originating from blood cell lineage in pediatric population are remediable and
are treated with combinations of chemotherapy drugs (1). Adverse drug events
usually happen during the course of chemotherapy and are the utmost reason of
interruption in the treatment plan of chemotherapy. In one recent study higher
incidence of ADRs in pediatric patients as compared to adult patients has been
documented (2). Many of these ADRs are anticipated and in many cases are
avertable (3). Dacarbazine as a part of many protocols is used in pediatric
malignancies in our hospital as per the guidelines (1). We describe, after
written informed consents from the patient’s attendants, five cases of PHL
population who during treatment with Dacarbazine, experienced symptoms like
fever, tachycardia and shivering during infusion.
6-years-old child presented with a history of left sided neck mass with
enlarged cervical lymph nodes and no B-symptoms, was diagnosed to have Mixed
cellularity Classical Hodgkin’s lymphoma, stage IIA. Patient was planned to
start chemotherapy COPDac alternating with ABVD. On the day of administration
of ABVD cycle 1 day 1 on 5th Sep 2017, during the infusion of Dacarbazine,
patient complained of shivering and fever. Dacarbazine infusion was held.
Patient was examined and found shivering with fever of 39C°and warm
extremities. Rest of the systemic exam was unremarkable. Intravenous
paracetamol 180mg, ceftriaxone 1400mg was advised along with pheniramine
maleate 20mg and hydrocortisone 40mg and administered immediately to the
patient. Blood sample was taken and sent to lab for any microbial culture
sensitivity. Patient was observed and found to be stable and afebrile after
conservative management. Remaining infusion of chemotherapy was resumed and
finished safely about after 3 hours of the reactions. Antibiotic administration
was advised and followed to have for at least 48hrs of getting afebrile after
fever spike. Since patient had no further fever spike and shivering episode
also microbial culture were negative for any sensitivity, antibiotic was
discontinued after 48 hours. Patient was given appointment for ABVD cycle 1 D15
accordingly and received Dacarbazine safely.
aged 6-years-old came with a history of on and off fever, generalized body
weakness, right cervical lymphadenopathy in association of B-symptoms. Cervical
lymph nodes biopsy and further work-up was done and a diagnosis of classical
Hodgkin’s lymphoma, stage IIIB was established. Chemotherapy COPDac alternating
with ABVD each of four cycles was planned. On 18th Aug 2017, day 15 of 2nd
cycle of ABVD was planned when patient started shivering, became febrile and
developed tachycardia just after 5 minutes of Dacarbazine infusion was started.
Chemotherapy was held till further orders. Fever of 38.5 C° with a raised in
blood pressure up to 140/90 mm/Hg with three consecutive readings and a pulse
of 125/min was documented. Apart from stopping the infusion, blood sample was
taken and sent for microbial analysis and patient was managed with immediate
intravenous administrations of pheniramine maleate 25mg, hydrocortisone 50mg,
paracetamol 250mg and antibiotic ceftriaxone 1725mg. in order to manage
hypertension, a calcium channel blocker nifedipine 10mg was administered with
an hourly monitoring of blood pressure for three hours. Once patient became
hemodynamically stable after 3 hours of reactions, remaining infusion of
dacarbazine was administered slowly and safely. Blood cultures were followed
and found negative for any sensitivity. Patient was given appointments for next
chemotherapy as per therapy schedule and received further doses safely.
boy with a history of bilateral palpable cervical and inguinal lymphadenopathy
for last 1.5 years and no B-symptoms was diagnosed as a case of Classical
Hodgkin’s Lymphoma stage III-AS. Patient
was planned for three cycles of chemotherapy COPDac alternating with ABVD.
Cycle 3 of chemotherapy COPDac was scheduled on 19th Aug 2017 and just after
starting the administration of day 1 Dacarbazine, patient developed shivering.
After clinical assessment, Dacarbazine infusion was stopped with the advice of
administration of injection pheniramine maleate 15mg and injection
hydrocortisone 30mg I/V. Patient’s vitals were monitored and were found
clinically unremarkable after every 15 min for the next hour. About after one
hour of the reaction when patient was found clinically stable, remaining
chemotherapy was resumed and administered safely. The subsequent infusions of Dacarbazine
on day 2 and day 3 were administered as per protocol with no episode of
aged 7-years-old young boy presented with swelling of right sided neck with no
B-symptoms from last three months. Biopsy from right cervical lymph node was
done and a diagnosis of Mixed Cellularity Classical Hodgkin’s Lymphoma, stage
IIA was made. Patient was planned to be started on chemotherapy COPDac
alternating with ABVD for each of three cycles. On 7th Sep 2017, day 1 of first
cycle of ABVD, patient developed shivering immediately after the Dacarbazine
infusion has been started. Chemotherapy infusion was stopped followed by vitals
checking, which were found unremarkable. Injection pheniramine 20mg and
injection hydrocortisone 40mg were administered to manage the symptoms
conservatively. Patient was observed clinically for symptoms for next hour, and
after that was considered fit for the remaining chemotherapy once became
asymptomatic. Next chemotherapy on day 15 was administered as per protocol
without happening of the adverse event.
