
chromatography/mass spectrometry method (Shionogi Analysis Centre Co.,
Ltd., Osaka, Japan)6. Safe handling and
closed-system-drug-transfer devices (JMS Co. Ltd., Hiroshima, Japan) are
the standard of our center to minimize the technical
exposure.7 This study was approved by the
institutional review board of Kyushu University. Five of 7 (71%)
infant’s and 2 of 8 (25%) adolescent’s mothers showed increased urine
levels of CPM. The median value of infant’s mothers (192 ng/10 mL, range
0~1,510) was significantly higher than that of
adolescent’s mothers (0 ng/10 mL, 0~58.4)
(p =0.005). CPM was detected in the saliva samples of two mothers
caring infants, but not in the urine or saliva of any medical staff
(Figure ). The environmental contamination in a room of the
infant whose mother showed the highest concentrations was assessed by
the modified method.6 High levels of CPM were
determined in the monitoring samples from a 17-year-old boy; toilet
floor (1020 times of the detection limit), toilet seat (167 times), wash
basin (45.6 times), a 13-year-boy; underwear (735 times) bed sheets (224
times), bed fence (34.8 times), bedside floor (20.9 times), exhaust vent
(13.1 times), bedside table (7.4 times), door knob (4.9 times), curtain
(4.7 times), and a 2-year-boy; bathing hot water (205 times) at 24 hours
after the first administration, respectively. No staff having detectable
CPM levels represented the control of HDs exposure in our hospital. In
contrast, the exposure was frequently found in attending mothers caring
infants. The higher levels of CPM in infants’ mothers than in
adolescents’ mothers are explained by the closer contact for care. The
environmental contamination has occurred from the body fluid of patients
but not the drug delivery.
The latest systems and guidelines have effectively controlled the
accidental exposures of drugs to medical staff, as shown in the present
results, throughout the process from the formulation in the pharmacy
department, transportation, and administration to bed-side patients. The
mother’s exposure is categorized as an intermediate risk. It may occur
in case of high-dose therapy with limited duration. However, the
metabolites of CPM including 4-hydroxycyclophosphamide show
cytotoxicity.9 The mixture of selected cytostatic
drugs has an augmented cytotoxicity leading to the late effects on
genome even at low concentrations.10 During the
long-term intense chemotherapy for pediatric cancer, the preliminary
results may raise the need for preventive measures for caregivers
according to the equivalent levels to medical staffs.