Keywords
cyclophosphamide - doxorubicin - headache - hyponatremia - SIADH
Introduction
Cyclophosphamide is a common chemotherapeutic agent that is used in the treatment
of several types of cancers, including breast cancer, lymphoma, and multiple myeloma.[1] This medication exerts its therapeutic effect by alkylating DNA, which eventually
leads to programmed cell death.
As with many antineoplastic drugs, cyclophosphamide can cause a range of side effects,
the most common being hemorrhagic cystitis, amenorrhea, myelosuppression, alopecia,
nausea, and vomiting. Rarer side effects include cardiotoxicity, pulmonary toxicity,
veno-occlusive liver disease, secondary malignancies, as well as syndrome of inappropriate
antidiuretic hormone secretion (SIADH).[1] In this case report, we discuss a case of severe hyponatremia induced in a patient
after receiving one cycle of cyclophosphamide.
Case Description
A 66-year-old patient, with a history of hypertension, stage 3 chronic kidney disease,
and recent diagnosis of estrogen receptor–positive left breast cancer, was brought
to the emergency department 3 days after her first chemotherapy cycle with doxorubicin
and cyclophosphamide adjuvant therapy. She complained of severe nausea, vomiting,
and headache associated with dizziness. Her vital signs were stable. Systemic examination
was unremarkable. Investigation showed low sodium ([Fig. 1]). She was started on supportive treatment with continuous 0.9% normal saline infusion.
The patient was discharged on request the next day in stable condition.
Fig. 1 Trend of Hyponatremia before and after fluid restriction.
She returned to the emergency department 1 day later with the worsening of her symptoms,
now accompanied by anorexia. Laboratory investigations revealed severe hyponatremia
([Table 1]). She was admitted and started on hypertonic saline and later switched to 0.9% normal
saline. Her thyroid function tests were within normal limits ([Table 1]). Cortisol level was normal ([Table 1]). Her plasma osmolality was low, and urine osmolality and random urinary sodium
were elevated ([Table 1]).
Table 1
Workup for hyponatremia
|
Component
|
Result
|
Reference range
|
|
Free T4
|
20 pmol/L
|
12–22 pmol /L
|
|
TSH
|
1.230 mIU/L
|
0.2–4.4 mIU/L
|
|
Cortisol (am)
|
630 nmol/L
|
133–537 nmol/L
|
|
Serum creatinine
|
0.85 mg/dL
|
0.5–0.90 mg/dL
|
|
Plasma osmolality
|
237 mOsm/kg H2O
|
275–295 mOsm/kg H2O
|
|
Urine osmolality
|
489 mOsm/kg H2O
|
50–1,200 mOsm/kg H2O
|
|
Urinary sodium, random
|
116 mmol/L
|
40–220 mmol/L as per patient dietary intake
|
The above lab results were consistent with the diagnosis of SIADH, and she was started
on fluid restriction of 1 to 1.5 liters per day. On the following days, her sodium
started to improve and later normalized ([Fig. 1]).
Given the suspicion that cyclophosphamide was the offending agent, her chemotherapy
regimen was adjusted to doxorubicin monotherapy, with discontinuation of cyclophosphamide.
Two months later, she completed four cycles of this treatment plan without any further
complications.
Discussion
SIADH is a condition defined by excessive release of the antidiuretic hormone (ADH)
from the pituitary gland or other nonpituitary sources. ADH exerts its effects by
increasing water reabsorption in the renal collecting ducts and by constricting peripheral
arterioles. This in turn affects the fluid volume, blood pressure, and plasma sodium
concentration. SIADH primarily presents with low sodium levels, which is the underlying
cause of all the symptoms and signs seen in affected patients. The initial presentation
of low sodium, when it falls below 125 to 130 mmol/L, includes nausea and malaise.
Other symptoms, such as headache, lethargy, obtundation, and finally seizures, occur
with further drops in sodium levels. Neurological signs usually indicate the development
of cerebral edema.
