Introduction

Metastatic spinal cord compression (MSCC) occurs in 3–5% of patients with cancer. Prostate, breast and lung cancer each account for 15–20% of cases; lymphoma, myeloma and renal cell cancer account for 10% and the remainder is due to colorectal cancers, sarcomas and cancers of unknown primary. Although more frequent in patients with known malignancy, MSCC is the presenting feature in up to 20% of patients with no prior diagnosis of cancer, particularly lung cancer.

Aetiology

The mechanisms by which MSCC may develop include:

Early stage compression of the cord results in oedema, venous congestion and demyelination, and neurological recovery may still be possible during this phase with prompt decompression. Continued compression causes secondary vascular injury and irreversible infarction. The most common location of compression is thoracic (50–70%) followed by lumbo-sacral (20–30%) and cervical spine (10–20%). Up to 85% patients have multiple vertebral metastases and importantly, around 17% of patients have two or more levels of compression at presentation.

Spinal cord metastases can be of three types depending on the location of tumour deposit:

Clinical features

Back pain is the most frequent (95%) first symptom, which commonly precedes the diagnosis of MSCC by up to 3 months in patients with known cancer and up to 5 months in those without a known malignancy. The pain may be localized or neurogenic and is typically worse when the patient is supine.

Limb weakness is the second most common symptom. Up to 85% of patients will have abnormal power in the limbs at presentation, which depends on the neurologic level of compression.

Sensory deficit may manifest itself as paraesthesia or sensory loss and is present in up to 65% of patients with MSCC. Up to 50% of patients will have a dermatomal sensory level, although this may vary by several dermatomes above or below the true level of compression.

Autonomic dysfunction is a late complication affecting up to 50% of patients with MSCC. It includes impotence, bladder and bowel dysfunction, with constipation occurring most frequently.

There are two clinical variants of MSCC, which require early recognition:

Investigations

MRI of the whole spine is the investigation of choice for suspected MSCC. CT is used only when MRI is contraindicated. A sagittal screening of the whole spine with T1 and short T1 inversion recovery (STIR) images should be done to ensure that multiple levels of compression are not missed and also to identify asymptomatic metastases. T2 weighted images help to detect the degree of compression by a soft tissue component and intramedullary lesions (Figure 23.1).

Figure 23.1 Imaging in cord compression. MRI scan shows spinal cord compression due to a collapsed vertebra (A,B) and an intramedullary metastasis from lung cancer (C).

In patients who have not been previously diagnosed with cancer, a histological diagnosis is required before definitive treatment can be planned. Patients should be investigated like any other patient with cancer of unknown primary and an appropriate area most amenable to biopsy should be established. However, treatment should not be delayed during these investigations and prompt neurosurgical involvement should be established if biopsy is not possible.

Management

The aim of treatment is to preserve or improve neurological function and achieve pain control. 70–100% patients who are ambulant at the beginning of treatment remain ambulant with prompt treatment, whereas only 30–50% patients who are non-ambulant regain the ability to walk and only 5–10% of paraplegic patients become ambulant. Hence it is important to have definitive treatment within 24 hours of presentation with suspected cord compression. Patients with MSCC secondary to a vascular event will not respond to treatment.

Specific measures

Definite treatment of MSCC depends on the histologic type and associated spinal stability. In patients with no prior history of cancer, surgical decompression with histologic confirmation is appropriate. If surgical decompression is not possible, a CT guided biopsy is needed.

Surgery may involve decompression, stabilization and or resection and reconstruction of the spinal canal. The patient’s overall prognosis and performance status should be taken into consideration and patients who have had no distal neurological function for >24 h should not be considered for surgery (Boxes 23.1 and 23.2).

Box 23.1
Patients with MSCC according to outcome after surgical intervention

Good surgical candidates	Poor surgical candidates
‘Good prognosis tumours’ e.g. breast cancer, testicular cancer etc.	‘Poor prognosis tumours’ e.g. lung cancer, melanoma
Single level of compression with solitary or few vertebral metastases	Multiple levels affected or multiple spinal metastases
Absence of visceral metastases	Presence of visceral metastases
Good neurological function	Poor neurological function
No previous radiotherapy	Recurrence following radiotherapy
Minimal co-morbidity	Medically unfit for surgery
Unknown primary or no histopathological diagnosis	Prognosis <3 months

Box 23.2
Indications for surgical treatment*

• Relapse after radiotherapy

• Progression while on radiotherapy

• Radiation resistant tumours

• Unknown primary tumour

• Unstable spine or pathological fractures

^* With a single site of cord compression and no total paraplegia for longer than 48 h.

