Hypercalcaemia

One in ten cancer patients develops hypercalcaemia, and malignancy accounts for about half the cases of hypercalcaemia amongst hospital inpatients. Hypercalcaemia occurs most frequently with myeloma, breast, lung and renal cancers, and 20% of cases occur in the absence of bone metastases. Hypercalcaemia, except in patients with myeloma, carries a poor prognosis and is associated with a median survival of 3 months. Most patients with hypercalcaemia of malignancy have disseminated disease and 80% die within 1 year. Thus hypercalcaemia is usually a complication of advanced disease and its treatment should be directed at palliation as it may produce a number of distressing symptoms (Table 40.2). The treatment of hypercalcaemia of malignancy frequently ameliorates these symptoms, and for this reason the diagnosis should always be sought.

In recent years there have been significant advances in our understanding of the biochemical processes that cause hypercalcaemia in malignancy, such that the factors involved in local osteolysis and in the evolution of humoral hypercalcaemia have now been delineated. A number of different cytokines have been implicated in the development of hypercalcaemia as a result of local osteolysis. The final common pathway of osetolysis at the molecular level involves a triad of osteoprotegerin (OPG), Receptor Activator of NF kappa B (RANK) and Receptor Activator of NF kappa B Ligand (RANKL). Bone destruction in the presence of osteolytic skeletal metastases is not caused directly by tumour cells but by osteoclasts. The tumour cells either directly produce RANKL or stimulate bone stromal cells to produce RANKL. RANKL is an osteoclast-activating factor that stimulates the RANK membrane receptor on osteoclast precursors. In conjunction with macrophage colony-stimulating factor (M-CSF), RANKL causes the differentiation of precursors into osteoclasts and the fusion and activation of osteoclasts into functional multinucleated osteoclasts that mediate bone resorption. OPG is a soluble decoy receptor for RANKL that inhibits RANK by competing for RANKL binding. OPG production is decreased in myeloma and metastatic prostate cancer. This RANKL/RANK/OPG equilibrium is disrupted by cytokines, chemokines and prostaglandins, uncoupling the usual homeostatic balance between osteoclastic bone resorption and osteoblastic bone formation.

Humoral hypercalcaemia was described in 1941 by Albright but it was only in the late 1980s that the humoral factor causing hypercalcaemia was characterized. In the 1970s hypercalcaemia was thought to result from the ectopic production of parathyroid hormone (PTH), but this hypothesis remained unproven because the use of PTH antisera failed to demonstrate excessive secretion of PTH in patients with humoral hypercalcaemia. In addition, low serum concentrations of 1,25-vitamin D3 and urinary cyclic adenosine monophosphate (AMP) levels failed to reflect excess PTH activity and no PTH mRNA was found in the tumours of patients with humoral hypercalcaemia.

In the late 1980s polyadenylated RNA from a renal carcinoma from a patient with humoral hypercalcaemia was used to construct a cDNA library which was screened with a codon-preference oligonucleotide, synthesized on the basis of a partial N-terminal amino acid sequence from a human tumour-derived peptide and a 2.0-kilobase cDNA was identified. The cDNA encoded a 177 amino acid prohormone, which consisted of a 36 amino acid leader sequence that is cleaved to produce a 141 amino acid, mature peptide and PTH-related peptide. The first 13 amino acids of the mature peptide have a sequence homology with PTH, and the N-terminal sequence is thought to be the PTH receptor-binding region. It turns out that PTH-related peptide is expressed in most normal human tissue, but its role is undetermined. The gene for PTH-related peptide has been mapped to the short arm of chromosome 12 whilst the PTH gene is on the short arm of chromosome 11. The gene for PTH-related peptide is complex and contains a six exon, 12 kilobase, single copy sequence, encoding up to five mRNA species. Exons 2, 3 and 4 are similar to the PTH gene.

A radioimmunoassay for PTH-related peptide was used to screen patients with hypercalcaemia-associated malignancy and the results contrasted with patients who were normocalcaemic and had malignant disease, patients with primary hyperparathyroidism and normal controls. PTH-related peptide was elevated in 19 of 39 (49%) patients with malignant hypercalcaemia, 12 of 74 (16%) normocalcaemic patients with malignancy and 4 of 20 patients (20%) with hyperparathyroidism, but in none of 22 normal controls.