Common causes of SIADH include central nervous system disturbances, such as stroke,
infections, or hemorrhage, recent surgeries, and use of certain drugs. The most common
drugs include carbamazepine, oxcarbazepine, chlorpropamide, cyclophosphamide, and
selective serotonin reuptake inhibitors.[1]
While some drugs, such as carbamazepine, are known to increase ADH activity by enhancing
receptor sensitivity to the hormone, the exact mechanism through which cyclophosphamide
can induce SIADH is still unknown.
Hyponatremia, albeit rare, is a well-documented side effect of cyclophosphamide therapy.
Most patients, when given high doses intravenously, also receive a high load of fluids
to avoid the risk of developing hemorrhagic cystitis. This often results in a fluid
overload state and hyponatremia. A few studies have also shown that it can induce
low sodium levels through the development of SIADH. The exact mechanism is unknown,
but a proposed mechanism is that cyclophosphamide or its active metabolite 4-hydroperoxycyclophosphamide
(4-HC) expresses vasopressor-like activity on the kidney.[2] Steinman et al and Campbell et al both reported patients who were known to have
diabetes insipidus and still developed SIADH following the use of cyclophosphamide.[2]
[3] This suggests that cyclophosphamide does not increase vasopressin release, as the
patients reported could not secrete vasopressin, but rather, causes a drug-induced
nephrogenic syndrome of inappropriate diuresis.[4]
The earliest correlation between cyclophosphamide use and SIADH was described in a
case by Harlow et al. This was a case of fatally severe hyponatremia in a 5-year-old
patient after a high dose of cyclophosphamide administration. Postmortem examination
of this patient showed loss of Herring's bodies and degranulation of various hypothalamic
neurosecretory organelles.[4]
Several case reports have been published that have shown evidence of hyponatremia
post-cyclophosphamide use. Bruining et al reported a case of a 64-year-old woman who
was due to receive three cycles of adjuvant chemotherapy containing 5-fluouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2 (FEC) for her breast cancer. She had a previous history of use of low-dose citalopram
7 years prior, with no reported side effects, which was reinstated 3 months before
starting chemotherapy. She developed severe hyponatremia following her second chemotherapy
cycle despite the use of low-dose cyclophosphamide (<15 mg/kg). The patient, however,
had been consuming excessive fluids after her first cycle, which may have triggered
the hyponatremia episode after her second cycle.[5] Few published reports also describe hyponatremia following low-dose cyclophosphamide
use in patients with various diseases, including multiple myeloma and systemic lupus
erythematosus.[6]
[7]
[8]
[9]
[10]
[11] Interestingly, a prospective observational study by Geng et al showed an 18.6% incidence
of hyponatremia following the first cycle of low-dose cyclophosphamide in breast cancer
patients.[11] However, none of the patients in this study developed hyponatremia of less than
125 mEq/L, and all patients recovered without specific management. Baker et al also
reported two cases of severe hyponatremic encephalopathy in patients with breast cancer,
one of whom had a similar course to our patient. She presented with hyponatremia of
117 mEq/L approximately 48 to 72 hours after completing her first chemotherapy cycle.
However, unlike our patient, the patient described in this study continued to deteriorate
over the next 3 days severely, finally developing altered sensorium.[12] Our patient developed severe hyponatremia, with the lowest value being 107 mEq/L.
Despite such dangerously low levels of sodium, she did not develop any neurological
signs or altered sensorium.
Conclusion
Hyponatremia following cyclophosphamide use is a well-known but rare side effect.
Although it is important to ensure that patients consume a large amount of fluids
and are administered Mesna to prevent hemorrhagic cystitis, it is necessary to ensure
that the fluid intake is controlled to prevent SIADH. High-risk patients must be monitored
for the development of any electrolyte abnormalities following their cycle of chemotherapy
with cyclophosphamide to avoid any preventable complications. More research and further
studies are still needed to elucidate the exact mechanism that could correlate SIADH
with cyclophosphamide use.