Radiotherapy is the treatment most frequently used and is most effective for patients with radiosensitive tumours who are ambulatory at the beginning of treatment. For those without mechanical pain or structural instability, radiotherapy may significantly improve pain control and neurological function. The most commonly used regimes are 20 Gy in five fractions (more appropriate for patients with expected short survival) or 30 Gy in 10 fractions (Box 23.3). Some patients may deteriorate during radiotherapy when the steroid dose may be increased or they may be considered for surgery if appropriate. Patients with established paraplegia are treated with an 8 Gy single fraction for pain control.

Box 23.3
Radiotherapy in spinal cord compression

• Position – supine or prone

• Treatment volume – one vertebra above and below MRI proven compression

• Ensure that all paravertebral disease is enclosed in the volume if feasible

• Direct posterior beam 6 MV (parallel lateral in cervical region if feasible)

• Prescription point – anterior spinal canal (either measured from MRI or arbitrary, see Figure 23.2)

• Dose – 30 Gy in 10 fractions or 20 Gy in five fractions

Figure 23.2 Radiotherapy in spinal cord compression – anatomical landmarks and arbitrary radiotherapy dose prescription points.

The issue of whether surgery or radiotherapy or a combination of both gives best functional outcome is yet to be resolved. A randomized study compared radiotherapy (30 Gy in 10 fractions) started within 24 hours of onset of MSCC with surgery within 24 hours followed by radiotherapy within 2 weeks of surgery. Results showed that initial surgery followed by radiotherapy offers a longer period with ability to walk compared with those treated with radiotherapy alone (median, 126 days vs. 35 days, p = 0.006). This study showed that surgery permits most patients to remain ambulatory and continent for the remainder of their lives, while patients treated with radiation alone spend approximately two-thirds of their remaining time unable to walk and incontinent. However, results of this study may not be extended to all patients as the study was limited to patients with less radiosensitive tumours and with different tumour types and presentations.

Chemotherapy alone is not an option for treatment even in chemosensitive tumours as the response to treatment is often slow and unpredictable. Hence MSCC in chemosensitive tumours is treated with a combination of radiotherapy and chemotherapy.

Prognosis

The median survival following a diagnosis of MSCC is 3–6 months, with 17% of patients alive at 1 year and 10% alive at 18 months. Pre-treatment motor function is an important predictor of the ambulatory outcome. Patients who develop motor dysfunction more slowly also may have a better outcome.

Recurrence of spinal cord compression

7–14% of patients can present with recurrence of spinal cord compression after initial decompression. If the second cord compression is in a different area, treatment is the same as that of the original compression. However, if patients present with spinal cord compression at the initial radiation portal, surgical decompression is the initial option, particularly if the recurrence is within three months of initial treatment. If they are not a candidate for surgery, re-irradiation may be considered. It is important to make sure that the total dose to spinal code is kept below 100 Gy₂ (biologically equivalent dose of 100 Gy when delivered as 2 Gy per fraction). Many clinicians use a dose of 20 Gy in 8–10 fractions.

Paediatric spinal cord compression

Paediatric MSCC differs from adult MSCC in that it is often caused by chemosensitive histological types not seen in adults such as neuroblastoma, Wilms’ tumour (p. 323). The usual pathogenesis is the direct invasion of tumour through neural foramina. The most common histologic type is neuroblastoma, which responds to chemotherapy. Decompressive surgery is offered when patients present with rapid progression or progress during chemotherapy. Radiotherapy is only offered when there is no response after chemotherapy and/or surgery and for those who require palliation after failure of multiple systemic regimens.

Intramedullary spinal cord metastasis

This is rare (1% incidence) and lung cancer is the most common primary. Sensory deficit (79%), sphincter dysfunction (60%) and weakness (91%) are common manifestations. Up to 40% patients will have brain metastases. Treatment is with corticosteroids and radiotherapy.