boy, aged 8-years with eleven months history of left cervical lymphadenopathy
but no B-symptoms was diagnosed with Classical Hodgkin’s Lymphoma of Mixed
Cellularity type stage IIIAS. Patient was planned to be started on chemotherapy
COPDac alternating with ABVD each of three cycles. 3rd cycle of chemotherapy
COPDac was planned on 18th Aug 2017 and just after the start of day 1
Dacarbazine infusion, patient started shivering. Chemotherapy infusion was
stopped and patient was assessed clinically. Upon clinical assessment, patient
was found afebrile and hemodynamically stable. To manage the symptoms of
shivering, intravenous administration of pheniramine maleate 22mg and
hydrocortisone 40mg was advised. Symptoms were resolved after conservative
management, but patient was kept under observation for next half an hour.
Vitals monitoring was ensured during the observation and once patient was
considered fit enough for chemotherapy, the remaining infusion was resumed as
per the protocol and finished safely. Subsequent doses on day 2 and day 3 of
this cycle were administered safely with no happening of adverse event.
to the WHO guidelines, an ADR is defined as “any response to a drug which is
noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis
or therapy (4).
class of alkylating agents (Triazene compounds), Dacarbazine shows its
antineoplastic activity after conversion to an active alkylating metabolite MTIC
[(methyl-triazene-1-yl) - imidazole-4-carboxamide]. MTIC causes methylation of
O6 guanine, which leads to double stranded DNA breaking and ultimately
institution, PHL patients are divided into different treatment groups according
to the presentation of disease at the time of diagnosis. Patients then receive
a current regimen which was adapted due to excessive toxicity perceived with
OEPA/COPDac; i.e. COPDac/ABVD alternating courses for a particular number of
cycles defined as per their treatment group (6). As per the protocol
recommendations for Dacarbazine in COPDac, the dosing recommendations for
Dacarbazine is 250mg/m2 from Day 1 to day 3, to be delivered over 30 minutes
after dilution in 100ml sodium chloride 0.9%. Whereas in ABVD, the dosing and
administration of Dacarbazine is as 375mg/m2 on day 1 & 15 diluted in 100ml
of sodium chloride 0.9% and to be administered in 15 minutes.
our knowledge, no documented data is available reporting shivering and
tachycardia resulting from Dacarbazine infusion. Only fever has been documented
as a part of flu like syndrome, as infrequent/post marking adverse event
according to the drug monograph (7). In our case series, case 1, 2 & 4 were
scheduled for ABVD, whereas 3 & 5 were given appointments for COPDac when
the reactions were observed. All patients developed shivering with an
additional fever spike which was documented in case 1 and 2. Case 2 also
reported tachycardia which was managed with the administration of
antihypertensive drug. Although the reactions were observed in quite similar
dates, but it is of particular interest that Dacarbazine has been infused to
other pediatric patients as well on the same days but with no episode of
reaction indicating that the batch for Dacarbazine shouldn’t be hold
accountable for these reactions. Also, processes for reconstitution, further
dilution by pharmacy technician and for nursing administration were retrieved
and found done according to the defined protocol and chemotherapy administration
guidelines of our institution.
cases belong to the adverse reactions induced by Dacarbazine infusion which was
kept held after the reaction and then the reactions were managed after
administering antihistamine and corticosteroid. All the cases were continued
with remaining chemotherapy as resolution of symptoms occurred within 1-3 hours
of reactions. Follow up also showed no issue with chemotherapy. The ADRs are
type B and are probable with a score of 6, as estimated by Naranjo’s adverse
drug reaction probability scale (8) and related to the administration time
defined for Dacarbazine infusion. Since a range of 15 to 60 minutes with other
infusion durations as well has been recommended as infuse over time (7), thus
it is suggested to review either the delivered over time allowed for
Dacarbazine in ABVD and COPDac chemotherapy protocols or the consideration of
antihistamine and corticosteroid as pre-medication. Our case series will serve
as local study to support and initiate further investigational studies for the
purpose of identifying safe infusion of Dacarbazine in PHL population.
case series reveals that administration of Dacarbazine infusion was associated
with shivering, fever and tachycardia in PHL patients. These adverse reactions
need to be considered while infusing Dacarbazine.
abstract or any part of this case series has not been published or presented
previously in any conference.
Conflict of interest:
are no financial, professional or personal interests.
sources of funding to disclose.
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