Metabolic emergencies
Metabolic abnormalities may occur in cancer patients as a result of the disease itself or following effective treatment for the cancer.

Hypercalcemia
This is the commonest life-threatening metabolic disorder associated with malignancy. It can be recognised only if the clinician has an index of suspicion when the patient presents with clinical features of nausea, thirst, vomiting, polyuria, lethargy, constipation, weakness or confusion and these may be often confused with the features of terminal malignancy1. However, the severity of symptoms may not be directly related to the degree of elevation of serum calcium. It must be emphasised that hypercalcemia may often occur in the absence of bone disease. The overall incidence is 10-20 per cent amongst all cancer patients. Moreover, cancer is the commonest cause of hypercalcemia in hospitalised patients. Symptomatic hypercalcemia is usually due to carcinoma of breast, bronchus, and kidney or due to myeloma or lymphoma. The various mechanisms involved in its pathogenesis are

Local Osteolytic Hypercalcemia
This occurs as a result of bone destruction by tumour cells. This is particularly observed in breast cancer or multiple myeloma patients who have extensive bone metastasis.

Humoral hypercalcemia
In 1941 it was observed that hypercalcemia could occur even without significant bony involvement. It was thereby hypothesised that tumour cells secrete a parathyroid hormone-like peptide (PTH-rP) that can humorally mediate hypercalcemia. Humoral factors have been recognised to play major etiologic role in current studies (30-80%)4. Increased osteoclastic activity and subsequent mobilisation of bone calcium may occur due to factors secreted locally by tumour cells, e.g. osteoclast activating factor (OAF), prostaglandins, tumour necrosis factor (TNF), and interleukin-1, TGF a has been found to be a significant factor in the increased bone resorption associated with some tumours.

Impaired renal calcium excretion
Impaired renal clearance of excess calcium occurs due to certain factors secreted by the tumor that cause increased tubular resorption of calcium.
Lung cancers account for 25-35 per cent of reported cases of cancer induced hypercalcemia and 30-40 per cent are accounted by breast cancer patients quite often after hormonal manipulation. One third of all patients of multiple myeloma develop hypercalcemia. Although hypercalcemia is rare in lymphoma, it affects majority of the patients suffering from T cell variant.
Diagnosis is established by measuring corrected serum calcium (serum calcium = total serum calcium - serum albumin g/dl + 4.0). It must be mentioned that although acidosis decreases serum calcium, alterations in its blood level with changes in pH are small and insignificant.

Management guidelines for hypercalcemia of malignancy chiefly include measures to improve renal calcium clearance and those to decrease osteoclastic bone resorption.

1. Fluid replacement
Polyuria and often vomiting result in dehydration due to hypercalcaemia. In symptomatic patients prompt rehydration with 4-6 litre/24 hr of isotonic saline infusion is necessary to restore fluid volume and improve glomerular filtration rate with regular monitoring of renal function and electrolytes. Some authors prefer to add 40-80 mmol of potassium to each litre of normal saline.

2. Diuretic
A loop diuretic like furosemide 40-80 mg I.V. every 12-24 hrs should be considered in order to induce natriuresis (only after the patient has been rehydrated). If serum calcium is >14 mg/dl then forced diuresis with normal saline (2-3 times the maintenance fluid volume) and high dose I.V. furosemide (2-3 mg/kg every 2 hours) is indicated. This method can reduce serum calcium by 3 mg/dl within 48 hours by blocking renal tubular absorption of calcium. But there is a high risk of further dehydration and dyselectrolytemia.

3. Calcitonin
This inhibits osteoclastic bone resorption within a few hours of treatment and may be continued for several weeks. Usual dose is 400 IU subcutaneously 8 hourly till serum calcium level is controlled. However, serum calcium may rise again despite continuing treatment due to the development of therapeutic resistance. Hence calcitonin may be combined with corticosteroids to overcome such resistance.

4. Corticosteroids
Prednisolone 40 mg/dl often proves to be very effective in cases of multiple myeloma, lymphoma or carcinoma of breast, i.e., those tumours that cause hypercalcemia by secretion of cytokines having osteoclastic activity. Reduction of calcium may take longer time of around 2 to 10 days.

