Tumour lysis syndrome following eribulin for metastatic uterine leiomyosarcoma

Abstract

A middle-aged woman with a history of leiomyosarcoma of the uterus treated with surgery and adjuvant chemotherapy suffered a bulky metastatic recurrence 1 year later. She elected treatment with palliative eribulin, presenting with acute renal failure and electrolyte abnormalities consistent with tumour lysis syndrome on cycle 1 day 8. Despite aggressive supportive care and treatment including intravenous hydration, bicarbonate and rasburicase, she continued to decline, ultimately foregoing haemodialysis in favour of palliative care and passed away in the hospital.

Background

Tumour lysis syndrome (TLS) is extraordinarily rare in leiomyosarcoma and has not previously been reported with eribulin. This case expands both the malignancies and cytotoxic agents that may lead to TLS. Increased awareness for this potentially fatal complication of cancer treatment is imperative for clinicians to optimally prevent and promptly diagnose and treat TLS.

Case presentation

A middle-aged woman presented to the emergency department (ED) for right upper quadrant pain. One year prior to presentation, she had been diagnosed with leiomyosarcoma of the uterus for which she had been treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy. In the operating room, she was found to have a 12 cm tumour filling the vagina and compressing the bladder and urethra. This mass was removed in addition to the uterus, fallopian tubes, ovaries and cervix. Intraoperative cystoscopy was normal, and she had an uncomplicated postoperative course. Pathology confirmed uterine leiomyosarcoma pT1b. No lymph node dissection was performed. CT 1 month postoperatively was negative for adnexal masses, adenopathy or metastatic disease. Adjuvant treatment was delayed 4 months postoperatively secondary to multiple patient-related logistical issues. She received docetaxel and gemcitabine x 4 cycles. Dosing was as follows: docetaxel at 75 mg/m² day 8 and gemcitabine at 900 mg/m² days 1 and 8 every 21 days with pegfilgrastim given on day 9 of every cycle. This regimen was chosen among the National Comprehensive Cancer Network recommended regimens due to the patient’s pre-existing heart failure with left ventricular ejection fraction 40%–45% by transthoracic echocardiogram and thus need to avoid potential cardiomyopathy of anthracyclines.¹

The patient underwent CT chest/abdomen/pelvis in the ED to evaluate her new right upper quadrant pain and was hospitalised for further management. CT demonstrated elevation of the right hemidiaphragm secondary to multiple intraparenchymal bilateral hepatic lesions, some of which were necrotic. A lesion in the posterior right hepatic lobe was noted to extend outside of the hepatic capsule (figure 1). A large right hilar mass (13.4×8.7×16 cm) had a mass effect on the right hepatic lobe, main portal vein, inferior vena cava and the right renal artery and vein, displacing the distal stomach, pancreatic head and right colon. There was no intrahepatic ductal dilatation. Soft tissue masses were identified in the right vaginal cuff (3.6×3×3.9 cm) and in the posterior right pelvis (1.6×1.6 cm). A small amount of free fluid was noted in the pelvis in addition to para-aortic and pelvic lymphadenopathy. A new 7 mm nodule was seen in the right lower lung along with a small right pleural effusion.

Figure 1.

Diffuse hepatic masses with severe right hepatic lobe extending outside the capsule of the liver into the soft tissues. Large hilar mass producing the mass effect.

An ultrasound-guided biopsy of the right liver mass was performed. Multiple core biopsy fragments involved malignant spindled cells with fascicular growth patterns. The cells demonstrated eosinophilic cytoplasm, moderate nuclear pleomorphism, frequent mitosis and associated necrosis. Immunohistochemistry demonstrated diffuse expression for smooth muscle actin and desmin (figure 2). The patient’s prior hysterectomy specimen slides were reviewed, and the current biopsy was noted to be morphologically similar to that of leiomyosarcoma identified in the hysterectomy specimen consistent with the metastatic recurrence.

Figure 2.

The biopsy of the liver lesion demonstrated a cellular spindle cell neoplasm with moderate nuclear atypia, eosinophilic cytoplasm and frequent mitoses (A). Areas of coagulative tumour necrosis were identified (B). The tumour cells showed diffuse expression for desmin (C) and smooth muscle actin (D) supporting the diagnosis of metastatic leiomyosarcoma.

The patient’s abdominal pain was controlled with tramadol 50 mg PO q4-6h. She was discharged from the hospital and followed up with her oncologist in the clinic to discuss palliative systemic treatment options. Therapy was initiated with intravenous eribulin mesylate: 1.4 mg/m² on days 1 and 8 of a 21-day cycle. Anthracyclines were again avoided due to the patient’s pre-existing cardiomyopathy. In light of the short disease-free interval from adjuvant chemotherapy to recurrence, previously used agents such as gemcitabine and taxanes were not preferred. Because a clinical trial was not immediately available and the patient’s symptoms required timely initiation of treatment, consideration was given to the options supported by the National Comprehensive Cancer Network guidelines. Ifosfamide would require hospital admission, and eribulin was chosen both for ease of outpatient administration and emerging data on the agent’s activity in sarcomas including leiomyosarcoma of the uterus.²

On presentation to the outpatient oncology infusion centre for cycle 1 day 8 of eribulin, our patient was evaluated for new symptoms of extreme fatigue, dyspnoea with light activity and poor appetite. She was noted to be hypotensive at 64/31 mm Hg. Labs were significant for creatinine of 5.99 (Cr 1 week prior: 0.77), blood urea nitrogen (BUN) of 88 mg/dL, potassium of 6.9 mmol/L, and sodium of 126 mmol/L. Eribulin therapy was held, and she was hospitalised for further evaluation and treatment of hypotension, acute renal failure and electrolyte abnormalities.

