21st June 2023

Oncological Emergencies

Introduction to Oncological Emergencies

The field of oncology is constantly evolving and, at first glance, can appear vast and complex. Exposure at undergraduate level can be limited and is typically integrated into the curriculum within the different body systems. New diagnoses of cancer arise in every medical specialty. Up to 40% of lung cancer diagnoses are made as an emergency presentation. However, while the treatment of cancers evolves on a seemingly week to week basis, it is imperative that all clinicians understand the fundamentals of managing oncological emergencies.

Malignant spinal cord compression

Overview of malignant spinal cord compression

Malignant spinal cord compression (MSCC), as the name suggests, is the compression of the spinal cord or cauda equina caused by a malignant process. Although more commonly referred to as ‘metastatic spinal cord compression’, there are several mechanisms by which compression can occur and is not always seen in the presence of metastatic disease.

• Direct invasion – a malignant tumour (either primary or secondary) directly invades into the spinal canal causing resultant compression of the cord/cauda equina.
• Vertebral collapse – a malignant process that causes a compromise in the integrity of a vertebra (typically the vertebral body) causing displacement into the spinal canal, resulting in compression. Again, this can be caused by invasion into the vertebrae, or secondary to a metastatic deposit. Bony metastases are radiologically characterised as sclerotic or lytic. Lytic metastases cause demineralisation of the bone and as such, present a higher risk of destabilisation. These should be differentiated from vertebral collapse secondary to osteoporosis as the approach to management will be different. Clinically, this can pose a challenge as a number of treatments can result in bone demineralisation e.g. aromatase inhibitors for breast cancer, LHRH analogues for prostate cancer and steroids in a variety of applications.
• ‘Spinal canal metastases’ – this describes an umbrella term of metastatic disease found within the canal and can be separated by the location within the canal.
  • Extradural – located outside of the dura mater of the spinal cord. This can be secondary to invasion originating from outside of the vertebral canal.
  • Dural/intradural – located within the dura mater. Less common but is seen in the context of ‘drop metastases’ from primary CNS tumours, above the metastasis.
  • Intramedullary metastasis – located within the spinal cord itself. Technically, this would not be classed as malignant spinal cord compression, but the patient may present and be managed in a similar fashion.

Investigation of suspected MSCC

The approach to managing a patient with suspected MSCC should be standardised and the goal of which is to prevent neurological damage and to further promote neurological function. Typical signs and symptoms which may prompt a clinical review include new onset back pain, particularly non-traumatic back pain with radiculopathy (band-like pain), worsened by movement. Other red-flag signs/symptoms include bilateral lower limb weakness, bilateral shooting leg pains, urinary retention (+/- incontinence due to overflow) and faecal incontinence.

Steps to assessment:

• The patient should be maintained on flat bed rest
• A full neurological examination should be performed including cranial nerves and peripheral nerves.
• Assess for spinal tenderness, using a log-roll technique and perform a digital rectal examination to assess for anal sphincter tone.
• 16 mg Dexamethasone should be administered, either as a STAT dose, or 8 mg BD, ideally morning and lunchtime dosing. This should be co-administered with a PPI.
• A whole spine MRI should be requested, specifically stating that the query is to determine the presence of metastatic spinal cord compression. This must be undertaken within 24 hours of a suspected diagnosis.
• Once a determination of MSCC has been confirmed, treatment should be delivered within 24 hours.
• Spinal Instability Neoplastic Score (SINS) should be calculated to determine the stability of the spine.

Management of MSCC

MSCC may be an acute presentation of metastatic disease. In which case, the underlying diagnosis and stage of the cancer should be ascertained.

The nature of treatment is dependent on a number of patient and biological factors. The Gold standard of treatment for the definitive management of MSCC is anterior direct decompression surgery followed by radiotherapy. However, in practice few patients are suitable for surgery. Factors affecting this include a patient’s comorbidities, perioperative morbidity, life expectancy, burden of disease and degree of spinal instability. Typically, those patients who are young, have a good performance status, have few comorbidities, have a good prognosis, have a single site of disease and for whom surgery might be the best method of tissue diagnosis should be considered for surgery.

In whom surgery is not practical or feasible, palliative radiotherapy is the typical treatment of choice. A single fraction of palliative radiotherapy has been shown to be non-inferior to multiple treatments. In some cases, the underlying biology of the malignancy might be conducive to primary systemic therapy as the treatment of choice e.g. high-grade lymphoma or small cell lung cancer. It is also worth considering that in some circumstances if lymphoma is suspected but a tissue diagnosis has yet to be obtained, if the patient has no neurological deficit, a biopsy may be prioritised over the initiation of steroids due to the exquisite sensitivity of high-grade lymphomas to steroid therapy. However, this should be considered on a case-by-case basis.

Neutropenic sepsis

Diagnosis

Neutropenic sepsis is diagnosed in patients who have a neutrophil count of ≤ 0.5 x 10⁹/litre with a temperature ≥38.0℃ (or <36.0℃) and/or with features suggestive of sepsis. It is a potentially fatal complication of systemic anticancer therapy or for those living with bone marrow failure. It should be suspected in patients with the aforementioned signs and symptoms in those who have undergone chemotherapy within the preceding 4-30 days. However, the risk is highest between days 7-12 after chemotherapy.