Introduction

Encephalopathy is an important complication of cancer, which presents with an acute confusional state or delirium subsequent to abnormal brain function resulting from interference with brain metabolism. A number of aetiological factors can contribute to the development of encephalopathy in cancer patients. Generally, these are due to infection, metabolic abnormalities (such as hyponatraemia, hypercalcaemia) and drugs. A number of anti-neoplastic agents such as ifosfamide, methotrexate, cisplatin, vincristine, cytosine arabinoside etc. can cause encephalopathy.

Clinical features

The usual presentation is cognitive and behavioural changes. Patients can present with insomnia followed by acute confusion and delirium. Occasionally focal signs such as ataxia may predominate.

Clinical examination shows an altered level of consciousness, abnormalities of respiration, small reactive pupils and spontaneously roving eye movements. Grading of encephalopathy is as follows:

Management

Investigations include biochemical tests, infection screening, MRI brain, EEG and CSF examination and drug level estimation in selected cases.

In most cases of anti-neoplastic induced encephalopathy, the management is cessation of the drug and continuation supportive measures until recovery, and a re-challenge is seldom attempted. One exception is ifosfamide.

Ifosfamide encephalopathy can occur within minutes or hours of starting ifosfamide, or up to 24 hours after the completion of ifosfamide. The risk factors for ifosfamide encephalopathy are pelvic tumour, low albumin, impaired renal function, previous cisplatin, high dose of ifosfamide and CNS disease. In patients on ifosfamide, encephalopathy can be prevented by prophylactic dose of methylene blue (50 mg IV 4 times daily).

In patients with ifosfamide encephalopathy, treatment is based on the grade of the encephalopathy:

Optic neuropathy

Anti-neoplastic drug-induced optic neuropathy (ON) can be acute with rapidly progressive loss of vision. Cisplatin, carboplatin, carmustine, 5-fluorouracil, methotrexate, vinca-alkaloids, paclitaxel, tamoxifen and bisphosphonates are reported to cause optic neuropathy.

Clinical examination reveals reduced visual acuity in the affected eye and there may be associated field defects. Eye pain can also occur secondary to optic nerve sheath oedema. If papilloedema is present this suggests anterior optic neuritis, but this sign will be absent in retrobulbar neuritis.

Investigations may be normal but MRI can exclude intracranial metastases. Visual evoked potentials may display reduced amplitudes and increased latency suggesting optic nerve involvement.

Treatment of drug-induced optic neuritis involves the immediate withdrawal of the drug and exclusion of other causes. Intravenous methylprednisolone has been used but there are no randomized data to support this. Recovery can occur with drug withdrawal. However, the majority of patients have some permanent visual deficit.

Choroidal metastasis

Choroidal metastasis can result in sudden loss of vision. It is most common with breast and lung cancer and up to 20% may be bilateral. Cancer patients presenting with visual symptoms require detailed ophthalmologic assessment including a slit lamp examination. CT scan or MRI of the brain is needed to rule out brain metastasis.

Urgent radiotherapy is needed to avoid further visual deterioration and maintain useful vision. The entire choroid and retina of the affected eye is treated with a dose of 20 Gy in five fractions or 30 Gy in 10 fractions at 2.5 cm depth using a posteriorly angled lateral beam (to avoid opposite lens).

Introduction

Febrile neutropenia is defined as an oral or tympanic membrane temperature of ≥38°C on two occasions, at least one hour apart within a 12 h period or a single temperature of >38.5°C with an absolute neutrophil count of ≤0.5 × 10⁹/l or ≤1.0 × 10⁹/l with a predictable decline to ≤0.5 × 10⁹/l in 24–48 h.

Febrile neutropenia is one of the most common complications of cancer treatment. 50–60% of patients with febrile neutropenia have an established or occult infection and 20% of patients with a neutrophil count ≤1.0 × 10⁹/l have bacteraemia.

Susceptibility to infection increases as the neutrophil count drops below 1.0 × 10⁹/l. The frequency and severity of infection are inversely proportional to the absolute neutrophil count, with the duration of neutropenia also contributing to overall risk. The timing of the neutrophil nadir depends on the type of chemotherapy and generally, it occurs 5–10 days after the last dose. Usually the neutrophil count recovers 5 days after the nadir.

In the majority of cases, bacterial pathogens are responsible for febrile neutropenic episodes with fungal (Figure 23.3), viral and protozoal infections occurring more commonly as secondary events. Currently, Gram-positive bacteria account for 60–70% of microbiologically detected infections, which may in part be due to the prevalent use of quinolones as prophylactic antibiotics. Other possible causes of this change in trend include widespread use of intravenous catheters, along with more profound and prolonged neutropenia due to intensive and recurrent treatment regimes.

