Ifosfamide is an alkylating agent, a structural analogue of
cyclophosphamide. In its initial days its use was limited secondary to
dose limiting hemorrhagic cystitis which was counteracted by using
mesna (2-mercaptoethane sulphonate) along with it [1]. Ifosfamide
has found several uses since then. One of its most important uses
is in advanced soft tissue sarcomas where it is used as adjuvant
chemotherapy along with doxorubicin [2,3]. The Italian cooperative
trial showed 5-year overall survival estimate to be 66.0% and 46.1%
for the treatment and the control groups, respectively (p=0.04) [4].
Ifosfamide and doxorubicin are also used with good results in advanced
rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Group trial
showed a complete response rate of 52% in patients treated with these
2 drugs [5]. Also, ifosfamide along with etoposide was found to be
superior to vincristine and melphalan in another study for advanced
rhabdomyosarcoma with an overall survival rate going up to 55% at
3 years [6]. In a study for Ewing’s sarcoma, cyclophosphamide and
ifosfamide were found to have similar efficacy but the former was
associated with higher rate of toxicity [7]. In children with recurrent/
refractory sarcoma, treatment with ifosfamide, carboplatin and
etoposide (ICE) as re-induction chemotherapy produced an overall
response rate of 51% with a significant improvement in overall survival
at 1 and 2 years [8]. Furthermore, in patients with relapsed or primary
refractory diffuse large B-cell lymphoma (DLBCL) the overall response
rate to ICE was found to be as high as 70%, with a complete response rate
of 25% to 30% [9]. When this regimen was combined with rituximab
(R), an even better response was seen [10].
In comparison to doxorubicin, ifosfamide is less convenient to use
as it has to be given over several days while doxorubicin can be given in
one day. However unlike doxorubicin, ifosfamide can be given at high
doses as it is not associated with dose limiting cardiotoxicity [11].
Overall, ifosfamide is a widely used chemotherapy agent and its
side effects include bone marrow suppression, hemorrhagic cystitis,
alopecia, nausea and neurotoxicity. The incidence of neurotoxicity or
encephalopathy is 10-30% and is increased with concomitant aprepitant
use as seen in a few recent case reports [12-14]. Here we present one
such case along with a review of the latest literature.
Case Report
A 58-year-old female with cystosarcoma phyllodes of the left breast
status post mastectomy, was found to have a left parasternal mass which
on biopsy was consistent with the primary cystosarcoma tumor. The patient
was admitted to the hospital for chemotherapy with doxorubicin,
ifosfamide and mesna. The dose for Ifosfamide was modest at 2500 mg/
m2 daily for 3 days. The pre- medications included ondansetron, lorazepam,
prochlorperazine, dexamethasone and aprepitant. Aprepitant
was given 125 mg orally on day 1 followed by 80 mg orally on days 2 and
3. Chemotherapy was initiated at 1400 hours on day 1. The patient was
tolerating it well until the morning of day 3 when she developed mental
status changes with disorientation and agitation along with difficulty
breathing. The patient remained oriented but was unable to lay still; she had incessant semi purposeful movements. She had only a transient
response to lorazepam. Her agitation and restlessness worsened over
the next 12 hours and she developed tachypnea. The third planned dose
of ifosfamide and doxorubicin was held temporarily since she could not
even lay still and this led to traumatic removal of the venous access
as well as incontinence and catheterization. She was treated with furosemide
for potential fluid overload, since a chest x-ray showed mild
interstitial prominence but with no relief. A CT thorax was obtained
which indicated no pulmonary embolism but noted progression of her
metastatic disease in the lungs. Additional lorazepam was administered
which appeared to calm her down so she could sleep. Chemotherapy
was restarted once the patient was calm. However within an hour, the
patient again became agitated and then the chemotherapy was discontinued.
The agitation persisted and was coupled with severe respiratory
distress and acute respiratory failure requiring endotracheal intubation
and mechanical ventilation. The patient was transferred to the medical
Intensive Care Unit (ICU), where she was started on 1% methylene blue
intravenously 50 mg every 8 hours for ifosfamide induced neurotoxicity.
She received a total of 5 doses of this agent and her mental status
came back to baseline. She was able to breathe spontaneously and was
extubated. She was then transferred back to the oncology floor and was
discharged home a week later. She received 2.5/3 of the total intended
dose of ifosfamide.