5. Bisphosphonates
The availability of bisphosphonates has radically altered the treatment of severe hypercalcemia6. These are chemical analogues of pyrophosphates that are adsorbed at the surface of crystalline hydroxyapatite and directly inhibit the release of bone calcium. There are three varieties that produce hypercalcemia, namely, etidronate, clodronate and pamidronate. Serum calcium usually falls to normal limit within 2 to 4 days following treatment with the bisphosphonates pamidronate, which has the maximum efficacy. Its optimum dose has not yet been established but the usual schedule is 60 to 90 mg IV infusion in normal saline over 4 to 24 hrs.

6. Miscellaneous
Indomethacin (75-100 mg/day), Octreotide7, Ethiofos (WR-2721) are other agents with anecdotal reports of efficacy.

Hyponatremia
This is usually a part of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Approximately 1 to 2 per cent of cancer patients develop SIADH. The clinico-biochemical features associated with this syndrome are enumerated in Table 1.

Table 1: Salient Features of SIADH

SIADH is most often associated with bronchogenic carcinoma (particularly in small cell lung cancer the incidence is 10%) but also occurs in carcinoid tumours, leukemias and lymphomas. Cyclophosphamide in high dose (>50 mg/kg), ifosfamide and vincristine has all been indicated in SIADH.

Management protocol is directed towards the control of underlying tumour and fluid restriction 500 ml to 1 litre/day8. In intractable cases demeclocycline 0.6 to 1.2 g/d may be beneficial as it blocks the effect of vasopressin on renal tubules thus reducing water retention. Infusions of hypertonic saline and rapid correction of serum sodium should be avoided as they may precipitate central pontine myelinolysis and usually correction is restricted to 0.5 - 1 mEq/l/hr.

Acute Tumor Lysis Syndrome (ATLS)
ATLS was perhaps one of the earliest recognised metabolic abnormalities in cancer treatment that was documented as early as in 1870 (Salkowski F)9. ATLS results from a rapid and massive release of cellular breakdown products consequent upon tumour cell death following effective therapy. This may overwhelm the normal excretory mechanisms and body's normal capacity to neutralise such products. This may lead to multi-organ system failure and death. The cardinal features of ATLS are enumerated in Table 2. Burkitt's lymphoma is a paradigm for ATLS and there is usually bulky chemosensitive disease at presentation.

Table 2: Cardinal biochemical features of ATLS

ATLS may develop not only with treatment like chemotherapy or radiotherapy, steroid therapy, cytokine or hormonal therapy but also may develop spontaneously due to tumour necrosis or fulminant apoptosis. For a given condition the likelihood of developing ATLS is related to the sensitivity of the tumour to the particular tredisease bulk or clinical stage and the patient's renal function. Areas of ischaemia within a tumour may favour rapid cell death during treatment. Elevated serum lactate, urate and LDH levels may be important predictors of ATLS in hemopoietic and non-hemopoietic malignancies.

Chasty and Liu-Yim (1993) from Manchester Royal Infirmary have proposed a risk factor scoring system (Table 3) to assess the chance of developing ATLS in order to help select appropriate management strategy in an individual case.

Table 3: Proposed Risk Score for ATLS

Score: 4-7= high risk; 3= medium risk; <3 = low risk

The common signs of ATLS usually develop within 1-5 days of therapy and include weakness, paralytic ileus, cardiac arrhythmias and acute renal failure. Patients at risk for ATLS should be well hydrated, urine alkalinised, allopurinol given and serum electrolytes closely monitored as prevention is an essential goal in good oncological practice14

Hydration requires the infusion of 1.5 litre/m2/24h of fluids while hyperhydration requires 31 litre/m2/ 24h of IV fluids. Usually 50 mmol of sodium bicarbonate is given per litre of IV fluid to maintain urinary pH around 7.0 -8.0.

In the presence of rapidly rising serum potassium level (>5.5 mmol/.l) infusion of 50 ml of 50 percent glucose together with 15U of insulin over 1 hour promotes cellular uptake of potassium. Oral sodium-potassium exchange resins can also be used to treat hypermalemia.

