Severe hyponatraemia in two patients with breast cancer caused by low-dose cyclophosphamide and precipitated by aprepitant

Abstract

Two postmenopausal women with breast cancer developed acute confusion and seizures, less than 24 hours after the first cycle of neoadjuvant chemotherapy with fluorouracil, epirubicin and low-dose cyclophosphamide. They were found to have severe, life-threatening hyponatraemia with sodium levels of 113 and 115 mEq/L, respectively. Both women made a full recovery within 24 hours of admission with slow correction of sodium levels. Following investigational workup, the most likely diagnosis was cyclophosphamide-associated syndrome of inappropriate antidiuretic hormone secretion (SIADH). Aprepitant - a commonly used antiemetic and moderate cytochromeP450 3A4 inhibitor was identified as the precipitating factor. Aprepitant was discontinued and both women were successfully re-challenged with full dose cyclophosphamide in an outpatient setting with no subsequent adverse events. This is a typical case of a rare cause of a common medical problem. A systematic approach to diagnosis and treatment of hyponatraemia in an oncology patient requires awareness of toxicities of systemic anticancer agents.

Background

Cyclophosphamide is a commonly used cytotoxic agent. High dose cyclophosphamide is often used in haematological cancers and sarcomas, while low dose cyclophosphamide is used for some solid tumours like breast cancers. It is also a widely used immunosuppressant in autoimmune and inflammatory diseases. Sudden onset, symptomatic and severe hyponatraemia (defined as less than <125 mEq/L, with normal range of sodium level 135-145mEq/L) is a rare and potentially fatal complication of cyclophosphamide. Cyclophosphamide can cause a syndrome of inappropriate antidiuretic hormone secretion (SIADH)-like presentation, and case reports link it to use in both high-dose and low-dose settings.¹ In the following case studies, the commonly used antiemetic agent aprepitant, which is also a moderate cytochrome P450 3A4 inhibitor, was clinically confirmed to be the precipitating factor for cyclophosphamide induced SIADH. Elimination of aprepitant from future cycles of chemotherapy allowed safe delivery of full-dose cyclophosphamide as part of neoadjuvant treatment for breast cancer.

Case presentation

Patient 1

A 70-year-old woman with hormone-positive, multifocal right breast cancer was referred for neoadjuvant chemotherapy in 2016. She had no significant medical history and was not on any regular medications. She received two cycles of fluorouracil (500 mg/m²), epirubicin (100 mg/m²) and cyclophosphamide (500 mg/m²) (FEC) chemotherapy. Supportive medication administered on the day included 8 mg dexamethasone and 8 mg ondansetron. Assessment of toxicities prior to cycle 3 of chemotherapy identified grade 2 emesis and grade 2 constipation. Aprepitant was added to premeditation for cycle 3 of treatment with 125 mg administered on the day of chemotherapy. Aprepitant is a neurokinin 1 inhibitor and is typically used in combination with other antiemetics to limit chemotherapy-induced vomiting.

On day 1 (less than 24 hours later), she was admitted with acute confusion and expressive dysphasia. She had a generalised seizure in the hospital that lasted 3 min and was terminated with intravenous diazepam. Sodium levels were 115 mEq/L, a drop of 22 mEq/L from a baseline of 137 mEq/L assessed 48 hours previously.

Patient 2

A 54-year-old postmenopausal woman with Human epidermal growth factor receptor 2 (HER2)-positive, hormone-positive and node-positive breast cancer was referred to oncology for neoadjuvant chemotherapy in 2021. Medical history included prior surgery for retinal detachment and two episodes of pneumonia a decade apart. She did not take any regular medications. She received her first cycle of FEC on day 0. Supportive medication administered on the day included 8 mg dexamethasone, 8 mg ondansetron and 125 mg of aprepitant.

On day 1 (18 hours later), her family noticed development of new-onset confusion. She had difficulty recognising her husband, was not oriented to time and left the house for a walk but struggled to return home. She also reported two episodes of vomiting. She suffered a generalised tonic clonic seizure on arrival to the emergency department, lasting about a minute, and it was terminated with 2 mg of intravenous lorazepam. Blood tests identified severe hyponatraemia with a sodium level of 113 mEq/L. Her baseline bloods done the day prior to chemotherapy showed Na levels of 139 mEq/L, thus indicating an acute 26 mEq/L drop in sodium levels.