The clinical manifestations of hypercalcaemia are varied (Table 40.2) and many symptoms may be wrongly attributed to the underlying malignancy. A diagnosis of hypercalcaemia can only be made by biochemical investigation, so all symptomatic patients with malignancy should have their corrected serum calcium measured if treatment is likely to be appropriate (Figure 40.1):

The mainstay of therapy is rehydration with large volumes of intravenous fluids followed by the administration of calcium-lowering agents, most commonly bisphosphonates. Low calcium diets are unpalatable, exacerbate malnutrition and have no place in palliative therapy. Drugs promoting hypercalcaemia (e.g. thiazide diuretics, vitamins A and D) should be withdrawn. The cornerstone of the re-establishment of normocalcaemia is treatment with a bisphosphonate. Bisphosphonates have multiple functions in hypercalcaemia. They reduce serum calcium levels by a direct effect on the osteoclast, by stabilizing hydroxyapatite crystals. There are two classes of effect of bisphosphonates. One group of bisphosphonates, which include clodronate and etidronate, acts through their incorporation into non-hydrolyzable analogues of adenosine triphosphate (ATP) that accumulates in osteoclasts and induces apoptosis. Conversely, agents such as pamidronate and zoledronate inhibit an enzyme called farnesyl diphosphate synthase (FPPS) which functions in the cellular metabolic pathway that is known variously as the mevalonate, HMG-CoA reductase or isoprenoid pathway and is necessary for the synthesis of steroids, haem and ubiquinones. Inhibition of this metabolic path at the FPPS level prevents the formation of metabolites required for protein prenylation that is the linking of small proteins to lipids of the cell membrane.

The bisphosphonates of choice are currently pamidronate, zoledronate and ibandronate. Approximately 80% of patients respond to hydration and bisphosphonate treatment by normalization of serum calcium levels. Calcium levels start to fall within the first 24 hours of treatment with bisphosphonates and usually reach normal levels within 3 days. It is dogma that treatment with bisphosphonates has to be repeated, usually on a 3–4-weekly cycle. However, there is some information that suggests that a single treatment may be sufficient with re-setting of the calcium-stabilizing mechanisms. As well as these actions, bisphosphonates have valuable analgesic activity in patients with metastatic bone pain and reduce skeletal morbidity in patients with breast cancer and myeloma. It may take 7–10 days for the symptoms of hypercalcaemia to resolve following normalization of calcium levels. In 20% of patients with hypercalcaemia, bisphosphonates do not work. Alternative treatments include the use of a somatostatin analogue such as octreotide which acts to reduce serum levels of PTH-related peptide. Other more old-fashioned treatments include calcitonin and mithramycin. Denosumab is a monoclonal antibody to RANKL that is used for postmenopausal osteoporosis and to reduce skeletal events in patients with bone metastases and myeloma. Its value in hypercalcaemia is under investigation.

Superior vena cava obstruction

Oncological emergency	ECG features	Tracings
Hypercalcaemia	Short QTBroad-based, tall, peaked T wavesWide QRSLow R waveDisappearance of P waves
Pericardial effusion	Sinus tachycardiaLow voltage complexesPR segment depressionAlternation of the QRS complexes, usually in a 2:1 ratio (electrical alternans)
Tumour lysis
Hypocalcaemia	Peaked T wavesFlattened P wavesProlonged PR intervalWidened QRS complexesDeep S wave
Hyperkalaemia	Long QT interval Narrow QRSReduced PR intervalFlat or inverted T wavesProminent U waveVentricular arrhythmia

The presenting symptoms of SVCO include dyspnoea, swelling of the face and arms, headaches, a choking sensation, cough and chest pain (see Figures 40.3 and 40.4). The most important clinical sign is loss of venous pulsations in the distended neck veins. This is usually accompanied by facial oedema, plethora and cyanosis and tachypnoea. The severity of the symptoms is determined by the rate of obstruction and the development of a compensatory collateral circulation. The symptoms may deteriorate when lying flat or bending, which further compromises the obstructed venous return. Careful assessment of the patient’s history is frequently suggestive of a long period with minor symptoms of SVCO. In 9 out of 10 cases, the cause of SVCO is a malignancy, most often lung cancer (disproportionately more often small cell lung cancer) (Figures 40.5a and b), lymphoma or metastatic breast or germ cell cancer. Rare non-malignant causes are listed in Table 40.4.

