Critical Reviews in Oncology/Hematology xxx (2005) xxxxxx

Metabolic emergencies
Silvia Spinazz e a, , Dirk Schrijvers b
a

START Project and Ospedale Reginale, Aosta, Italy b ZNA Middelheim, Antwerp, Belgium Accepted 15 April 2005

Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. General information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Referral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Published reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Clinical section: diagnosis and physiopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. General indication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypercalcaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Incidence, risk factors and pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Signs, symptoms and diagnostic strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. General information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1. Incidence, risk factors and pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2. Syndrome of inappropriate anti-diuretic hormone secretion (SIADH) caused by tumours and by drugs . . . . . . . . . . . 5.1.3. Syndrome of inappropriate anti-diuretic hormone secretion associated with hypovolemia . . . . . . . . . . . . . . . . . . . . . . . 5.1.4. Salt-wasting nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Signs, symptoms and diagnostic strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Treatment of hyponatremia and SIADH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tumour lysis syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Incidence, risk factors and pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Signs, symptoms and diagnostic strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Treatment of tumour lysis syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.1. Prophylactic measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.2. Management of specic metabolic disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypoglycaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Incidence, risk factors and pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Signs, symptoms and diagnostic strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hyperammoniemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. Incidence, risk factors and pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.1. Signs, symptoms and diagnostic strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00

2. 3. 4.

5.

6.

7.

8.

Corresponding author.

1040-8428/$ see front matter 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2005.04.004 ONCH-911; No. of Pages 11

S. Spinazz e, D. Schrijvers / Critical Reviews in Oncology/Hematology xxx (2005) xxxxxx

9.

Lactic acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1. Incidence, risk factors and pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2. Signs, symptoms and diagnostic strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Adrenal failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1. Incidence, risk factors and pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2. Signs, symptoms and diagnostic strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abstract

00 00 00 00 00 00 00 00 00

Life-threatening metabolic complications observed in cancer patients are: hypercalcaemia, hyponatremia, hyperurcaemia, tumour lysis syndrome, hypoglycaemia, hyperuremia and hypercreatininemia secondary to renal failure, hyperammoniemia, lactic acidosis and adrenal failure. They may be associated with any kind of neoplastic disease causing dysfunction of vital organs, which can be determined by neoplastic spread, anti-cancer treatment or, more rarely, by paraneoplastic phenomena. The clinical presentation of metabolic complications is typically aspecic. Encephalopathy, raging from mild confusion to coma, is the most common and clinically most severe symptom. The severity of consciousness impairment is related to both the rate of onset and the magnitude of the metabolic disorder. The denitive diagnosis will be established by laboratory examination and radiological work-up. Cancer patients presenting metabolic should be referred to oncologic departments or intensive care units. The treatment of metabolic disorders include: prophylactic measures, emergency measures to preserve vital functions and to restore biological parameters and the treatment of the underlying primary. 2005 Elsevier Ireland Ltd. All rights reserved.
Keywords: Hypercalcaemia; Tumour lysis syndrome; Metabolic emergencies

1. Introduction 1.1. General information Life-threatening metabolic disorders in patients with cancer include: hypercalcaemia, hyponatremia, hyperurcaemia, tumour lysis syndrome, hypoglycaemia, hyperuremia and hypercreatininemia secondary to renal failure, hyperammoniemia, lactic acidosis and adrenal failure. Encephalopathy, ranging from mild confusion to coma, is the most common and most conspicuous clinical manifestation of metabolic emergencies. This frequent manifestation is, next to pain, the most common symptom found in patients referred to the Neuro-Oncology Unit of the Memorial Sloan-Kettering Cancer Center. Metabolic emergencies may occur in all cancers capable of causing dysfunction of vital organs, and thus, may be expected in every patient with generalized cancer. 1.2. Referral Patients with metabolic emergencies need to be treated in a medical oncology department or in an intensive care unit (ICU). The department should provide facilities for cardiac monitoring and invasive haemodynamic monitoring, temporary cardiac pacing, ventilatory support and pumpcontrolled administration of infusions. Facilities for blood gas, haemoglobin and electrolyte measurements should be provided in the ICU or in the immediate vicinity. Facilities for haemodialysis or haematological rescue must be present.

1.3. Published reviews See Refs. [24].

2. Diagnosis 2.1. Clinical section: diagnosis and physiopathology Aspecic encephalopathy, ranging from confusion to coma, is almost invariably found as the main clinical manifestation of metabolic disorders. The severity of consciousness impairment is related to both the rate of onset and the magnitude of the metabolic disorder. With the exception of seizures which may be generalized but also partial and of a Babinski sign, the neurological examination will seldom reveal focal signs. The clinical presentation of metabolic encephalopathy is, thus, fairly unspecic. However, associated signs, such as dyspnea, cyanosis, icterus, hyperpnea (metabolic acidosis) or hypopnea (metabolic alkalosis), weakness and depressed reexes, cardiac arrhythmia (hypokalemia and hypercalcemia) may provide clues as to the nature of the underlying metabolic disorder. The denitive diagnosis will be established by laboratory examination and radiological work-up. The main pathophysiological mechanisms of metabolic and toxic emergencies specically related to cancer are: (1) Dysfunction of vital organs, such as lung, liver, kidney and urinary tract caused by neoplastic spread. These complications are more common in the late stages of the neoplastic diseases.