Investigations

Retroperitoneal ultrasound demonstrated normal renal cortical echogenicity bilaterally with no hydronephrosis. The right kidney measured 11.7 cm in length, and the left kidney measured 12.7 cm in length. Multiple masses were identified next to the right kidney, corresponding to known metastatic disease in the liver, without mass effect on the kidneys. The urinary bladder was not seen, likely from being decompressed. Urinalysis was unremarkable.

Differential diagnosis

The differential diagnosis for the patient’s acute renal failure included prerenal azotemia secondary to dehydration due to poor oral intake vs. ischaemic acute tubular necrosis from hypovolaemic hypotension vs TLS. Sepsis was also considered due to her leucopaenia and hypotension; however, she was afebrile with alternative explanations for her clinical and laboratories abnormalities. Her white blood cell count (WBC) nadir on day 2 hospitalisation was 1700 with absolute neutrophil count of 1050 which was attributed to chemotherapy. WBC increased with neutrophilic predominance throughout the hospital stay consistent with recovery from chemotherapy. By hospital day 5, her WBC reached 19 600 with 84% neutrophils which was believed to represent a leucaemoid reaction to physiologic stress. Her hypotension resolved with fluid resuscitation, and she provided a history of very limited oral intake over the preceding days. For the quick Sequential (sepsis -related) Organ Failure Assessment (qSOFA) method of evaluating sepsis, she did have systolic blood pressure ≤100 mm Hg but did not meet the other two criteria. Her respiratory rate was 18 rather than 22 breaths/minute or more, and she did not have altered mental status. In the SOFA scoring system to evaluate for sepsis, she had no abnormalities in PaO₂/FiO₂ (pulse oximeter 95% on room air), Glasgow Coma Scale (15), bilirubin (total bilirubin 0.7) or platelet count (459 000). Her hypotension did not require vasopressor support. She did have markedly abnormal creatinine and urine output attributable to TLS. This would give a qSOFA score of 1 and a SOFA score of 5 neither of those meet the criteria for sepsis.³

In the setting of TLS, an increase in uric acid excretion can result in the precipitation of uric acid in the renal tubules and renal vasoconstriction.⁴ This impairs autoregulation, reducing renal blood flow and producing acute kidney injury. One may argue that our patient’s acute renal failure was due to her hypovolaemic state. However, her markedly elevated uric acid and lactate dehydrogenase (LDH) in addition to hyperkalaemia and hyperphosphataemia are more consistent with TLS than dehydration. Urine/Plasma creatinine was 70 (420/6 mg/dL), which is typically <20 in acute tubular necrosis, and no pathognomonic muddy brown epithelial casts were seen in the urine to support acute tubular necrosis either. Prerenal azotemia is associated with a BUN/creatinine >20, and our patient was not consistent with this at 13 (80/6 mg/dL). Additionally, TLS is supported by the clinical picture with hypotension and reduced urine output in the days immediately following the initiation of chemotherapy for bulky necrotic liver metastases. Our patient meets criteria for the Cairo-Bishop definition of TLS.⁵ The Cairo-Bishop classification system requires two or more of the following laboratory values from 3 days before to 7 days after treatment is initiated: uric acid ≥8 mg/dL, potassium, ≥6 mEq/dL, phosphorus ≥6.5 mg/dL and calcium ≤7 mg/dL. A change from baseline of any two of these values by ≥25% also constitutes laboratory criteria for TLS by the Cairo-Bishop system. Clinical TLS is laboratory TLS with increased creatinine, seizures, dysrhythmia or death.

Treatment

The patient was noted to be hypotensive at the presentation at 64/31 mm Hg. Her blood pressure responded to fluid resuscitation with 2 L NS bolus followed by 2 L LR bolus. She did not require vasopressor support and was subsequently maintained on an infusion of 150 mEq bicarb in D5W for her acute renal failure.

Peaked T waves and an old LBBB were noted on initial EKG. Peaked T waves resolved with successful treatment of hyperkalaemia with intravenous bicarbonate along with calcium gluconate, insulin and glucose, and kayexelate.

She was unable to void spontaneously and catheterisation revealed a mass from the introitus extending out, occluding the view of the urethra. Once Foley catheter was in place, urine was noted to be tea-coloured with urine output <30 mL/hour. On hospital day 2, laboratory findings were remarkable for a uric acid of 21.4, potassium of 6.2, phosphorus of 7, calcium of 8.3 and LDH of 910. Due to high suspicion for TLS, intravenous hydration was continued and 3 mg intravenous rasburicase was administered. She declined haemodialysis.

