Oncological Emergencies Flashcards
What is neurofibromatosis?
A rare genetic disorder that typically causes benign tumors of the nerves and growths in other parts of the body, including the skin.
What are the 3 types of neurofibromatosis?
- neurofibromatosis 1 (NF1)
- neurofibromatosis 2 (NF2)
- schwannomatosis
What gene is involved in neurofibromatosis 1?
NF1
Inheritance of neurofibromatosis 1 and 2?
Autosomal dominant
What mutation occurs in neurofibromatosis 1?
The NF1 gene provides instructions for making a protein called neurofibromin. This protein is produced in many cells, including nerve cells and specialized cells surrounding nerves (oligodendrocytes and Schwann cells).
Neurofibromin acts as a tumor suppressor, which means that it keeps cells from growing and dividing too rapidly or in an uncontrolled way.
Mutations in the NF1 gene lead to the production of a nonfunctional version of neurofibromin that cannot regulate cell growth and division.
What characteristic sign is seen in neurofibromatosis 1?
Early childhood –> cafe au lait spots
These are flat patches on the skin that are darker than the surrounding area. These spots increase in size and number as the individual grows older. Freckles in the underarms and groin typically develop later in childhood.
What chemical can often cause angiosarcomas?
Vinyl chloride
What cancer can long-term exposure to high levels of benzene in the air lead to?
Leukaemia
What are aromatic amines?
Aromatic amines are chemicals found in industrial and manufacturing plants, tobacco smoke, commercial hair dyes, and diesel exhaust
What type of cancer can exposure to aromatic amines lead to?
Bladder cancer
What type of cancer can exposure to wood dust lead to?
Nasal adenocarcinoma
How can low fibre intake lead to increased risk of colorectal carcinoma?
Increased bowel transit time –> increase carcinogen exposure
What cancer can increased smoked food intake predispose to?
Gastric carcinoma
What cancer can topoisomerase inhibitors (used in chemotherapy) predispose to?
Acute leukaemia
Which HPV strains are most commonly associated with cervical & anal cancer?
16 and 18
Gastric MALT lymphoma is strongly linked to what infection?
H. pylori
Eradication of H.Pylori may lead to tumour regression
What is a MALT tumoiur?
MALT tumours (mucosa-associated lymphoid tissue type of NHL –> most commonly in stomach
What can be asked about in history with a potential cancer patient?
- Pain
- Lumps
- Bleeding e.g. haemoptysis, rectal bleeding, haematuria
- Change in function e.g. bowel habit, cough, dyspnoea, weight loss, fever, confusion
- Socioeconomics e.g. occupation, environmental exposure
- Risk factors e.g. smoking, FHx, PMHx, drugs, diet, alcohol
Describe the TNM staging for cancer
T: Primary Tumour
o TX: Cannot be assessed
o T0: No Evidence
o Tis: Carcinoma in situ
o T1-4: Increasing in size and/or local extent
N: Regional Lymph Nodes
o NX: Cannot be assessed
o N0: No regional lymph node mets
o N1-3: Increasing involvement in lymph nodes
M: Distant Metastasis
o Mx: Cannot be assessed o M0: No distant mets
o M1: Distant mets
What are tumour markers?
- Substances produced either by, or in response to tumour
- Present in blood or other tissue fluids and can be quantified
- Should be both high sensitive and highly specific
Sensitivity vs specificity?
Sensitivity –> ability to detect those with the
disease
Specificity –> ability to accurately define those who are disease free
What conditions can cause an elevated hCG?
Pregnancy
If not pregnant –> raises suspicion of germ cell tumour, particularly choriocarcinoma
Gestational trophoblastic disease (GTD):
- Hydatiform mole
- Choriocarcinoma
- Non-seminomatous testicular cancer
- Seminoma
What is a choriocarcinoma?
Choriocarcinoma is a very rare type of cancer that occurs in around 1 in 50,000 pregnancies. It can develop if the cells left behind after a pregnancy become cancerous. The abnormal cells start in the tissue that would normally become the placenta.
This can happen after any pregnancy, but it’s more likely after molar pregnancies.