S. Spinazz e, D. Schrijvers / Critical Reviews in Oncology/Hematology xxx (2005) xxxxxx

(2) Dysfunction of vital organs related to anti-cancer treatments, mainly intensive chemotherapy, are also preferentially seen in patients with widespread disease. (3) Paraneoplastic phenomena due to the production by tumour cells of biologically active substances are rare. Paraneoplastic symptoms are unrelated to the stage of the tumour; in many cases they precede the diagnosis of the underlying cancer.

3. Treatment 3.1. General indication Therapy of metabolic emergencies consists of: (a) Prophylactic precautions; (b) Emergency measures to preserve vital functions and to restore biological parameters; (c) Treatment of the underlying cancer. 4. Hypercalcaemia 4.1. Incidence, risk factors and pathophysiology Hypercalcaemia is common, developing in around 1020% of patients with solid tumours, but this percentage varies with the underlying cancer diagnosis. It is most common in multiple myeloma, breast, lung, kidney and head and neck cancers. Hypercalcaemia is due to increased mobilization of calcium from bone and decreased renal tubular calcium excretion. The mechanisms are: (a) Production by the tumour of a parathyroid hormone related protein (PTHrP), which mediates hypercalcaemia in patients with non-metastatic tumours. PTHrP stimulates both osteoclast activity and tubular renal reabsorption of calcium. Increased blood levels of PTHrP are found in patients with epidermoid tumours. Patients with high levels of PTHrP have an inferior hypocalcaemic response to biphosphonates. (b) Induction of local osteolysis by a number of mediators (including PTHrP) released by neoplastic and nonneoplastic cells present at the sites of metastases. Most of these patients (80%) have extensive osteolytic bone metastases, rarely osteoblastic. (c) Increased production of calcitriol (a metabolite of Vitamin D3), as observed in most cases of Hodgkins disease and in some cases of non-Hodgkins lymphomas [1]. Hypercalcaemia induced by such mechanisms usually responds to corticosteroids [24]. 4.2. Signs, symptoms and diagnostic strategy Most patients with hypercalcaemia present with nonspecic symptoms: fatigue (70%), anorexia (60%), nausea,

constipation (60%), weight loss (60%), bone pain (60%), polyuria and polydipsia or dehydration. Neurological symptoms range from muscle weakness and lethargy to confusion, delirium and coma, as a function of both the severity and the rate at which hypercalcaemia develops. The most important renal signs are nephrogenic diabetes insipidus (polyuria and polydipsia, dehydration, electrolyte abnormalities) and acute or chronic renal failure. Frequent monitoring of hydroelectrolyte balance (uid intake, urine output, serum calcium, creatinine, potassium, sodium and magnesium) is recommended. 4.3. Treatment Treatment of the underlying cancer is the standard option on a type C basis, if effective treatment is available. The incidence of hypercalcemic episodes has fallen during recent years because long-term prophylactic bisphosphonate therapy is now a standard option on a type 3 level of evidence for patients with multiple myeloma and breast cancer. It has been shown that pamidronate, clodronate and zolendronate signicantly decrease either the severity of bone pain or the incidence of skeletal morbidity (bone pain, fractures and hypercalcaemia) in patients with bone metastases from breast carcinoma or with advanced multiple myeloma [58]. Prophylactic bisphosphonate therapy in patients with nonmetastatic breast cancer could decrease the incidence of bone metastases but this therapy is still investigational. Several agents inhibit osteoclastic activity and bone calcium resorption and tubular renal reabsorption of calcium: Bisphosphonates are potent inhibitors of osteoclast activity, but the mechanisms of actions are complex and not fully understood. The response to bisphosphonates is inferior in patients with high levels of PTH-rP (such as epidermoid carcinomas). The reasons for this reduced activity are unknown; it has been proposed that increased renal tubular reabsorption of calcium induced by PTHrP could not be inhibited by bisphosphonates. However, high doses of biphosphonates are able to normalize bone resorption and to overcome the contributing role of the kidney, as well. Intravenous bisphosphonates every 2128 days are standard treatment for malignant hypercalcemia on a type C basis [3,4,9]. Numerous bisphosphonates are presently available, including pamidronate, etidronate, clodronate, alendronate, ibandronate and zolendronate. Intravenous pamidronate has been studied at 30, 60, 90 mg dose levels and has been compared to clodronate, etidronate and zolendronate. Pamidronate 90 mg as a single intravenous infusion over 224 h, is suitable for individual clinical use on a type 2 level of evidence [1013]. With this schedule, normocalcaemia is observed within 48 h in 7090% of patients, and normocalcaemia is maintained for 24 weeks. At this high dose level, the effects on calcemia or renal calcium excretion are not inuenced by tumour type or by the presence of bone metastases. In comparative studies, pamidronate 90 mg is more potent and has a longer lasting effect than oral clodronate. Pamidronate 60 mg as a single intravenous