Discussion
Ifosfamide induced neurotoxicity is one of the rarer side effects seen
with this drug [15], with a few cases showing increased incidence with
aprepitant use [12-14]. Aprepitant is a neurokinin-1 inhibitor which is
used as an antiemetic. As per the latest NCCN guidelines for antiemesis
aprepitant is indicated for moderate to highly emetogenic chemotherapeutic
regimens [16]. Ifosfamide is included in moderate to highly
emetogenic chemotherapy depending on the total dose being less than
or greater than 10 g per meter square [17]. Aprepitant is a moderate
inhibitor of CYP3A4, an enzyme responsible for numerous drug metabolism
pathways [16]. Ifosfamide is a prodrug that requires hepatic
activation to its cytotoxic metabolite, ifosfamide mustard. The latter is
hydroxylated through CYP3A4 to active alkylating agents, ifosforamide
mustard and 4-hydroxy-ifosfamide. Ifosfamide is also converted by CYP3A4
to inactive, neurotoxic metabolites: the 2- and 3-dechloroethylifosfamide
and chloroacetaldehyde. Competition with 4-hydroxylation
is the major oxidative pathway that causes the dechloroethylation and the formation of the neurotoxic metabolites chloroacetaldehyde and
2-and3-dechloroethylifosfamide. The potential inhibition of CYP3A4
by aprepitant [18] may increase the levels of ifosfamide metabolites resulting
in accumulation and further risk of encephalopathy and other
side effects like hemorrhagic cystitis or neutropenia [14].
The exact pathophysiological mechanisms responsible for the
development of ifosfamide-induced encephalopathy are not known.
Küpfer et al. [19] presented possible pathways by which Ifosfamide
metabolites can induce neurotoxicity. These hypotheses were based
on the finding of glutaric acid and sarcosine in the urine of a patient
with ifosfamide-induced encephalopathy. The same products are also
found in the urine of patients with congenital glutaric aciduria [19].
In these patients a metabolic dysfunction is caused by the absence of
glutaryl CoA (type 1) or by a lack of electron transferring flavoproteins
in the mitochondrial respiratory chain (type 2). Further investigations
showed a relation between glutaric aciduria and chloroethylamine but
not with any of the other metabolites of ifosfamide. This led to the
conclusion that chloroethylamine may be the principal neurotoxic
metabolite of ifosfamide [19]. Chloroethylamine conjugates with
cystein, thus forming thialysine, which can be metabolized to thialysine
ketimine. The latter can inhibit the electron-binding flavoproteins
in the mitochondrial respiratory chain. Thialysine ketimine could
have CNS effects on its own. The inhibition of the mitochondrial
respiratory chain may also lead to a disturbance of the intracellular
NAD/NADH balance with the accumulation of NADH. This in turn
prevents the dehydrogenation of aldehydes, such as the ifosfamide
metabolite chloracetaldehyde, which need NAD for their oxidation
[20]. Chloracetaldehyde is a potential neurotoxic substance. It is closely
related to chloral hydrate, a known hypnotic, and to acetaldehyde which
is the neurotoxic metabolite of ethanol. Ifosfamide and its metabolites
can penetrate the blood brain barrier. Another important pathway may
be mediated by monoamineoxidase in the extrahepatic tissues and in
plasma by which chloracetaldehyde can be formed.
Durand et al. [13] reported a case of acute encephalopathy following
an ifosfamide infusion that they believed was triggered by aprepitant. A
pharmacokinetic evaluation was performed in the patient who received
ifosfamide and aprepitant and presented with marked sleepiness,
dizziness, visual and auditory hallucinations. It revealed an increase
in the neurotoxic metabolites- 2- and 3- dechloroethyl ifosfamide
by 66.7% and 37.3%, respectively. Both are metabolized by CYP3A4.
There was also an increase in 4-hydroxy ifosfamide an active form of
ifosfamide, by 28.1% at 2 hours and 27.7% at 4 hours post infusion
[13]. This pharmacokinetic data supports the increase in accumulation
of toxic metabolites by a drug-drug interaction of ifosfamide and
aprepitant. Other risk factors which have been implicated to increase
the risk of ifosfamide induced neurotoxicity include hypoalbulinemia
and elevated creatinine [20].
Conclusion
Increased incidence of ifosfamide induced neurotoxicity secondary
to concomitant aprepitant use is being increasingly seen as depicted in
this case. The treatment for this is methylene blue which can also be used
for secondary prevention. It has been shown to shorten the duration of
neurotoxicity. It is used at a dose of 50 mg IV every 4-8 hours. It can
be taken orally for prevention [21]. Clinicians need to be aware of this
increased incidence of neurotoxicity and avoid the use of these drugs at
the same time to prevent this life-threatening complication.
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