Name some oncological emergencies
- Neutropenic sepsis
- Tumour lysis syndrome
- Metastatic spinal cord compression
- Superior vena cava obstruction
- Hypercalcaemia
What is neutropenic sepsis?
N.B. can also be called febrile neutropenia and neutropenic fever
Neutropenic sepsis is defined by NICE as a neutrophil count of 0.5 × 109 per litre or lower, plus one of the following:
1) Temperature ≥ 38°C or
2) Other signs or symptoms consistent with significant sepsis
N.B. The definition of neutropenic sepsis varies between sources. In some hospitals, neutropenic sepsis is diagnosed in patients with a neutrophil count of 1 × 109 per litre or lower.
What is the most common medical emergency amongst oncology and haematology patients?
Neutropenic sepsis
What is the major cause of neutropenic sepsis in cancer patients?
Recent chemotherapy (most commonly within 7 – 10 days) –> causes neutropenia through bone marrow suppression
The risk of neutropenia varies in both severity and timescale between different chemotherapy treatment regime.
Give some other causes of neutropenia:
- Malignant bone marrow infiltration
- Extensive radiotherapy
- Bone marrow failure secondary to non-malignant disease (e.g. aplastic anaemia)
- Hypersplenism
- Megaloblastic anaemia
- Drug-induced (e.g. clozapine)
What drug can induce neutropenia?
Clozapine (atypical antipsychotic)
Risk factors for neutropenic sepsis and associated complications?
- Patients over the age of 60
- Advanced malignancy
- Previous neutropenic sepsis
- Mucositis (chemotherapy can induce mucosal damage and allow bacterial translocation)
- Poor performance status
- Significant co-morbidities (the risk increases further in the presence of multiple co-morbidities)
- Indwelling central venous catheters
- Corticosteroids (causes immunosuppression)
- Prolonged hospital admission
- Severe or prolonged neutropenia
What grading system is used to grade the severity of neutropenia?
Common Terminology Criteria for Adverse Events (CTCAE)
Describe the neutrophil count for grade 1-4 of the CTCAE for neutropenia
Grade 1: >1.5
Grade 2: 1.0-1.5
Grade 3: 0.5-1.0
Grade 4: <0.5
What is the typical presentation of neutropenic sepsis?
Many patients will present from home with isolated pyrexia.
However –> neutropenic sepsis may present without fever in some patients, including older patients and those taking immunosuppressive medications such as steroids.
Therefore, neutropenic sepsis should be considered in any patient at risk of neutropenia who presents unwell, irrespective of temperature.
Symptoms of neutropenic sepsis may be non-specific symptoms of sepsis or reflect the underlying source of infection.
What are some non-specific symptoms of sepsis?
- Fatigue
- Feeling warm or cold
- Rigors or shaking
- Feeling sweaty or clammy
- Palpitations
- Dizziness
- Subjective confusion or disorientation
Some symptoms that may reflect a specific infective source in neutropenic sepsis:
Chest source: shortness of breath, cough, chest pain, sore throat.
Urine source: dysuria, increased frequency, urgency or any other lower urinary tract symptoms.
Skin source: rashes, blisters, pain.
Gastrointestinal source: diarrhoea, nausea, vomiting, rectal bleeding, abdominal pain, sore mouth (due to mucositis).
Indwelling line source: pain around the line or rigors after use of the line.
What is important to cover in patient history in potential neutropenic sepsis?
- Symptoms
- Past medical history (e.g. details of cancer diagnosis including previous treatments)
- Chemotherapy history (e.g. type of chemotherapy, date of the most recent cycle)
- Drug history (e.g. steroids, antibiotic prophylaxis, granulocyte-colony stimulating factor use and details of any allergies)
- Recent procedures which may
predispose to infection (e.g. placement of an indwelling vascular access device) - Previous episodes of pyrexia or neutropenic sepsis (to guide the identification of a source or causative organism)
What approah should patients with neutropenic sepsis be examined with?
ABCDE approach
Patients with neutropenic sepsis are at risk of sudden deterioration. The initial examination should focus on determining how unwell the patient is and establishing what immediate care they require.