The management of SVCO depends upon the cause and severity, along with the patient’s prognosis, and includes relieving symptoms as well as treating the underlying cause. SVCO is an oncological emergency in the presence of airway compromise, and delays whilst histological findings are confirmed may adversely affect the outcome. In such circumstances patients are treated empirically with steroids and radiotherapy. However, when it is safe to do so, it is important to establish the diagnosis as this will determine the optimum treatment and a delay of 1–2 days to obtain a histological diagnosis is often appropriate, particularly in the context of a patient with minor symptoms and a long clinical history. Diagnostic procedures should include a plain chest X-ray (CXR), sputum cytology, bronchoscopy, thoracoscopy or mediastinoscopy, computed tomography scans (Figure 40.6a) or magnetic resonance imaging and venography. A palpable lymph node may be amenable to biopsy, thereby providing a diagnosis.

Patients may respond to being sat upright with oxygen therapy and intravenous corticosteroids should be administered. In the acute setting, insertion of expandable wire stents under radiological guidance can be effective (Figures 40.6b–e). Studies report instantaneous symptomatic relief. In the majority of cases subsequent radiotherapy is the most appropriate treatment modality and relieves symptoms in most patients within a fortnight. Where a diagnosis of lymphoma, small cell lung cancer or germ cell tumour has been obtained, chemotherapy may be the optimal initial treatment. Although relief of the obstruction can be achieved surgically, surgery is usually only reserved for patients with benign causes of SVCO.

Spinal cord compression

The earliest symptom of cord compression is vertebral pain, especially on coughing and lying flat. Subsequent signs include sensory changes one or two dermatomes below the level of compression. A complaint of back pain with focal weakness and bladder or bowel dysfunction with a sensory level requires urgent investigation in a patient with cancer. This will progress to motor weakness distal to the block and finally sphincter disturbance. If spinal cord compression is missed, or left untreated, patients can develop severe neurological deficits and double incontinence.

Spinal cord compression should be treated as a medical emergency. High-dose intravenous corticosteroids should be initiated on clinical suspicion alone to prevent further evolution of neurological deficit. Plain X-rays of the spine looking for vertebral collapse and MRI of the spinal axis to define the presence and level(s) of spinal cord compression should then be performed (Figures 40.7, 40.8, 40.9 and 40.10). Twenty to thirty per cent of patients have multiple levels of cord compression and imaging of the whole cord is therefore essential. If appropriate, a neurosurgical opinion should be obtained regarding the potential of surgical decompression, especially if there is vertebral instability or if the level of the compression has been previously irradiated. Otherwise, the definitive treatment is urgent local radiotherapy. It is important to provide adequate analgesia. Pretreatment ambulatory function is the main determinant of post-treatment gait function, thus prompt diagnosis and treatment is the key to gait and continence preservation. In clinical trials it has been shown that surgery using an anterior approach is more effective than steroids and radiotherapy in relieving cord compression. However, it takes a considerable time to recover from such extensive surgery and so surgery is often avoided as patients with cord compression have a median survival of 3 months.

Cancer-related obstruction

Tumours obstruct “tubes” in the body by exerting local pressure on them or occasional growing within them. The most frequently affected tubes include the bowel, urinary tract, bronchi and cerebral ventricular system (Figures 40.11, 40.12, 40.13 and 40.14). The consequences are intestinal obstruction, hydronephrosis, bronchial obstruction and hydrocephalus. After localizing the obstruction, relief is often achieved by radiological or endoscopic stenting (see Figures 3.5 and 14.2).

Cancer-related thromboses

The incidence of venous thrombosis and thromboembolism in cancer patients is variably reported (Figures 40.15 and 40.16). One study looked at a group of patients presenting to A&E with deep venous thromboses. Screening of these patients showed that almost 30% had a cancer that was most commonly a pelvic malignancy. As always in medicine, there is initial positive reporting and later studies showed the true incidence of previously undetected cancer in patients presenting with venous thrombosis to be in the order of 5%. Once cancer has been diagnosed, thromboembolic events are remarkably common and described in about 10% of all patients. The incidence increases significantly when long lines (Hickman or PICC) are inserted in cancer patients for the purposes of chemotherapy or supportive care. In this group of patients the incidence of thromboembolism increases to 20%. For this reason prophylaxis with low-dose warfarin is recommended and this decreases the risk of subsequent thrombosis to between 2% and 5%. These statistics, however, are considered controversial and are debated endlessly. Because of the high risk of thrombosis in cancer patients it has been suggested that anticoagulation should be prophylactically prescribed. Logically, the best way of preventing thromboembolism would be with a heparin-like compound rather than with a coumarin. At the moment the evidence is that the low molecular weight heparins are probably more effective than warfarin in the prophylaxis of thromboembolism. There is an additional unexpected benefit to anticoagulation with low molecular weight heparins and this is the modest survival advantage for anticoagulated patients, as demonstrated by randomized clinical trials. In some patients with pelvic tumours and recurrent thromboses, filters may be inserted into the inferior vena cava to reduce the risk of pulmonary embolism (Figures 40.17, 40.18 and 40.19). The benefits of filters are transient. For central venous access catheter-associated thrombosis, removal of the line and anticoagulation should be commenced.