Figure 23.3 CT scan of the chest shows diffuse fungal infection in a neutropenic patient.

Clinical presentation and assessment

Fever, rigors, hypotension or generalized malaise may be the only presenting features of infection in the neutropenic patient, and even they may be masked by concurrent use of NSAIDs or steroids. Clinical deterioration can be rapid (especially in those aged <45 years) and therefore, prompt assessment is essential. Due to lack of neutrophils, most infections present with atypical manifestations.

It is important to enquire and look for signs of infection at the following sites:

Antibiotic treatment should not be delayed whilst waiting for results; however, urgent investigations should include:

Management (Figure 23.4)

The mainstay of management is the prompt administration of broad-spectrum antibiotics. The Multinational Association for Supportive Care in Cancer (MASCC) scoring system categorizes patients with febrile neutropenia into low and high-risk groups (Box 23.4). Patients with low-risk febrile neutropenia can be managed with oral antibiotics and discharged after 24 hours observation, whereas those with high risk febrile neutropenia require intravenous antibiotics (Figure 23.4).

Figure 23.4 Management of febrile neutropenia.

Low risk – a score of >21.

High risk – score of ≤21.

^a Choose 1 item only.

^b Does not apply to patients <16 yrs. Initial monocyte count >1.0 × 10⁹/l, no co-morbidity and normal chest radiograph findings indicate children at low risk for significant bacterial infections.

Monitoring

Intravenous antibiotics should be reviewed daily and modified depending on organism sensitivities and patient response. The median time to clinical response after the administration of antibiotics to febrile neutropenic patients is 5–7 days and patients who fail to respond to first-line antibiotics should be discussed with a microbiologist who may consider anti-fungal or anti-viral treatments. Antibiotic therapy may be discontinued when no infection is identified after 3 days of treatment, if the neutrophil count is ≥0.5 × 10⁹/l for 2 consecutive days and if the patient has been afebrile for ≥48 h. Recovery of the neutrophil count is the single most important determinant of successful antibiotic treatment.

Prophylactic antibiotics

For regimes that are associated with a high risk of febrile neutropenia (stem cell transplantation, acute leukaemias and neutropenia for greater than 10 days), or for patients who have had a previous febrile neutropenic episode, quinolones are often used prophylactically on days 8–15 of the chemotherapy cycle. Trials have consistently shown that the use of prophylactic antibiotics in the afebrile neutropenic patient reduces the number of febrile episodes; however, data demonstrating beneficial effects on mortality are more variable and less convincing. With the growing problems of antibiotic resistance and antibiotic associated infection, the use of prophylactic antibiotics in all aspects of medicine is being questioned.

Haematopoietic colony stimulating factors

Haematopoietic colony stimulating factors (CSFs) such as granulocyte CSF (G-CSF) and granulocyte-macrophage CSF (GM-CSF) are glycoproteins that stimulate the proliferation and differentiation of haematopoietic cells. A pegylated formulation of G-CSF has the benefit of being given as a one-off dose rather than a daily subcutaneous dose.

CSF use is recommended in both the therapeutic and the prophylactic setting for patients at high risk of developing infection-associated complications or who have prognostic factors predictive of a poor clinical outcome (Box 23.5).

The risk of febrile neutropenia and hospitalization due to febrile neutropenia is substantially reduced by the prophylactic use of CSFs. CSFs may also have a beneficial effect on infection related mortality, although effects on overall mortality remain to be established.

Introduction

Superior vena cava obstruction (SVCO) can occur as a result of either extrinsic compression of the superior vena cava or intrinsic obstruction to blood flow. Lung cancer is responsible for nearly three-quarters of cases of malignant SVCO and SVCO occurs in 2–4% of patients with lung cancer. The remainder of cases is largely due to lymphoma (12%) and metastatic malignancies (most commonly from a breast primary).

Clinical presentation

Malignant SVCO usually presents insidiously over a period of weeks. The most common symptoms are cough and dyspnoea (>50%). Clinical examination shows facial puffiness (80%), distended veins (>60%), and arm oedema (46%). Symptoms are commonly progressive, although there may be some clinical improvement with the formation of a collateral circulation over time. Symptoms tend to be worse first thing in the morning and can be exacerbated by manoeuvres that increase venous pressure, e.g. bending forwards, coughing, sneezing and straining.