What are some general clinical findings in neutropenic sepsis?
A
B
- Respiratory rate –> tachypnoea
- O2 sats –> hypoxia
C
- Blood pressure –> hypotension
- Heart rate –> tachycardia
- Fluid balance –> reduced urine output
D
- Consciousness –> reduced
E
- Temperature –> pyrexia
- Mottled/ashen appearance
It is important to remember that examination findings are often MINIMAL in neutropenic sepsis.
Other potential findings:
Chest source: increased work of breathing, crepitations, dullness to percussion, reduced air entry.
Urine source: suprapubic or flank pain, cloudy urine in catheter bag (if applicable).
Skin source: rashes, blistering, tenderness.
Gastrointestinal source: abdominal tenderness, dehydration (if reporting vomiting or diarrhoea), evidence of oral mucositis, jaundice.
Indwelling line source: surrounding erythema, tenderness on palpation, pain or rigors on flushing.
Differential diagnoses of neutropenic sepsis?
The most common cause of a fever in cancer patients is an infection, with or without neutropenia.
Other causes of fever to consider include:
- Underlying malignancy (both solid and haematological)
- Immunotherapy toxicities
- Inflammatory disorders (e.g. SLE, vasculitis, rheumatoid arthritis)
- Drug-induced
- Hypothalamic dysfunction
- Thyroiditis
What are most cases of neutropenic sepsis caused by?
Underlying bacterial infection (but also important to consider viral and fungal infections)
What are the most common gram-negative bacilli seen in neutropenic sepsis?
Can all produce extended-spectrum beta-lactams:
- E. coli
- Klebsiella spp.
- Pseudomonas aeruginosa
- Enterobacter spp.
- Proteus spp.
What are the most common gram-positive bacilli seen in neutropenic sepsis (more common)?
- Staphylococcus aureus (including methicillin resistant – MRSA)
- Coagulase-negative staphylococci (eg. Staphylococcus epidermidis)
- Streptococcus pneumoniae
- Viridans group streptococci
- Enterococcus spp. (including vancomycin-resistant types – VRE)
- Group A streptococci
What fungi can cause neutropenic sepsis?
- Candida spp.
- Aspergillus spp.
- Mucorales
What should form a critical part of the assessment of a patient with neutropenic sepsis?
Reviewing previous microbiological results as this may help identify an underlying cause and guide treatment.
Investigations will depend on the clinical context and the suspected source of infection in neutropenic sepsis.
What bedside investigations may be done?
Urinalysis: to look for urinary tract infection.
ECG: should be performed in all acutely unwell patients.
Capillary blood glucose: to exclude hypoglycaemia.
Investigations will depend on the clinical context and the suspected source of infection in neutropenic sepsis.
What lab investigations may be done?
Baseline blood tests (FBC, U&E, coagulation, CRP, LFTs): white cells may be low or raised and CRP may also be raised.
Serum lactate: performed as part of the sepsis six care bundle.
Group and save: the patient may require a blood transfusion.
Blood cultures: at least two sets from a peripheral vein plus a set from an indwelling line if present to look for a causative organism.
Arterial blood gas: to assess the extent and severity of any respiratory failure.
Microbiological cultures: wounds, urine, stool, sputum, and line tip (if indwelling line infection suspected).
Viral respiratory swab: if viral respiratory infection suspected.
Investigations will depend on the clinical context and the suspected source of infection in neutropenic sepsis.
What imaging investigations may be done?
- Chest X-ray: to look for evidence of pneumonia.
- High-resolution chest CT: if fungal pneumonia is suspected.
- Abdominal ultrasound or CT abdomen: if biliary or abdominal infection suspected.
What investigation should be done if an atypical chest source is suspected, such as Pneumocystis jirovecii?
Bronchoalveolar lavage
Management of neutropenic sepsis?
1) Patients with suspected or confirmed neutropenic sepsis should receive EMPIRICAL ANTIBIOTIC THERAPY within ONE HOUR of arrival at hospital. Antibiotic therapy must NOT be delayed to wait for confirmation of neutropenia.