Calcium gluconate can be given to correct hypocalcemia. A standard dose for allopurinol is 300 mg/day but for high-risk patients with normal renal function a loading dose of 500 mg/m2 reduced after 2 days to 200 mg/m2 has been suggested. Uric acid oxidase (uricase) has been used to catalyse conversion of uric acid to soluble allantoin but this drug has high toxicity at injection site. The summary of management schedule of ATLS is given in Table 4.

Table 4: Management of Tumor Lysis Syndrome

Lactic Acidosis
This is a less well-identified metabolic complication of malignancy15. Amongst type A (with hypoxia) and Type B (without hypoxia) the latter variety is observed in malignancies. It is most commonly associated with lymphoreticular malignancies (commonest with acute leukemias and high grade lymphomas) and less commonly with solid tumours unless it is well-advanced and extensive metastatic disease (especially hepatic metastasis). Lactic acidosis in cancer patients may be due to excessive production (tumour derived) as well as due to impaired elimination (hepatic metabolism and renal clearance). Type Alactic acidosis (due to circulatory or respiratory insufficiency) may develop due to leukostasis leading to hypoxia and anaerobic metabolism. Presently with the advent of total parenteral nutrition (TPN) lactic acidosis is an important complication in cancer patients. Clinically, patients with this metabolic emergency present with features like nausea, vomiting, abdominal pain, diarrhoea, altered sensorium, loss of consciousness, dehydration, hypotension and circulatory collapse.

The laboratory parameters that provide diagnostic clue are:

1. Blood lactate level > 2 mmol/l (venous plasma)
2. Arterial pH < 7.25
3. Anion gap > 22 mEq/l
4. Usually lactate: pyruvate:: 10:1.

A study of 25 patients with lactic acidosis associated with cancers was reviewed. More than two thirds were associated with leukaemia and lymphoma while one third were associated with solid tumors.

The chief aim of overall treatment is to restore the pH but not raise it above 7.2 and maintain bicarbonate around 8-10 mmol/l. This is usually achieved by giving 50-100 mEq bicarbonate over 30 to 60 minutes as isotonic/hypertonic solution. One must be cautious as bicarbonate itself may exacerbate lactic acidosis. It must be mentioned that in extra cases dialysis may be required but dialysis fluid itself contains lactate that may interfere with laboratory estimation of blood lactate but does not contribute any further to the acidosis.

Neurological emergencies
Spinal cord compression is the second commonest neurological emergency of cancer after cerebral metastasis and this most often is due to extradural spread from vertebral metastases16. Failure to recognise this oncological emergency results in severe disability with paraplegia and incontinence.

The dorsal cord is the commonest site of compression with most frequent primary sites being breast, lung, prostate and kidney. Clinical features suggestive of spinal pain and backache should be assumed to be due to spinal metastases in a cancer patient unless proved otherwise. Urgent neurological investigations and neurosurgical consultation is required. Neurosurgery is undertaken if there is no definite diagnosis and there is a rapidly progressive neurological picture. Laminectomy decompression is sufficient to relieve tumours that reach epidural space via intervertebral foramina. However, the prognosis following surgery has not been shown to be superior to that following radiotherapy. The majority of patients in the different cancer centres and general hospitals are usually treated urgently with corticosteroids and radiotherapy. Radiotherapy must include the entire extent of the tumour, which is best delineated by MRI. Emergency chemotherapy may be very effective in certain tumor types like lymph Ewing's sarcomas.

Superior Vena Caval Syndrome (SVCS)
Impedance of venous return from the head, upper extremities and upper thorax to the heart as a consequence of obstruction of blood flow through superior vena cava constitutes the superior vena caval syndrome. The underlying mechanism may be the invasive disease process in the superior mediastinum including extrinsic compression, invasion and thrombosis.

This syndrome commonly presents with characteristic features of facial swelling, chest pain and cough with or without dysphagia. Distension of neck, superficial thoracic veins and conjunctival oedema are almost always detectable. In extreme conditions proptosis with cerebral oedema may occur leading to altered consciousness. Lung cancers and mediastinal lymphomas account for 75 and 15 per cent of all cases of superior vena caval syndromes17. Palliative emergency radiotherapy and corticosteroids are advised for immediate treatment.