Investigations

A plain chest radiograph will often show a right paratracheal mass or widened mediastinum. A CT scan will demonstrate SVC compromise and distinguishes between external compression and thrombus (Figure 23.5). In patients without a histologic diagnosis, a biopsy is required prior to deciding treatment.

Figure 23.5 Superior vena caval obstruction. CT scan (A) shows significant compression of SVC (arrow) and SVC stent in situ (B).

Management

The management of SVCO depends on the underlying aetiology and severity of symptoms. In patients with no prior diagnosis of cancer, a histologic diagnosis is essential.

General measures include oxygen, dexamethasone 16 mg daily, and diuretics. Endovascular stent insertion (Figure 23.5) is the gold-standard treatment which relieves obstruction in 95% of cases, usually within 72 h (Box 23.6). Complications of stent placement are in the region of 3–7% and include: transient chest pain, infection, misplaced stent, stent migration and pulmonary emboli. SVCO recurs in approximately 11% of patients (due to stent occlusion secondary to either thrombus or tumour in-growth). However, secondary patency rates are good and long-term patency is achieved in 92% of patients.

Radiotherapy was traditionally used first line for the treatment of SVCO prior to endovascular stenting. In radiosensitive tumours, radiotherapy results in symptomatic response rates of up to 78% at 2 weeks. However, complete resolution of obstruction is seen in only 31% on serial venograms with a partial resolution in 23%.

Radiotherapy is given to a dose of 20 Gy in five fractions or 30 Gy in 10 fractions.

Chemotherapy is useful in chemosensitive tumours. Chemotherapy alone relieves SVCO in 80% of patients with non-Hodgkin’s lymphoma or small-cell lung cancer and 40% of patients with non-small cell lung cancer.

Prognosis

The median survival for patients with SVCO is generally 6 months; however, this varies widely depending on the aetiology. Prognosis appears to be determined by the underlying malignancy with overall survival being equal between patients of the same tumour type and stage, with or without SVCO.

Introduction

Hypercalcaemia (a corrected serum calcium concentration >2.6 mmol/l) occurs in up to 30% of cancer patients during their illness. The mechanisms of hypercalcaemia include secretion of parathyroid-related-protein (80%), osteolytic hypercalcaemia (20%) and rarely due to increased secretion of 1,25-D3 and ectopic secretion of PTH.

Clinical presentation

The symptoms of hypercalcaemia are typically non-specific and their severity depends on the rapidity with which the calcium level rises. When the serum calcium concentration increases above 2.6 mmol/l, symptoms include fatigue, malaise, depression, anorexia, nausea, vomiting, bone pain, polydipsia, polyuria, constipation and muscular weakness. If the concentration continues to rise above 3.6 mol/l, neurological symptoms become more prevalent and patients may become confused, leading to coma and death.

Hypercalcaemia has few examination findings specific to its diagnosis. However, a thorough history and physical examination may help yield the underlying cause.

Investigations

Along with serum corrected calcium, baseline laboratory investigations should include a full blood count, urea, creatinine and electrolytes, liver function tests, serum phosphate, magnesium and PTH concentrations. ECG changes consistent with hypercalcaemia include a shortened QT and prolonged PR interval. At very high levels, a broad QRS complex may develop, T waves may flatten or invert and a variable degree of heart block can occur.

All further investigations are aimed at establishing a cause and are likely to include imaging, particularly of the chest. In a patient without a diagnosis of cancer, a myeloma screen should be considered and in some patients a bone scan may be helpful.

Management (Figure 23.7)

Saline rehydration is an important aspect of the management of hypercalcaemia. Hydration alone may adequately treat mild hypercalcaemia. Hypercalcaemic patients are universally dehydrated as a result of calcium-induced nephrogenic diabetes insipidus and poor oral intake. The speed of administration of normal saline depends on the degree of dehydration and renal impairment, the level of hypercalcaemia and the patient’s underlying cardiac function. Fluid balance must be carefully monitored. The aim of saline treatment is two-fold, firstly, to increase the glomerular filtration rate (GFR) and thereby increase the filtered load of calcium into the tubular lumen from the glomerulus. Secondly, calcium reabsorption is inhibited in the proximal nephron because of the calciuretic effects of saline. Once dehydration has been adequately treated, loop diuretics can be used to increase calcium excretion. Any drug that may be contributing to the hypercalcaemia e.g. thiazide diuretics, lithium and calcium supplements should be discontinued. Hypophosphataemia is common and phosphate levels should hence be monitored and replaced as appropriate.