2) The SEPSIS SIX care bundle should be completed.
What is the empirical antibiotic therapy for neutropenic sepsis?
Local guidelines regarding the choice of antibiotic therapy must always be followed. If in doubt, seek advice from microbiology.
1st line –> usually IV piperacillin with tazobactam (Tazocin)
2nd line (e.g. penicillin allergy) –> may include intravenous meropenem although this will depend on local guidelines.
Additional anti-microbial cover –> (e.g. teicoplanin) for gram-positive organisms may be required for patients with indwelling central venous catheters.
Anti-fungal treatment –> may be considered when the fever persists beyond 4 – 6 days.2,5
Specimens for microbiological culture should ideally be taken BEFORE commencing antibiotic therapy however this should NOT delay treatment.
If low risk neutropenic sepsis, can give oral antibiotics.
What Abx are given?
Usually quinolone + co-amoxiclav
What features may suggest low risk neutropenic sepsis?
- hemodynamically stable
- does not have acute leukaemia
- no organ failure
- no soft tissue infection
- no indwelling lines
What can be used or both prophylaxis and treatment of neutropenia to reduce the risk of neutropenic sepsis?
Recombinant granulocyte-colony stimulating factor (G-CSF)
What is G-CSF?
Works by stimulating the bone marrow to produce neutrophils and may form part of specific chemotherapy regimens.
What is an example of a G-CSF drug?
Filgrastim
Compliations of neutropenic sepsis?
Single or multi-organ failure (e.g. renal failure, heart failure and acute respiratory distress syndrome)
Venous thromboembolism (e.g. pulmonary embolism)
Disseminated intravascular coagulation
Opportunistic or hospital-acquired infections
Delirium
Psychological complications (e.g. anxiety regarding future infections and chemotherapy treatment)
Delays in chemotherapy leading to worse cancer outcomes
Risk of mortality of neutropenic sepsis?
10%
What is a malignant spinal cord compression (MSCC)?
A medical emergency caused by compression of the spinal cord or cauda equina
Characterised by compression or displacement of arterial, venous, and cerebrospinal fluid spaces, including the spinal cord itself.
What causes MSCCC?
It can result from direct pressure, vertebral collapse or instability due to metastatic or local spread of tumours.
It occurs in 5-10% of cancer patients and will be the presenting feature of cancer in 20% of patients with MSCC.
Some mechanisms of MSCC:
- Direct compression from tumour expansion into the epidural space: most commonly due to metastases
- Direct compression from collapsed vertebral bodies: most commonly due to metastases; the most common region of bony metastases is the thoracic spine (around 70%), followed by the lumbosacral (20%) and cervical (10%)
- Direct extension of an intra-abdominal or intra-thoracic primary malignancy
- Direct compression from a primary malignancy of the vertebral body
- Compression from intradural spinal cord malignancies
While any malignancy has the potential to metastasise to the spine, it is more common in certain types of cancer.
What are the most common types of cancer that can lead to MSCC?
1) Prostate cancer (20%)
2) Lung cancer (20%)
3) Breast cancer (17%)
4) Renal cancer (12%)
5) Multiple myeloma
The risk of MSCC is also related to the duration of the disease.
What is the median age of patients at the time of MSCC diagnosis?
65
What is the most common presenting complaint in MSCC?
Back pain - may have been present for several weeks before MSCC is diagnosed.
What are the RED FLAG features of back pain that may suggest MSCC (particularly in patients with a known cancer diagnosis)?
- Thoracic or cervical pain
- Progressive lumbar pain
- Spinal pain aggravated by straining
- Localised spinal tenderness
- Nocturnal pain preventing sleep
Other symptoms of MSCC can vary depending on the level of compression.
What are some other symptoms?
The compression leads to oedema, venous congestion and demyelination. This leads to loss of neurological function, which is variable depending on the level of the lesion(s).