Historical mortality rates of between 2-21% resulted in the ‘National Confidential Inquiry into Patient Outcome and Death – Systemic anticancer therapy: For better or worse?’ report in 2008. This, and subsequent reports, highlighted deficiencies in the provision of care for patients undergoing chemotherapy in the management of neutropenic sepsis, resulting in avoidable deaths. This led to the provision of 24-hour contact numbers for patients to report symptoms and for the provision of emergency empirical antibiotic treatment.

Management

Patients suspected of neutropenic sepsis should be managed with intravenous broad-spectrum antibiotics within 1 hour of presentation (the mantra of ‘door to needle time’ of less than 1 hour). Typically this should be a beta-lactam based antibiotic such as piperacillin + tazobactam (Tazocin). Bloods should be taken including FBC, U&Es, CRP, lactate, and blood cultures. A full clinical examination, observations, and appropriate septic screen investigations (i.e. chest x-ray, urine cultures) should be undertaken. Note that patients with septic shock or signs of severe sepsis should be aggressively managed with intravenous fluids and with early discussion with ITU.

The MASCC (Multinational Association for Supportive Care in Cancer) score can be employed as a triaging tool to ascertain overall risk. It incorporates information on the underlying cancer, patient factors (age, comorbidities) and clinical factors (hypotension, hypovolaemia). Those at ‘low-risk’ may be managed with oral antibiotics in the community, provided they have adequate support networks.

The use of granulocyte-colony stimulating factor (G-CSF) may be employed prophylactically within a chemotherapy regimen if there is an associated significant risk of neutropenia. It can also be considered in patients with prolonged or profound neutropenia.

Malignant hypercalcaemia

Aetiology

Malignant hypercalcaemia is a common electrolyte abnormality occurring in up to 30% of patients with cancer. There are several mechanisms which can lead to hypercalcaemia in the context of cancer:

• PTH-related protein (PTHrP) secretion – this is the most common cause. PTHrP is typically secreted by squamous cell carcinomas, breast, ovarian, kidney and bladder cancers. The protein shares homology with PTH and so binds to the PTH-1 receptor, resulting in bone resorption distal tubular calcium reabsorption.
• Osteolytic metastases – caused by the local breakdown of bone due to the presence of bony metastases, promoting osteoclast production. Most commonly associated with breast cancer and multiple myeloma.
• Ectopic PTH secretion – a rarer entity, seen associated with ovarian cancers, small cell and squamous cell cancers of the lung.

Management

Treatment depends on the severity of the hypercalcaemia and the patient’s symptomatology.

• Mild hypercalcaemia: <3.00mmol/L
• Moderate hypercalcaemia: 3-3.50mmol/L
• Severe hypercalcaemia: >3.50mmol/L or symptomatic

Treatment for malignant hypercalcaemia should firstly include conservative measures, targeting potential contributing factors, such as avoiding thiazide diuretics, calcium supplementation and dehydration. Initially, patients should be managed with intravenous fluid resuscitation as concurrent hypovolaemia is common and correcting this will promote renal excretion. Typically 2L of fluid is required every 24 hours for 48-72 hours. Following this, if renal function is permissive, zoledronic acid 4 mg IV should be administered, re-checking the calcium after 4-7 days. If GFR is 30-50 ml/min, administer a reduced dose of 3 mg.

If malignant hypercalcaemia is recurrent, especially in the context of malignancy with extensive bony metastases, denosumab may be administered prophylactically. This has the additional benefit of aiding with bony pain. It is important that prior to its administration, serum vitamin D levels are checked. Supplementation with calcium and vitamin D should be co-administered if denosumab is to be continued. Denosumab is licensed for the treatment of bony pain in all solid tumours with bony metastases except prostate cancer, where zoledronic acid should be employed.

Tumour lysis syndrome

Diagnosis

Tumour lysis syndrome (TLS) is a serious and potentially preventable oncological emergency which carries a profound risk of morbidity and mortality. The underlying mechanism is massive tumour cell lysis, typically seen in highly chemosensitive or bulky cancers in response to systemic anticancer therapy. The resulting cell breakdown causes the release of intracellular contents including nuclear material. Nucleic acids are broken down into uric acid, which precipitates in the renal tubules, causing severe acute kidney injury. Alongside this, large volumes of potassium and phosphate are released into circulation. In the presence of hyperphosphataemia, calcium is lost from the circulating volume as calcium phosphate precipitates in the renal tubules.