Acute management and investigations

Both patients had basic investigations for acute illness on admission. Full blood counts, renal function, calcium, magnesium and potassium levels were within normal physiological limits for both patients. Liver function tests were slightly deranged for patient 2 on admission: Alanine transaminase (ALT) 60 U/L (normal range 0–35) and serum bilirubin 34 umol/L (normal range 0–21). Chest X-ray and ECGs on admission were unremarkable. A single dose of pipperacilin–tazobactam was administered to both patient in the emergency department but subsequently stopped when sepsis was ruled out. Significantly low sodium levels were found in both patients.

Patient 1

She was treated with fluid restriction and sodium levels gradually improved from 115 mEq/L to 127mEq/L within 48 hours of admission. She felt clinically better and could not remember the circumstances of her admission to the hospital. By the third day of inpatient management, sodium levels had returned to near normal levels of 134 mEq/L.

Patient 2

Sodium chloride (hypertonic saline, 150 mL of 2.7%) was administered intravenously over 20 min as part of acute management. Six hours after admission, her Na level was 118 mEq/L. Our patient then received 1 L of normal saline infusion over 8 hours as part of response assessment and diagnostic workup. Sodium levels slightly decreased to 117 mEq/L. Thereafter, intravenous fluids were stopped and free water was restricted. Twenty-four hours after admission, she felt much better; her confusion had resolved and she had no memory of the events of the previous day. Approximately 48 hours after admission, her Na levels were 130 mEq/L; and she was subsequently discharged a few days later with a normal level of 136 mEq/L.

Neurological workup for patient 1 included a CT scan and MRI scan of the head and a lumbar puncture to look for malignant cells in the cerebrospinal fluid. Patient 2 had a CT scan of the head. No significant abnormality was identified in any of the tests.

Subsequent investigations included morning cortisol levels and thyroid function tests to rule out Addison’s disease and hypothyroidism. Cortisol levels were low in patient 1 (90 nmol/L) but was explained by suppression due to dexamethasone received with chemotherapy. Cortisol levels in patient 2 were >900 nmol/L (normal). Paired plasma and urine osmolalities (plasma=243 mOsm/kg and urine 416 mOsm/kg for patient 1, and plasma=269 mOsm/kg and urine=345 mOsm/kg for patient 2) suggested hypoosmolar hyponatraemia with impaired free water excretion. Random urine sodium levels were also requested for both patients, which would have helped determine the extracellular fluid volume status and provided a measure of renal tubular function. Urine sodium levels are typically >30 mEq/L at presentation in SIADH.² However, urine sodium levels were sent after 48 hours of acute management for patient 1 (urine sodium=11 mEq/L or low), and appropriate sample collection and testing were not completed for patient 2.

Diagnosis

Both patients received inpatient input from the oncology and endocrinology teams.

Given the absence of other comorbidities or medications, normal renal function, no evidence of neurological or endocrine pathology, and the close temporal relationship to chemotherapy, the most likely aetiology was cyclophosphamide-induced SIADH. Aprepitant was identified as a precipitating factor. Patient 1 developed severe hyponatraemia only with cycle 3 of chemotherapy and the singular change in her medications had been the addition of aprepitant. Patient 2 developed severe hyponatraemia after cycle 1 of chemotherapy when aprepitant was used with low-dose cyclophosphamide as part of routine protocol. Further exploration for other contributory factors for hyponatraemia raised two episodes of vomiting in patient 1 and increased oral fluid intake after chemotherapy in patient 2 secondary to feeling thirsty. However, on balance, these events were clinically judged to be minor factors.

Outcome and follow-up

Our patients were reviewed in the oncology outpatient clinic prior to further cycles of FEC chemotherapy. Aprepitant was avoided for future cycles of chemotherapy, and both were successfully rechallenged with full-dose cyclophosphamide under close outpatient monitoring. Alternative antiemetic regimens were used for subsequent cycles of chemotherapy including ondansetron and metoclopramide. Sodium levels dropped to 134 mEq/L or mild hyponatraemia 24 hours after chemotherapy in patient 1. However, she remained asymptomatic and levels recovered spontaneously. Patient 2 had sodium levels 48 hours after the next cycle of FEC and sodium levels were 138 mEq/L, that is, normal. Both patients completed neoadjuvant chemotherapy without any further adverse events and proceeded to surgical resection of breast cancer.