- Limb weakness (e.g. the limb feeling “heavy” or “stiff”, difficulty climbing stairs)
- Loss of coordination
- Sensory disturbance below compression level (‘feels like walking on cotton wool’
- Autonomic dysfunction (e.g. urinary retention, faecal incontinence due to loss of anal tone, constipation)
- Cauda equina syndrome (bladder/bowel dysfunction, saddle anaesthesia, leg weakness, gait disturbance, back pain)
Patients with suspected MSCC should have a full neurological examination.
What are some potential examination findings BELOW the level of compression?
- Limb weakness or paralysis (assess using the MRC muscle power scale)
- Sensory disturbance
- Brisk reflexes
- Increased muscle tone
- Clonus
- Upgoing plantars
- Reduced anal tone
- Palpable, distended bladder
Investigations in MSCC?
- Neuro exam
- Urgent MRI of spine within 24 hours
If an MRI is contraindicated in MSCC (e.g. pacemakers and metallic foreign bodies), what is the next best imaging modality?
CT
Relevant bedside investigations in MSCC?
Bladder scan: to assess for urinary retention
Relevant lab investigations in MSCC?
- Baseline blood tests (FBC, U&Es, LFTs): to assess general fitness and for imaging
- Bone profile: to assess for hypercalcaemia
- Clotting and group & save: if the patient is likely to require surgery
- LDH: higher levels are associated with poor prognosis
- Myeloma screen: if the patient does not have a known cancer diagnosis
- Tumour markers: may help with the assessment of cancer stage and suitability for treatment or diagnosis if MSCC is the initial presentation
Imaging investigations in MSCC?
- Urgent MRI
- Up-to-date staging CT is needed to help assess the cancer stage and suitability for treatment.
How is MSCC diagnosed?
By imaging (spinal MRI or CT).
The scan should also be reported within 24 hours of patient presentation to enable rapid treatment.
Management of SUSPECTED MSCC?
Dexamethasone (16mg OD or 8mg BD) –> to reduce inflammation and oedema
Omeprazole (or alternative PPI) –> for stomach protection
Low molecular weight heparin (or alternative) –> for thromboprophylaxis
Contact the local MSCC coordinator to arrange admission and MRI spine (follow local referral guidelines)
Immobilise the spine if instability is suspected
Analgesia
What drug is used to manage oedema and inflammation in suspected MSCC?
Dexamethasone (16mg OD or 8mg BD)
Definitive management for confirmed MSCC?
- Surgery +/- radiotherapy
- Radiotherapy alone (this is generally the management of choice for most patients)
- Best supportive care (frail, unwell, short life expectancy)
The management choice depends on various factors, including the patient’s performance status, the extent of their malignancy, other comorbidities, level(s) of compression and neurological deficit at presentation.
What may indicate that treatment is unlikely to improve neurological function in MSCC?
- Patient has had paraplegia
- Loss of sphincter control for >48 hours
In which patients can surgical depression in MSCC be considered?
1) Life expectancy >6 months
2) Some preserved neurological function
3) Limited levels of compression
Purpose of radiotherapy in MSCC?
1) Improve function.
2) Can also be given for palliative pain relief in those with a life expectancy of <6 months, low-performance status and established paraplegia >24 hours.
What are some common considerations in rehabilitation for MSCC?
- Pain control
- Thromboprophylaxis
- Weaning of dexamethasone
- Breathing exercises and forced expiratory techniques to aid chest clearance
- Prevention of contractures/spasticity
- Continence management
- Prevention of pressure ulcers
- Communication assistance
- Mobility aids
- Psychological care
Complications of MSCC?
- Pressure ulcers
- Autonomic dysreflexia
- Deep vein thrombosis
- Pulmonary embolism
- Falls
- Urinary tract infections
- Pneumonia
- Muscle contractures
- Psychological complications
What causes superior vena cava obstruction (SVCO)?
can occur due to
a) external pressure
b) malignant infiltration
c) thrombus formation within the vessel
What is SVCO?
This obstruction causes reduced venous return to the heart from the head, thorax and upper limbs. It is essential to recognise SVCO as it can cause life-threatening upper airway obstruction.
What is the most common cause of SVCO?
External pressure from lung cancer (affects 2-4% of patients)
Function of the superior vena cava (SVC)?
