Oncological emergencies: from febrile neutropenia to spinal cord compression

Definition. Neutropenia means a neutrophil count (segmented and band forms) below 500/µL, or below 1000 with an expected fall below 500 over the next 2 days; fever means an oral temperature ≥38.3 °C on one occasion, or ≥38.0 °C lasting at least 1 hour or recorded twice in 12 hours ^[16].

Why it matters. In data from 115 US centres (41,779 admitted patients), in-hospital mortality from febrile neutropenia was 9.5%; it was 2.6% without major comorbidity, 10.3% with one comorbidity and ≥21.4% with more than one, and invasive fungal infection, gram-negative sepsis and pneumonia were independent risk factors for death ^[17].

Time is decisive. The ASCO/IDSA guideline recommends giving the first dose of empirical antibiotic within 1 hour of triage ^[1]. In a cohort of 307 episodes, each hour of delay was associated with an HR for 28-day death of 1.18 (95% CI 1.10 to 1.26), and 28-day mortality was 3.0% with antibiotics started within ≤30 minutes versus 18.1% with a start at 31 to 60 minutes ^[5]. All febrile neutropenic patients should be treated promptly with gram-positive and gram-negative cover, and risk stratification is the starting point for decisions ^[18].

Initial assessment. Before antibiotics, take at least two sets of blood cultures from two separate sites; with a central venous catheter add one set from the catheter (and from every lumen of a long-term catheter). Routine repeat cultures after starting treatment are of no benefit except with new fever, clinical deterioration or growth of Staphylococcus aureus or Candida ^[4]. Imaging is guided by symptoms: low-dose chest CT with respiratory symptoms; a plain chest X-ray is not recommended because of its low sensitivity in neutropenia. Procalcitonin helps estimate the probability of bacteraemia, and previous antibacterial prophylaxis is stopped when empirical treatment starts ^[4].

Tumour lysis syndrome arises from the rapid destruction of malignant cells and release of potassium, phosphate and nucleic acids (and hence uric acid), and can lead to acute kidney injury, arrhythmia, seizures and death; it is most common in highly proliferative, bulky tumours such as acute lymphoblastic leukaemia and Burkitt lymphoma ^{[20, 21]}. Precipitation of uric acid, xanthine and calcium phosphate crystals in the renal tubules is the main cause of kidney injury, and treatment with allopurinol can cause xanthine nephropathy through xanthine accumulation ^[22].

Classification. In the Cairo–Bishop system, laboratory TLS means at least two metabolic abnormalities (hyperuricaemia, hyperkalaemia, hyperphosphataemia, hypocalcaemia) from 3 days before to 7 days after the start of treatment, and clinical TLS means laboratory TLS with a rise in creatinine, seizures, arrhythmia or death ^{[20, 22]}. Howard and colleagues proposed that the abnormalities be simultaneous (within a 24-hour window), that the "25% change from baseline" criterion be dropped, and that any symptomatic hypocalcaemia count as clinical TLS ^[22].

Risk factors. Tumour burden (bulky mass, involvement of liver, spleen, kidney or bone marrow), lytic potential (high LDH, intrinsic sensitivity of the tumour to treatment, intensity of initial treatment) and patient features (pre-existing nephropathy, oliguria, dehydration, hypotension and acidic urine) determine the risk; in borderline cases, an LDH above 2 times the upper limit of normal or a high uric acid moves the patient into a higher-risk group ^[22]. The international panel of Cairo and colleagues, based on the same variables (laboratory TLS, proliferation, tumour bulk and stage, and kidney failure or involvement), divides patients into low, intermediate and high risk ^[21].

Targeted drugs also cause TLS. In the venetoclax label for CLL, the risk of TLS over the 5-week dose ramp-up is a continuum and rises especially with a creatinine clearance below 80 mL/min and with tumour burden: low burden (all lymph nodes under 5 cm and absolute lymphocyte count below 25,000) with oral hydration and outpatient allopurinol; high burden (any node ≥10 cm, or lymphocytes ≥25,000 with a node ≥5 cm) with IV hydration at 150 to 200 mL an hour, allopurinol (and rasburicase if baseline uric acid is high), and admission for the 20 and 50 mg doses with tests at 4, 8, 12 and 24 hours ^[23].

Treating established TLS. Hyperkalaemia is the most dangerous component: potassium every 4 to 6 hours, continuous cardiac monitoring, potassium and phosphate restriction, and haemodialysis if needed; calcium gluconate reduces the risk of arrhythmia until dialysis. Asymptomatic hypocalcaemia needs no treatment, and calcium is given only at the lowest dose needed for symptoms, because the calcium × phosphate product (especially above 60) increases calcium phosphate precipitation. The threshold for dialysis in TLS is lower than for other causes of acute kidney injury ^[22].