The Cairo-Bishop definition of biochemical TLS is any two of the following:

• Uric acid: >476 µmol/L
• K⁺: >6.0 mmol/L
• PO₄³⁻: >2.1 mmol/L
• Ca²⁺: <1.75 mmol/L

Commonly associated malignancies include:

• High-grade non-Hodgkin’s lymphoma – particularly Burkitt’s lymphoma
• Acute lymphoblastic leukaemia
• Acute myeloid leukaemia
• Chronic lymphocytic leukaemia
• Small cell carcinoma – particularly of the lung
• Germ cell tumours

Management

Pre-treatment factors should be considered to reduce the risk of developing TLS. Dehydration, oliguria, underlying intrinsic renal disease and pre-existing hyperuricaemia should be addressed. In those patients at very high risk of developing TLS, pre-treatment hydration, alongside prophylactic rasburicase is recommended. Rasburicase catalyses the oxidation of uric acid into allantoin, a soluble inactive metabolite, thus actively reducing serum uric acid levels. In those with an intermediate risk of TLS, pre-hydration and allopurinol should be employed. Allopurinol is a xanthine oxidase inhibitor, preventing the conversion of the purine hypoxanthine to xanthine and, in turn, into uric acid. Unlike rasburicase, allopurinol reduces uric acid formation, but does not lower serum uric acid levels.

Treatment of tumour lysis includes:

• Rasburicase 0.2 mg/kg
• Aggressive fluid resuscitation
• Correction of electrolyte abnormalities
  • Hyperkalaemia – requires most rapid correction due to the risk of cardiac dysrhythmia. Continuous cardiac monitoring should be employed. Calcium gluconate can be used temporarily to stabilise the myocardium, however, the lowest effective dose should be used (see below). Correction with insulin-dextrose can be employed, but potassium-lowering agents may also be required (e.g. patiromer)
  • Hyperphosphataemia – may be corrected with intravenous fluids and phosphate binders
  • Hypocalcaemia – calcium levels should be corrected cautiously until serum phosphate levels have been adequately corrected. This is due to the risk of calcium phosphate deposition. Calcium should be replaced to correct symptoms of hypocalcaemia including dysrhythmia and tetany.
• Renal replacement therapy – may be necessitated if measures including rasburicase and fluids are insufficient. Indications include anuria, refractory pulmonary oedema, and hyperkalaemia.

Superior Vena Cava Obstruction (SVCO)

Aetiology

Malignant SVCO can arise from a number of different mechanisms. These include extrinsic compression from an adjacent tumour, whether from a primary lung/mediastinal tumour or from locoregional lymphadenopathy. There can also be direct invasion into the superior vena cava from adjacent malignancy and obstruction secondary to malignancy-associated thrombosis or embolism.

The most common malignancies associated with SVCO are lung cancers, particularly small cell carcinoma (found in 10% of these patients) as well as non-small cell lung cancer (2-4% of these patients). Typically, tumours sited in the right upper lobe pose the greatest risk due to their anatomical location. Lymphomas are also a common cause, in particular diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma. Other malignancies of the mediastinum including thymoma, thymic carcinoma, germ-cell tumours and mesothelioma contribute to the remaining causes.

The archetypal presenting symptoms include upper limb, neck and facial swelling, dyspnoea, and chest discomfort. These symptoms may be further aggravated by leaning forward. Persistent swelling can lead to oedema of the larynx, leading to stridor and dysphagia. Furthermore, patients can develop cerebral oedema leading to headaches, confusion, and brainstem herniation. Thankfully, due to the greater availability of early imaging, these severe sequelae (airway compromise and cerebral oedema) are becoming increasingly rare. Depending on the underlying tumour biology, the development of SVCO tends to be gradual, which typically allows for the patient to develop venous collaterals, allowing the patient to compensate.

Most patients will have an abnormal chest x-ray. Further imaging in the haemodynamically stable patient is with cross-sectional imaging i.e. CT thorax or MRI (particularly in the case of a ‘Pancoast’ tumour). Duplex ultrasonography can be useful in determining the coexistence of thrombus. Dedicated venography (CT/MRI) may have an application in the planning of endovenous recanalisation. In those patients without a tissue diagnosis, it is imperative that this is sought, and this may be done concurrently with initial management.

Management

The management of malignant SVCO is dependent on the severity of the symptoms and the underlying biology of the malignancy. In those patients presenting in extremis, urgent SVC stenting should be sought via Interventional Radiology. It may be possible for a tissue diagnosis to be obtained at the same time. In patients who present with mild-moderate symptoms, the management should be tissue-directed. In those patients with known chemosensitive disease e.g. small cell lung cancer, germ-cell etc, early chemotherapy may be the treatment of choice. In those patients with less sensitive disease, exploration of SVC stenting should be sought in the first instance and where this is not possible, palliative radiotherapy should be considered.

The use of glucocorticoid steroids is not evidence-based but is commonly employed. They can be used for steroid-responsive conditions such as lymphoma or concurrently with radiotherapy. However, in patients with mild-moderate symptoms it is important to remember that in those patients lacking a tissue diagnosis, a biopsy should be prioritised. This is particularly relevant in the case of suspected lymphoma, where early administration of steroids will provide a rapid clinical response, at the expense of obtaining a tissue diagnosis. This would ultimately lead to delays in diagnosis and subsequent definitive management. The concurrent use of anticoagulation should be employed in patients with confirmed thrombosis, however, prophylactic use is debated and so no consensus statement can be offered on its empirical use.