The SVC drains blood from the head, neck and upper extremities into the right atrium.
Why is the SVC prone to obstruction?
Has thin walls
What happens if SVCO occurs gradually?
If the obstruction occurs gradually, collateral circulation is recruited via the azygous, internal mammary, and long thoracic venous systems.
This collateral circulation is responsible for some of the symptoms of SVCO (e.g. oedema of the upper body and dilated neck veins).
What happens if SVCO occurs suddenly?
there is no time for collateral circulation to establish, and the presentation can often be life-threatening.
Give some risk factors for SVCO
- Lung cancer: particularly small-cell lung cancer
- Lymphoma
- Metastatic disease: particularly breast cancer, colon cancer and oesophageal cancer
- Smoking: due to the increased risk of lung cancer, rather than a direct association
- Central venous catheter use: may be used in cancer patients for the administration of medication
- Radiation to the mediastinum
What type of lung cancer is particularly associated with SVCO?
Small cell lung cancer
What are the symptoms of SVCO patients typically associated with?
What are these symptoms?
Increased venous pressure in the upper body:
- Breathlessness
- Visual disturbance
- Dizziness
- Headache (worse on stooping)
- Cough
- Swelling of the face, neck and arms
What are some typical clinical findings in SVCO?
- Localised oedema of the face, neck and upper limbs
- Facial plethora
- Distended neck and chest veins (non-pulsatile)
- Lymphadenopathy (particularly if lymphoma is the cause)
- Hoarse voice: may be due to laryngeal oedema or the underlying malignancy
- Stridor: due to laryngeal oedema or compression
- Cyanosis
- Papilloedema
What is Pemberton’s sign?
A positive Pemberton’s sign is indicative of superior vena cava syndrome (SVC).
The patient should lift both arms until they touch the side of the face. A positive Pemberton’s sign is the presence of facial congestion, cyanosis and respiratory distress after ~1 minute (due to worsening of symptoms).
Imaging investigations in SVCO?
1) CXR
2) CT chest with contrast
3) Doppler US
What may a CXR show in SVCO?
may show a widening of the superior mediastinum and right hilar prominence to indicate a mediastinal mass
Where would a mass be seen in a CXR in SVCO?
Right hilar mass compressing the SVC
https://geekymedics.com/superior-vena-cava-obstruction-svco/
What is the imaging modality of choice in SVCO?
CT chest with contrast –> shows the location and severity of obstruction and may help with identification/staging of underlying malignancy
Other investigations in SVCO?
If the underlying malignancy is unknown, a biopsy can be performed via bronchoscopy or transthoracic needle aspiration.
How is a diagnosis of SVCO made?
The diagnosis of SVCO can be made clinically for significant symptoms and a likely underlying aetiology.
Otherwise, it can be made via a chest CT with contrast.
Management of SVCO?
If airway obstruction –> ABCDE approach
- Securing the airway (endotracheal intubation, surgical airway)
- Corticosteroids
- Diuretics
- Endovascular stenting
- Radiotherapy (management of underlying malignancy)
- LMWH (if thrombus)
Which corticosteroid is used in SVCO management? Why?
Dexamethasone –> reduces swelling and pressure of tumour surrounding SVC
What should be given alongside steroids in patients with dyspeptic symptoms?
PPI
Symptomatic treatment in SVCO?
- Elevating the head
- Loosening restrictive clothing
- Benzodiazepines and opioids to relieve breathlessness and agitation
- Oxygen to maintain oxygen saturations if required
Complications of SVCO?
Laryngeal oedema
Acute upper airway obstruction
What is endovascular stenting?
Superior vena caval stenting is an image guided technique that restores the venous return in patients with superior vena cava obstruction.
What are some complications of endovascular stenting in SVCO?
- Stent thrombosis
- Stent migration
- Superior vena cava dissection or perforation
- Infection
- Volume overload/acute decompensation of heart failure: due to the sudden increase in venous return after relief of the obstruction
What is hypercalcaemia defined as?
An adjusted serum calcium of 2.6 mmol/L or higher, on TWO occasions
What is the most common life-threatening metabolic disorder in cancer patients?