Hypercalcaemia occurs in 10 to 30% of cancer patients (most often in breast cancer, lung cancer, non-Hodgkin lymphoma and multiple myeloma); about 80% is caused by parathyroid hormone-related protein (PTHrP) and about 20% by bone metastases, and it signals a poor prognosis. Symptoms (anorexia, nausea, constipation, polyuria, confusion up to coma) depend more on how fast calcium rises than on its absolute level; the ECG may show a short QT, long PR and wide QRS ^[15]. Albumin-corrected calcium = serum calcium + 0.8 × (4.0 − albumin) ^[9].

Severity and initial treatment. Urgent treatment can be deferred for calcium below 12 mg/dL; 12 to 14 is treated according to clinical judgement and symptoms; above 14 is usually symptomatic and needs intervention. Hydration with isotonic saline (a bolus of 1000 to 2000 mL then 200 to 300 mL an hour, aiming for a urine output of 100 to 150 mL an hour) is the basis of treatment, and a loop diuretic is used only in a euvolaemic or volume-overloaded patient ^[15]. The zoledronic acid label also stresses that diuretics should not be given before dehydration is corrected ^[27].

Endocrine Society guideline (2023). In adults with hypercalcaemia of malignancy, treatment with denosumab or an IV bisphosphonate is strongly recommended; the conditional suggestions (with low certainty of evidence) are: preferring denosumab over an IV bisphosphonate; combining calcitonin with an IV bisphosphonate or denosumab as initial treatment of severe hypercalcaemia; denosumab for hypercalcaemia that is refractory or recurrent despite a bisphosphonate; and, in tumours with high calcitriol (as in some lymphomas) with severe or symptomatic hypercalcaemia despite glucocorticoids, adding an IV bisphosphonate or denosumab ^[8]. The pamidronate label also regards glucocorticoids as useful in hypercalcaemia of haematological malignancies ^[9]. Treating the underlying disease is the key to lasting control ^[8].

Comparative evidence. In a pooled analysis of two randomised trials (corrected calcium ≥12 mg/dL), complete response by day 10 was 88.4% with zoledronic acid 4 mg versus 69.7% with pamidronate 90 mg, and the median duration of complete response was 32 versus 18 days ^[28].

Clinical suspicion. In a patient with a history of cancer or active cancer, progressive or severe back pain, mechanical pain, night pain that disturbs sleep, pain made worse by coughing or straining, and radicular pain are warning signs of spinal metastases; limb weakness, gait disturbance, numbness or paraesthesia and bladder or bowel dysfunction are signs of spinal cord or cauda equina compression and call for immediate contact with the MSCC coordinator or on-call team ^[10].

Imaging. Whole-spine MRI is the recommended diagnostic test ^[31]. NICE recommends MRI as soon as possible when MSCC is suspected and always within 24 hours (sagittal T1 and/or STIR sequences of the whole spine, sagittal T2 and axial images at abnormal levels) ^[10].

Corticosteroids. In a patient with neurological symptoms or signs of MSCC, dexamethasone 16 mg orally (or the IV equivalent) is given as soon as possible and continued daily until surgery or radiotherapy, then tapered; stop it if MSCC is excluded ^[10]. In a randomised trial, high-dose dexamethasone (a 96 mg IV bolus, then 96 mg orally for 3 days and tapered over 10 days) with radiotherapy increased the proportion keeping the ability to walk from 63% to 81%, and at 6 months 59% versus 33% of patients were walking; significant side effects occurred in 11% ^[32]. In another trial, a bolus of 10 mg versus 100 mg (then 16 mg daily) made no difference to pain, walking or bladder function ^[33].

Surgery: the Patchell trial. 101 patients were randomised to direct decompressive surgery followed by radiotherapy or to radiotherapy alone (both 30 Gy in 10 fractions), and the study was stopped early under its stopping rule: the ability to walk after treatment was 84% versus 57% (odds ratio 6.2; 95% CI 2.0 to 19.8), the median time walking was kept was 122 versus 13 days, and in patients who entered unable to walk, walking was regained by 62% versus 19%; the need for corticosteroids and opioids was also lower in the surgery group ^[11].