Figure 23.7 Management of hypercalcaemia.

Bisphosphonates have been shown to be superior to saline alone in the treatment of malignancy-associated hypercalcaemia. Bisphosphonates inhibit osteoclastic bone resorption by adsorbing to the surface of bone hydroxyapatite. The bisphosphonates of choice for the treatment of malignancy-associated hypercalcaemia are intravenous zoledronate, ibandronate and pamidronate. Pamidronate (60–90 mg IV in 500 ml normal saline over 2 h) or Zoledronate (4 mg IV in 50 ml normal saline over 15 min) are the most widely used bisphosphonates for this indication in the UK. The nadir response to intravenous bisphosphonates is generally reached at 7–10 days, with the beginnings of a biochemical response evident at 2–4 days. Up to 90% of patients will achieve normocalcaemia after a single dose; however, a second dose can be given after 7–10 days if the calcium remains elevated. Patients with renal impairment may require a dose reduction and this differs between products. Although the administration of bisphosphonates should not be delayed, prior rehydration may reduce the risk of further renal impairment. Another common adverse effect of intravenous bisphosphonates is a transient flu-like syndrome with fever, myalgias and chills. For patients in whom bisphosphonates are unsuccessful, alternative treatments such as glucocorticoids, calcitonin and gallium nitrate can be tried following specialist endocrine advice.

Prognosis

Malignancy related hypercalcaemia carries a very poor prognosis with more than 50% of patients dying within 30 days of treatment. Overall, median survival is less than 12 months.

Introduction

Acute tumour lysis syndrome (ATLS) is a group of metabolic abnormalities that occur following the destruction of large quantities of rapidly dividing tumour cells. Typically, it occurs 12–72 h after the initiation of treatment with cytotoxic chemotherapy, cytolytic antibody therapy and/or radiation therapy.

ATLS is most frequent in patients with non-Hodgkin’s lymphoma (especially Burkitt’s lymphoma), acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). It has also been rarely reported following the treatment of ovarian, breast and small-cell lung cancer. Several characteristics inherent to the tumour type predispose to TLS and these include high tumour proliferation rate, large tumour burden, tumour chemosensitivity and increased lactate dehydrogenase (LDH) levels. Pre-existing uraemia or hyperuricaemia, decreased urinary flow, low urinary pH, dehydration, oliguria and renal impairment have also been identified as risk factors for TLS.

Clinical features

ATLS is characterized by hyperuricaemia, hyperphosphataemia, hypocalcaemia and hyperkalaemia. These biochemical abnormalities lead to a range of non-specific symptoms (Table 23.1). When the electrolytes are severely deranged, patients are at risk of seizures, cardiac arrhythmias and sudden death.

Table 23.1 Biochemical and clinical features of tumour lysis syndrome

Introduction

Nearly all systemic agents used to treat cancer have the potential to cause hypersensitivity reactions; however, severe reactions are rare. Provided patients receive appropriate pre-medication, close monitoring and prompt intervention when required, severe hypersensitivity reactions occur in less than 5% of patients. Platinum compounds, taxanes and monoclonal antibodies are most likely to cause a reaction, although the timing of such reactions may differ, as do their likely underlying aetiology (Table 23.3).

Table 23.3 Showing the incidence of any grade hypersensitivity in a range of chemotherapy agents

Platinum compounds such as cisplatin, carboplatin and oxaliplatin classically cause reactions following multiple cycles of treatment, typically after 6–8 doses. This is consistent with a type 1 hypersensitivity reaction following repeated exposure to the drug and leads to IgE-mediated release of histamine, leukotrienes and prostaglandins from mast cells in the tissues and basophils in the peripheral blood. This causes smooth muscle contraction and peripheral vasodilatation, leading to urticaria, rash, angioedema, bronchospasm and hypotension.