Hypercalcaemia of malignancy (occurs in 10-20% of patients with advanced cancers)
What are the 3 main mechanisms that result in hypercalcaemia of malignancy?
1) Secretion of parathyroid hormone-related protein (PTHrP)
2) Osteolytic metastases
3) Secretion of 1,25-dihydroxyvitamin D (calcitriol)
Depending on the cancer, hypercalcaemia may occur via one or a combination of these mechanisms.
What is the most common cause of hypercalcaemia in malignancy?
PTHrP secretion
What cancers is PTHrP secretion generally associated with?
1) Renal cancer
2) Ovarian cancer
3) Endometrial cancer
4) Squamous cell carcinoma
How does PTHrP secretion result in hypercalcaemia?
1) PTHrP STIMULATES osteoclastic resorption (i.e. breakdown of bone minerals, releasing calcium & phosphorus) and INHIBITS osteoblast formation of bone, resulting in excessive calcium release from the skeleton.
2) It also acts in the kidney to reduce calcium clearance, further increasing calcium levels in the blood.
What are osteolytic metastases?
How can it lead to hypercalcaemia?
Osteolytic metastases develop when metastatic cancer cells break down too much of the bone, making it very weak. Holes may develop in the bones as the bone is destroyed.
Is a result of increased OSTEOCLAST activity.
This results in excessive calcium release which overwhelms the kidney’s ability to clear it from the body.
What cancers are associated with osteolytic metastases?
1) Breast cancer
2) Multiple myeloma
Osteoblast vs osteoclast?
Osteoclast –> dissolve old and damaged bone tissue so it can be replaced with new, healthier cells created by osteoblasts
Osteoblasts –> form new bones and add growth to existing bone tissue.
How can calcitriol secretion lead to hypercalcaemia?
1) There is overexpression of 1-alpha hydroxylase, the enzyme responsible for converting 25-hydroxyvitamin D to calcitriol.
2) This leads to excessive production of calcitriol (the active form of vitamin D), resulting in increased intestinal absorption of calcium and increased osteoclast activity.
What type of cancers does calcitriol-mediated hypercalcaemia usually occur in?
Lymphomas
Effect of calcitriol on calcium?
Causes increased intestinal absorption and increased osteoclast activity
What is the main risk factor for hypercalcaemia of malignancy?
The type of cancer the patient has.
While hypercalcaemia can occur in any cancer, there are some types that it is more associated with:
- Multiple myeloma: via osteolytic metastases
- Breast cancer: via PTHrP and osteolytic metastases
- Lung cancer (squamous cell carcinoma): via PTHrP
- Renal cancer: via PTHrP
- Thyroid cancer (squamous cell carcinoma): via PTHrP
- Lymphomas (all types): via calcitriol
What medications can worsen hypercalcaemia?
Thiazide diuretics, lithium and over-the-counter supplements containing calcium or vitamin D.
Symptoms of hypercalcaemia?
The common presenting features are often remembered as stones, bones, groans and psychiatric moans (renal calculi, bone pain, abdominal pain and psychiatric features).
- Confusion
- Nausea and vomiting
- Fatigue
- Thirst: due to increased urine production causing dehydration
- Polyuria: due to increased urine production via nephrogenic diabetes insipidus
- Constipation
- Anorexia
- Bone pain: either due to the hypercalcaemia or due to bony metastases
- Abdominal pain
- Renal colic
Clinical features of hypercalcaemia?
Few examination findings are specific to hypercalcaemia. There may be findings related to the underlying cancer (e.g. lymphadenopathy or hepatosplenomegaly).
- Signs of dehydration: dry mucous membranes, sunken eyes, reduced skin turgor
- Hyporeflexia
- Tongue fasciculations
- Abdominal distension due to constipation
- Bony tenderness
What is the key investigation in hypercalcaemia?
The adjusted serum calcium level.
What adjusted serum calcium level is considered abnormal?
Above 2.6 mmol/L.
Hypercalcaemia can be further categorised according to severity.
What are the levels?