Radiotherapy. For MSCC unsuitable for surgery, urgent radiotherapy within 24 hours is recommended, except in complete paraplegia or tetraplegia for more than 2 weeks with controlled pain or a poor overall prognosis; NICE prefers single-fraction 8 Gy radiotherapy unless the risk of side effects is high (a large field or previous radiotherapy) ^[10]. In the SCORAD trial (686 patients; 44% prostate), walking at week 8 was 69.3% with single-fraction 8 Gy and 72.7% with 20 Gy in 5 fractions; the lower bound of the one-sided confidence interval (−11.5%) slightly exceeded the non-inferiority margin (−11%) and non-inferiority was not proven, although 12-week survival was similar (HR 1.02) ^[34]. After surgery, adjuvant radiotherapy is recommended once the patient has recovered from surgery, and the SINS instability score and the revised Tokuhashi prognostic score can help decisions alongside clinical assessment ^[10].

Causes. Non-small cell lung cancer (22 to 57%), small cell lung cancer (10 to 39%) and lymphoma (1 to 27%) are the commonest malignant causes; thrombosis and benign causes can also be responsible. Common symptoms are swelling of the neck and face, breathlessness, swelling of the upper limbs and trunk, cough and collateral veins on the chest ^[12].

Tissue diagnosis first. Up to 59% of patients present without a previous diagnosis of cancer, and minimally invasive methods (sputum or pleural fluid cytology, biopsy of a superficial lymph node) make the diagnosis in about two thirds. In most patients no link has been seen between the duration of symptoms and the treatment outcome; so a tissue diagnosis before radiotherapy makes optimal treatment of the underlying cause possible ^[12].

Life-threatening cases. In the Yu classification, grade 4 means significant cerebral oedema (confusion, reduced consciousness), laryngeal oedema (stridor) or haemodynamic compromise (syncope without another cause, hypotension, kidney failure); this group is about 5% of patients and is an indication for urgent venography, stenting and, if needed, thrombolysis. If stenting is possible, urgent radiotherapy is not first line, because a stent relieves symptoms faster ^[12].

Treatment options. An endovascular stent relieves symptoms within 0 to 72 hours in 80 to 95% of patients (treatment-related death 3 to 4%); radiotherapy works within 3 to 30 days and chemotherapy within 1 to 2 weeks. Chemotherapy is the main treatment in sensitive tumours (small cell lung cancer, non-Hodgkin lymphoma, germ cell tumours); in thrombosis, anticoagulation is first line. No trial or review has shown a symptomatic or long-term benefit of corticosteroids; their use should be limited to airway oedema or prevention of radiation-induced oedema and, if prescribed, given at high potency for a short time ^[12].

Hyperviscosity

The commonest cause is Waldenström macroglobulinaemia (40 to 90% of cases), followed by multiple myeloma; the classic triad is mucosal or skin bleeding, visual disturbance and focal neurological deficit. Blood transfusion can make the condition worse and should be avoided as far as possible ^[15]. In patients with bleeding or neurological manifestations, plasmapheresis is the treatment of choice and relatively safe, and if clinical suspicion is high and the features are typical, it can start without measuring viscosity (although a sample should be sent for confirmation); asymptomatic hyperviscosity does not need plasmapheresis ^[13].

Hyperleukocytosis and leukostasis

Hyperleukocytosis usually means a white cell count above 100,000/µL in acute leukaemia, and its danger comes from leukostasis (especially in the brain and lungs), tumour lysis syndrome and DIC; the risk of complications is greater in acute leukaemias, especially AML, than in chronic leukaemias, and the condition is a haematological emergency ^{[35, 36]}. Up to 20% of patients with AML present with hyperleukocytosis, and mortality of up to 8% at 24 hours and 29% in the first week has been reported ^[37]. Rapid cytoreduction is done with leukapheresis, hydroxyurea or chemotherapy, but in a meta-analysis of 13 retrospective studies (1743 patients), leukapheresis did not reduce early death (RR 0.88; 95% CI 0.69 to 1.13) ^[37]. Hydroxyurea takes a few days to work, and because both methods are temporary, leukaemia-specific treatment should start as soon as possible ^[14]. In hyperviscosity due to a high white cell count, also avoid blood transfusion ^[15].

Neutropenic enterocolitis (typhlitis)

A life-threatening complication, mainly in haematological malignancies, that has become more common with the wider use of mucositis-causing drugs such as taxanes. In a neutropenic patient with fever and abdominal symptoms (cramping pain, bloating, diarrhoea, gastrointestinal bleeding), bowel wall thickening of more than 4 mm on imaging is the key sign; Clostridioides difficile infection and other causes (such as GVHD) must be excluded. Complications include bacteraemia, often polymicrobial, bleeding and perforation or abscess. Treatment: bowel rest, correction of cytopenias and coagulopathy, broad-spectrum antibiotics and an antifungal; surgery for complications (bleeding, perforation) and, if possible, after neutropenia recovers ^[38].