Outcome and follow-up

Following initiation of rasburicase, the patient remained oliguric but demonstrated improvement in electrolyte abnormalities (potassium 4.6, phosphorus 7.5, calcium 6.7) and uric acid levels (6.4). On hospital day 3, she had a single episode of large volume haematemesis (1900 mL) with hypotension at 60/40 mm Hg. She was transferred to the medical intensive care unit where nasogastric tube (NGT) suction produced an additional 500 mL of coffee-ground material. Her hypotension was unresponsive to fluid resuscitation but responded to vasopressors. Intravenous proton pump inhibitor was initiated. Gastroenterology was consulted and suspected either uraemia or gastropathy as the aetiology of bleed but did not recommend endoscopy as active bleeding had resolved. She received 3 units of pRBCs. Her lowest haemoglobin/haematocrit values were 9.5 g/dL and 29%. On hospital day 5, the patient and her family on discussion with the intensive care unit physician elected comfort care only. The NGT was removed, pressors were stopped, and vital sign and laboratory monitoring was discontinued. She continued to receive pain medication and oxygen and was offered paracentesis for comfort. She was visited by hospital chaplain at 11:01 am and on the nursing check at 11:25 am had passed away which was hospital day 6.

Discussion

TLS is an oncological emergency characterised by extensive cell lysis resulting in hyperkalaemia, hyperuricaemia, hyperphosphataemia, hypocalcaemia and lactic acidosis.⁴ Clinical manifestations may include nausea, vomiting, diarrhoea, anorexia, fatigue, haematuria, heart failure, dysrhythmias, seizures, muscle cramps and sudden death.⁶ It most commonly occurs in the initial therapy of rapidly proliferating haematological malignancies such as Burkitt’s lymphoma and acute leukaemias.⁷ In contrast, TLS is rarely seen in the treatment of solid tumours, although it has been reported in germ cell tumours, small cell carcinoma, neuroblastoma, medulloblastoma, sarcoma, ovarian cancer and gastrointestinal stromal tumours.^8–12

Therapies commonly associated with TLS include alemtuzumab, rituximab, imatinib, bortezomib, fludarabine, lenalidomide, obinutuzumab, radiation and glucocorticoids.^{13 14} TLS has the potential to occur with any highly active cytotoxic agent in the setting of initiation of treatment and a large tumour burden. Current advances in targeted oncological therapies have resulted in an emergence of TLS in cancers that have not previously been associated with such complications. This is to our knowledge the first report of initial treatment of leiomyosarcoma of the uterus resulting in TLS and also the first reported case of TLS with eribulin.

Pubmed search for ‘tumor lysis syndrome’ and ‘leimyosarcoma’ brings up two case reports. The first involved a patient with leiomyosarcoma and rhabdomyosarcoma of the uterus who developed TLS during her second cycle of therapy with vincristine, actinomycin-D and cyclophosphamide.¹⁵ On cycle 2 day 7, she presented with decreased urinary output and confusion. Laboratory data were significant for hyperkalaemia (6.4 mEq/L), hyperuricaemia (8.5 mEq/L), hypocalcaemia (8.1 mEq/L) and an elevated Cr at 7.3 mg/dL. Risk factors for this patient included large tumour burden that was extremely responsive to therapy, decreasing by >80% of its original size. Similarly, our patient had a large tumour burden with evidence of necrosis on imaging that suggests a response to eribulin and/or outgrowth of vascular supply. Notably, our patient’s urine pH was 5.0 on admission which is an additional risk factor for TLS.¹⁶ The second case report involved spontaneous TLS in a patient presenting with a large (16×20 cm) partially necrotic leiomyosarcoma of the uterus with lung metastases.¹⁷

Eribulin is a microtubule inhibitor. It exerts its antimitotic effects through inhibition of the formation of mitotic spindles, arresting the cell cycle at the G2/M phase.¹⁸ It may be used as therapy for metastatic breast cancer or metastatic/unresectable liposarcomas. A phase II study of eribulin in patients with previously treated late-stage or metastatic soft tissue sarcoma found pancyptopaenia and febrile neutropaenia to be the most common adverse effects.¹⁹ Additional side effects of eribulin include fatigue, alopecia, gastrointestinal manifestations, peripheral neuropathy and QT prolongation. Currently, no documented cases of TLS with eribulin treatment have been reported. We propose that our case is the first report of tumour lysis in a patient receiving eribulin.

Our case raises awareness of TLS in advanced uterine leiomyosarcoma. This disease is often treated by gynaecological oncologists who have limited experience with this potentially life-threatening treatment complication more commonly seen with leukaemias and lymphomas. Recognition of the risk of TLS can lead to prevention and early detection and thus prompt initiation of treatment with the potential to improve outcomes in this oncological emergency.

Learning points.

• Tumour lysis syndrome (TLS) is not limited to haematological malignancies.

• Aggressive bulky necrotic solid tumours, such as our patient’s leiomyosarcoma of the uterus, are at risk of TLS at presentation and initiation of treatment.

• Our patient’s case uncovers a previously unreported adverse effect of eribulin.