Mild: <3.0 mmol/L
Moderate: 3 – 3.5 mmol/L
Severe: >3.5 mmol/L
Why is an ECG a relevant bedside investigation in hypercalcaemia?
Hypercalcaemia can lead to abnormalities such as bradycardia, shortened QT interval and heart block
What labs should be done in hypercalcaemia?
- U&Es
- PTH
- PTHrP
- Phosphate
- Calcitriol
- Vitamin D
- Immunoglobulins and electrophoresis
Why are U&Es important in hypercalcaemia?
1) Renal function is necessary for planning treatment
2) AKI is a complication of hypercalcaemia
How does hypercalcaemia affect the kidneys?
Can lead to AKI
Due to reduced glomerular filtration rate, increased sodium excretion and depletion of total body water, leading to increased bicarbonate reabsorption and metabolic alkalosis,.
Why is PTH level an important investigation in hypercalcaemia?
To help identify a cause of hypercalcaemia –> PTH will often be suppressed in malignancies producing PTHrP
How will PTH be affected in malignancies producing PTHrP?
Will often be suppressed
Why should a PTHrP level be requested in hypercalcaemia?
to help identify a cause of hypercalcaemia (request if initial PTH level is low)
What phosphate level is hypercalcaemia typically associated with?
Hypercalcaemia can also be associated with hyperphosphatouria and hypophosphataemia due to the action of PTHrP
When would immunoglobulins and electrophoresis investigations be indicated in hypercalcaemia?
If underlying myeloma is suspected
Imaging investigations in hypercalcaemia?
Chest X-ray: if underlying lung cancer is suspected
CT scan: to help stage any underlying cancer or assess for bony metastases
Management of hypercalcaemia?
Medications for associated symptoms e.g. laxatives for constipation, anti-emetics for nausea and vomiting and analgesia for bone pain.
Any medications contributing to hypercalcaemia should be stopped (thiazide diuretics, calcium supplements, vitamin D supplements and lithium).
Medications that can worsen renal function (e.g. NSAIDs and ACE inhibitors) should also be reviewed and potentially withheld.
Specific measures to combat hypercalcaemia consist of rehydration and administration of bisphosphonates.
When can hypercalcaemia be managed as an outpatient?
Asymptomatic patients with adjusted calcium <3 mmol/L can be considered for outpatient management, but most will require admission.
What are 2 specific management steps in hypercalcaemia?
- Rehydration
- Bisphosphonates
What is the rehydration target in hypercalcaemia?
Rehydration will often require IV fluids with a target of at least three litres in the first 24 hours (unless the patient has comorbidities that put them at risk of fluid overload).
Why are bisphosphonates given in hypercalcaemia of malignancy?
Bisphosphonates inhibit osteoclastic bone resorption
What is the first-line bisphosphonate used in hypercalcaemia of malignancy?
IV zoledronic acid
The dose given may need to be adjusted based on the patient’s renal function.
What is the second-line bisphosphonate used in hypercalcaemia of malignancy?
Disodium pamidronate
For zoledronic acid for hypercalcaemia of malignancy, what is the:
1) Dose (IV)
2) Onset of effect
3) Maximum effect
4) Duration of effect
1) 4mg
2) <4 days
3) 4 to 7 days
4) 4 weeks
Note: bisphosphonates do not immediately reduce serum calcium levels, and the dose should not be repeated until at least day 5.
Serum calcium levels should be monitored, and if hypercalcaemia persists 7 days after bisphosphonate treatment, what should be given?
Further bisphosphonate doses or denosumab (off-license) can be considered under specialist advice.
Complications of hypercalcaemia of malignancy?
- Transient flu-like syndrome due to bisphosphonate treatment
- Acute kidney injury (AKI)
- Acute pancreatitis
- Cardiac arrhythmias
- Seizures
- Coma
How does hypercalcaemia act as a prognostic indicator for patients with cancer?
Hypercalcaemia is also a poor prognostic indicator for patients with cancer, with a mean survival of 2-3 months. This is not necessarily directly due to hypercalcaemia but because it tends to represent an advanced cancer stage.