Pleural effusions

Although not strictly an emergency, approximately 40% of all pleural effusions are due to malignancy (Table 40.5) and their presence frequently indicates advanced and incurable disease. The pleural space is normally filled with 10–40 mL of hypoproteinaceous plasma that originates from the capillary bed of the parietal pleura and is drained through the parietal pleura lymphatics. A pleural effusion is often the first manifestation of malignancy, and lung cancer and breast cancer account for almost two-thirds of cases. Malignant pleural effusions may be asymptomatic or cause progressive dyspnoea, cough and chest pain which may be pleuritic in nature. Malignant pleural effusions are usually exudates and this may be confirmed by a fluid lactate dehydrogenase (LDH) of >200 U/mL, a fluid:serum LDH ratio >0.6, a fluid:serum protein ratio >0.5 and a fluid:serum glucose ratio of <0.5. The fluid may be blood stained and is typically hypercellular, containing lymphocytes, monocytes and reactive mesothelial cells; exfoliated tumour cells may also be present.

The management of malignant effusions should be tailored to the patient’s symptoms as only half the patients will be alive at 3 months and over 90% of effusions will recur within 30 days of thoracocentesis. Reaccumulation of pleural effusions may be delayed by chemical pleurodesis (usually using talc or tetracycline) or video-assisted thoracic surgery (VATS) with pleurectomy and/or talc insufflation. Pleuroperitoneal shunts or chronic indwelling catheters may be considered for patients who fail pleurodesis, but this is rarely appropriate.

Pericardial effusions

The accumulation of fluid in the pericardial space around the heart may adversely affect cardiac function and like all effusions may be transudate, exudate or haemorrhage. Cardiac tamponade occurs when the pressure on the ventricles in diastole prevents them from filling, thus reducing the stroke volume and cardiac output. The classic sign of cardiac tamponade is Beck’s triad of hypotension because of decreased stroke volume, jugular–venous distension due to impaired venous return to the heart and muffled heart sounds due to fluid inside the pericardium (Figure 40.20). Tamponade is relived either by direct aspiration or surgically by forming a “pericardial window”.

Ascites

The most frequent malignancies causing ascites are primary tumours of the ovaries, pancreas, stomach and colon, breast and lungs (Figures 40.21 and 40.22). The distressing symptoms of ascites include abdominal distension or pain; dyspnoea due to diaphragmatic splinting; oedema of the legs, perineum and lower trunk; and a “squashed stomach syndrome” leading to anorexia. If these symptoms are distressing, paracentesis is indicated which offers rapid symptom relief but poor long-term control. Whilst anticancer therapy may reduce the subsequent re-accumulation of ascites, if this is not an option or is unsuccessful, diuretics may be helpful. Rarely a peritoneovenous shunt may be surgically placed under general anaesthetic if the ascites cannot be controlled.

Hyperviscosity syndrome

Neutropenia

Antibiotic policies vary from hospital to hospital, but there is good evidence that treatment with single-agent ceftazidime is as effective as treatment with combination antibiotic regimens. In the United Kingdom patients are generally admitted, though it is interesting to note that this conservative management policy is not strictly necessary. In one randomized study, treatment with oral ciprofloxacin in the community was compared with inpatient treatment with intravenous ceftazidime. The results were absolutely identical in terms of control of fever and patient outcome.

Over the last decade marrow growth factors have become available, and granulocyte colony-stimulating factor (G-CSF), which stimulates the marrow to produce granulocytes, has entered wide use. There is limited evidence that prophylactic use of G-CSF prevents neutropenic sepsis or septic deaths. The evidence for its use in established infection is poor and the consensus view is that G-CSF is of value only in patients with established neutropenic sepsis who have a non-recovering marrow and in whom, additionally, an infective agent has been identified. Nevertheless G-CSF has been adopted as a panacea by oncologists who prescribe it widely as primary and secondary prophylaxis against neutropenia. In contrast G-CSF is of enormous value in transplantation programmes, where the mean period of time to engraftment has been reduced from 28 to 18 days by the use of these agents.