Discussion

Hyponatraemia is a common electrolyte abnormality in patients admitted to the hospital³ and is present in up to half of inpatients with cancer.⁴ The presence of hyponatraemia has been associated with worse cancer outcomes, especially in metastatic cancer.^{5 6} The systematic approach to the diagnosis of hyponatraemia in patients with cancer is complicated and needs awareness of pathophysiological processes related to both the tumour and the expanding compendium of anticancer therapies. SIADH is the most common underlying process in most cancer or cancer therapy-associated hyponatraemia.⁷

Cyclophosphamide is a classic cytotoxic agent, and incidence of severe hyponatraemia with high-dose cyclophosphamide has been reported as 5.8% in a retrospective study.⁸ However, severe hyponatraemia with low-dose cyclophosphamide is a rare phenomenon, and one prospective observational study in patients with breast cancer from Japan reported an 18% incidence of all grades of hyponatraemia but 0% of severe hyponatraemia.⁹ Patients are sometimes also instructed to drink generous amounts of fluids to reduce the risk of cystitis with cyclophosphamide. This, in turn, can lead to an overload of free water and correspondingly low sodium. The mechanism of cyclophosphamide-associated SIADH is unknown though, and hypotheses proposed include both increased release of vasopressin from the posterior pituitary¹⁰ and direct action of the drug on renal tubules potentiating the effect of vasopressin. Importantly, cyclophosphamide-associated hyponatraemia manifests acutely within 4–12 hours of infusion and sometimes up to 48 hours after.¹¹ It usually corrects within 24 hours with appropriate management.

Published reports include severe hyponatraemia induced by a single 500 mg oral dose of cyclophosphamide.¹² Others report hyponatraemia due to a combination of low-dose cyclophosphamide with other precipitating factors such as nephritic disease or nephrotoxic medication such as cisplatin, ibuprofen or ACE inhibitors.¹ These are the first case reports of a drug reaction between aprepitant and low-dose cyclophosphamide causing severe hyponatraemia. The link is strengthened by the lack of complications once aprepitant was discontinued with future cycles of full-dose cyclophosphamide chemotherapy.

Aprepitant is a selective neurokinin-1 receptor antagonist and is recommended as an antiemetic with high-risk emetic chemotherapy regimens. It is also a moderate CYP450 3A4 inhibitor. Crossover trials have shown that aprepitant does not affect the drug concentration of the active 4-OH metabolite of cyclophosphamide but does significantly increase the exposure to the parent drug.¹³ Successful rechallenge of cyclophosphamide after severe hyponatraemia has been reported in literature,¹⁴ although this has been in an inpatient setting supported by infusions of normal saline. To our knowledge, ours is the first published set of cases of successful rechallenge in an outpatient setting after cessation of aprepitant and without need for any other interventions. While it is possible that the toxicity of severe hyponatraemia due to cyclophosphamide is inconsistent or transient, our case reports strongly suggest a plausible drug interaction with aprepitant. Furthermore, a potential drug interaction of aprepitant with ifosfamide was been hypothesised with an increased risk of encephalopathy due to this combination.¹⁵ In the absence of ways to predict these rare reactions and to identify uniquely susceptible patients, clinical awareness and appropriate follow-up are important.

A modified practical flowchart for the initial laboratory investigation of hypo-osmolar hyponatraemia (most common type) in a patients with cancer is illustrated in figure 1.¹⁶ A systematic approach can help identify the underlying cause of hyponatraemia and highlight potential modifiable factors. An appropriate aetiopathological diagnosis will guide both acute management and future systemic anticancer treatment.

Figure 1.

Initial algorithmic approach to the diagnosis of the aetiology of hyponatraemia in a patient on active systemic anticancer therapy. SIADH, syndrome of inappropriate antidiuretic hormone secretion.

Patient’s perspective.

Soon after the seizure, I wondered if the fact that I had had an extremely busy and demanding week beforehand affected the situation. I suffered feelings of a muzzy head, painful neck and headaches for about two weeks after the seizure and unstable balance for about three weeks. Word finding was also an occasional problem during this time.

The reaction against aprepitant made very poorly and confused. I was in the ward for a few days. This made me very nervous, going for more treatment.

Learning points.

• This is a typical case of a rare cause of a common medical problem. Cyclophosphamide can cause acute life-threatening hyponatraemia secondary to drug-associated syndrome of inappropriate antidiuretic hormone secretion.

• A drug interaction between aprepitant and cyclophosphamide can precipitate severe hyponatraemia. This toxicity can be avoided by cessation of aprepitant, a moderate cytochrome P450 3A4 inhibitor.

• Systematic diagnosis of the aetiology of hyponatraemia in patients with cancer requires awareness of toxicities of systemic anticancer agents.

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