Although a similar clinical picture can be produced following administration of a taxane, 95% of these reactions occur during the first or second exposure to the drug and 80% occur within the first 10 minutes of the infusion. In this scenario, IgE-mediated type-1 hypersensitivity is unlikely, and it is postulated that direct effects on mast cells and basophils lead to release of immunomodulators and an anaphylactoid reaction. The solvent used in paclitaxel, but not docetaxel (Cremophor EL) has been shown to cause histamine release and hypotension and is felt to be partly responsible for the hypersensitivity reactions seen with paclitaxel.

Monoclonal antibody infusions can also produce hypersensitivity reactions, which become less likely with each subsequent infusion. Delayed reactions are still seen in 10–30% however, the underlying aetiology of these reactions is largely unknown.

Clinical features

The National Cancer Institute Common Toxicity Criteria (NCI-CTC) distinguish between hypersensitivity and acute infusion reactions (Table 23.4).

Clinical features of hypersensitivity include pruritis, rash, urticaria, rigors/chills/fevers, headache, arthralgia/myalgia, tumour pain, fatigue, dizziness, sweating, nausea/vomiting, cough, dyspnoea, bronchospasm, hypotension/hypertension and tachycardia.

Management

Prophylaxis with antihistamines and corticosteroids is recommended for infusions that carry a high risk of hypersensitivity reactions and for any patient that shows early signs of a hypersensitivity reaction. Pre-medication for paclitaxel would likely include 20 mg dexamethasone (preferably given several hours before the infusion), chlorpheniramine 10 mg and cimetidine 300 mg. Patients should be closely monitored throughout all infusions.

Treatment of anaphylaxis is outlined in Figure 23.8.

Figure 23.8 Management of anaphylaxis.

Re-challenging patients following a hypersensitivity reaction depends on the aim of treatment and the severity of the reaction. The majority of patients who have a mild–moderate reaction during their first drug exposure (often seen with taxanes and monoclonal antibodies) are likely to tolerate re-challenge of the drug if pre-medication is used with a slower rate of infusion. Desensitization protocols have been used with some success in patients who have a reaction to taxanes, however, re-challenge of platinum compounds is usually less successful with approximately 50% of patients experiencing recurrent hypersensitivity reactions.

Introduction

An extravasation injury is any tissue damage that occurs as a result of leakage of cytotoxic drugs into the surrounding tissue.

Vesicant drugs are more likely to lead to extravasation because of their potential for endothelial damage (Table 23.5). The risk of vesicant extravasation is very low, in the range of 0.01–6% and although the use of implanted ports reduces the risk of extravasation, it can still occur.

Table 23.5 Vesicant vs non-vesicant drugs

Tissue damage occurs due to three main factors:

Clinical features

Symptoms and signs of extravasation include:

Management

Prevention is the key. The technique of cannulation and administration of the drug is important. Cannulas should ideally be inserted in the back of the hand where they are readily accessible and extravasation can be easily detected. Use of a central venous access device is preferable; however, vesicant administration should only proceed when there is blood return through the device.

Management of extravasation includes stopping the infusion and aspirating from the intravascular device. Extravasation of anthracyclines is initially managed with cooling of the area, however, heat application is generally used following the extravasation of plant alkaloids. Early review by the plastic surgeons for consideration of surgical debridement is vital when tissue necrosis is possible.

Hyaluronidase increases the permeability of connective tissue and can be injected into the extravasation sites of plant alkaloids. Used in combination with a saline flush out of the area, it aids the dispersion of the vesicant drug.

Dexrazoxane is a derivative of EDTA that chelates iron. It has shown benefit in the treatment of extravasation from intravenous anthracycline therapy; although the exact mechanism of action is unknown. It is a systemic treatment that is infused over 1–2 h each day for three days into a large vein, away from the extravasation site. Side effects include nausea and vomiting, diarrhoea, stomatitis, bone marrow suppression, elevated liver enzymes and infusion site burning.

Chemotherapy induced haemorrhagic cystitis

High-dose cyclophosphamide as a marrow ablative regime as well as ifosfamide can produce significant haemorrhagic cystitis. It is produced by a metabolite of these agents, acrolein, by an unknown mechanism. Sodium 2-mercaptoethane sulfonate (mesna) is used as a uroprotective agent along with these agents. Mesna needs to be started prior to the chemotherapy and continued after the last dose of chemotherapy.

Malignant obstructions and bleeding

The management of malignant obstructions and bleeding is dealt in individual chapters.