Previously quite often with a single chest film this potentially fatal emergency was treated even without histologic diagnosis. Diagnostic procedures like supraclavicular lymph node biopsy, bronchoscopy and thoracotomy were considered hazardous because of an anticipated excessive bleeding. However in a series of 843 invasive and semi-invasive diagnostic procedures there were only 10 non-fatal complications. At present it is considered essential to establish the cytologic or histologic diagnosis of SVCS as different treatment modalities are required based on different histology. CT Scan has now become a routine procedure in SVCS not only to identify SVCS anatomy but also to evaluate surrounding vital structures. The place of MRI is yet to be established but appears promising. CT guided FNAC has become a safer alternative to mediastinoscopy or thoracotomy biopsy. Treatment prior to pathologic diagnosis may render biopsy done later is not interpretable.

In 2 different series of lung cancer, patients together totalling 8960 cases, SVCS was identified in 3.3 per cent. Amongst 370 cases of lung cancer causing SVCS small cell cancer appeared to be commonest (38%) followed by squamous cell carcinoma (26%), adenocarcinoma (14%), large cell cancer (12%) and unclassified (9%). In a large series of 915 non-Hodgkin lymphomas, 36 cases (4%) of SVCS, 64 percent were diffuse large cell lymphomas and 33 percent were lymphoblastic lymphomas. Interestingly, although Hodgkin's disease commonly involves mediastinum it rarely causes SVCS unlike NHL. Other less common causes of SVCS are thymoma, mediastinal germ cell tumours and neuroblastoma.

The objectives of treatment of SVCS are to provide symptomatic relief and to attempt to cure the underlying cancer. NHL, small cell lung cancers and mediastinal germ cell tumours account for 50 per cent of all SVCS and are potentially curable. Usually relief starts by 7-10 days of chemotherapy. It must be warned that veins of lower limbs are preferred as venous access than arm veins. Diuretics may release venous pressure but may increase risk of thrombosis. Corticosteroids act by decreasing peritumoral and peri-irradiation inflammation.

Radiotherapy is the treatment of choice in SVCS where histologic diagnosis is not established and in those who show progressive clinical deterioration specially when there is compression of vital structures like trachea, bronchi, oesophagus and spinal cord. It is also the treatment of choice for non-small cell lung cancer. Interestingly, the symptomatic improvement resulting from radiotherapy may not always be due to improvement in blood flow through superior vena cava but probably as a consequence of development of collateral channels as pressure in the mediastinum gets relieved.

Surgical bypass graft may be attempted in extreme cases. Other techniques include venesection, reconstruction of SVC, angioplasty and stenting.

Leukostasis
The presence of high numbers of circulating leukemic cells is associated with early morbidity and mortality due to leukostasis in pulmonary and cerebral vasculature. Hyperleukocytosis is defined as a leukocyte count >100,000/ml most often observed in childhood ALL. Clinically significant hyperleucocytosis occurs with >2 lacs/mm3 count in AML, >3 lacs/mm3 in ALL and >6 lacs/mm3 in CML. In myeloid leukemias the common complication is stroke.

Excess leukocytes obstruct circulation in brain and lungs by forming aggregates and thrombi in small veins. Moreover, they compete for oxygen and damage vessel walls with subsequent bleeding. Myeloblasts and monoblasts, which tend to be larger and more rigid, are more likely to obstruct than lymphoblasts and granulocytes. If hematocrit is above 30 per cent then the risk is further increased. Clinical presentations include altered sensorium, frontal headache, seizures, papilledema or retinal venous distension, dyspnea, hypoxaemia and cardiac failure. Chest x-ray may reveal diffuse interstitial infiltrates.

There is no controlled study on ideal therapy but mainly includes prompt hydration, alkalinization and allopurinol. Platelet packs are transfused to maintain count >20,000/mm3 to avoid intracranial haemorrhage. Rise in hematocrit should be avoided. Exchange transfusions and leukopheresis are conventional and well tolerated therapies with mean WBC reduction of 66 percent and 48 percent. Problems include rebound increase in leukocyte counts and need for anticoagulation.

Conclusion
Over the past several decades, the prognosis for cancer has improved and a substantial percentage of patients are cured. There is need for recognition and treatment of complications associated with cancer patients that are true emergencies. Attention must be focussed on these problems that threaten vital organs or compromise the long-term quality of life. Quite often before the oncologist can give definitive therapy, the primary care physician may have to stabilise such patients.