S. Spinazz e, D. Schrijvers / Critical Reviews in Oncology/Hematology xxx (2005) xxxxxx

infusion over 224 h is suitable for individual clinical use on a type R basis for patients with mild hypercalcaemia and bone metastases. Clodronate 1500 mg as a single intravenous infusion achieves normocalcaemia in approximately 80% of cases; its use is suitable for individual clinical use on a type 3 level of evidence [14]. Zoledronate 4 mg as a single 1015 min infusion every 4 weeks is standard option on a type 1 level of evidence. When compared to pamidronate 90 mg, zolendronate showed better results in term of complete response rate (88% versus 70%) and response duration (32 days versus 18 days). Moreover, zolendronate has the advantage of shorter infusion time (1015 min versus at least 2 h infusion). Zolendronate 8 mg is suitable for individual clinical use on a type 2 level of evidence for relapsed or refractory hypercalcemia [15,16]. Ibandronate 46 mg is suitable for individual clinical use on a type 3 level of evidence [17,18]. Side effects of bisphosphonates are mild and include low-grade fever (1015%), venous irritation, asymptomatic hypocalcaemia, nausea/vomiting (2%) and elevation of serum creatinine (25%). Pamidronate is usually safe in patients with hypercalcaemia and mild renal insufciency [19]; however, since hypocalcemic crises have seldom been described in patients with moderate to severe renal failure, a dose reduction of bisphosphonates (pamidronate 3045 mg, for instance) is suitable for individual clinical use on a type R basis in order to avoid symptomatic hypocalcaemia [16]. Other previously used drugs are no longer recommended because of their poorer clinical prole (higher toxicity and/or reduced efcacy) and bisphosphonates tend to be favoured. Gallium nitrate is a potent inhibitor of bone resorption, irrespective of mechanism or cancer type. Gallium nitrate 200 mg/(m2 day) by continuous intravenous infusion, up to 5 days is suitable for individual clinical use suitable for individual clinical use [2022]. With this schedule, normocalcaemia is observed within 48 h in 7080% of patients, and normocalcaemia is maintained for 12 weeks. The high response rate is observed even in patients with osteolysis mediated by PTH-rP (epidermoid carcinomas) in which the response to bisphosphonates may be inferior. This drug is associated with a higher frequency of renal toxicity (10%) than bisphosphonates [19]; the prolonged infusion is a disadvantage as well. Calcitonin reduces serum calcium by inhibiting bone resorption and increasing renal calcium excretion. Calcitonin 8 IU/kg IM every 6 h for 5 days achieves normocalcaemia in 30% of patients for 12 days. Owing to its rapid onset of action (within 24 h of administration), its use in combination with pamidronate or zoledronate is suitable for individual clinical use on a type 3 level of evidence in patients with acute severe hypercalcemia [23]. Plicamycin 1050 g/kg IV by brief infusion (because it is a sclerosing agent) is suitable for individual clinical use on a type 3 level of evidence for patients who do not response to other modalities. Toxicity (hepatotoxicity, renal insufciency, haemorrhagic diathesis, thrombocytopenia) occurs after multiple injections [19]. In cases of acute severe hypercalcaemia, isotonic saline hydration is a standard option on a type C basis. Saline will

decrease the signs and symptoms arising from dehydration and hypovolemia (secondary to vomiting, decreased uid intake and polyuria), improve renal function and inhibit the increased tubular reabsorption of calcium secondary to volume depletion. The rate of uid administration depends on the severity of dehydration, cardiovascular status and renal function. Infusion of 13 L of isotonic saline over 14 h is suitable for individual clinical use on a type R basis. The administration of diuretics (furosemide 2040 mg intravenously twice daily) after adequate rehydration has been achieved, is suitable for individual clinical use on a type R basis in cases of uid overload. Hydration and forced diuresis alone are usually ineffective to maintain normocalcaemia (observed in only 2030% of treated patients). Moreover, such treatment is toxic because uid overload, pulmonary oedema and hypernatremia or hypovolemia have been reported frequently [2,3]. Therefore, bisphosphonate therapy should be started as soon as proper rehydration has been obtained. Dialysis is suitable for individual clinical use on a type R basis for patients with severe hypocalcaemia, profound mental changes and/or severe renal failure or congestive heart failure. Glucocorticoids, for example prednisone 40100 mg/ daily, are effective notably in malignancies producing 125 (OH)2 Vitamin D, such as multiple myeloma, lymphoma, leukemias. Its use is suitable for individual clinical use on a type R basis in these patients. New inhibitors of bone resorption (osteoprotegerin) are investigational [24].

5. Hyponatremia 5.1. General information 5.1.1. Incidence, risk factors and pathophysiology Hyponatremia is probably the most common metabolic disorder seen in hospitalized patients, including cancer patients. Hyponatremia is dened as a serum Na level < 130 mEq/L. In a recent prospective study the observed incidence of hyponatremia in medical cancer patients was around 4% [25]. Its causes are multifold [2,3]. 5.1.2. Syndrome of inappropriate anti-diuretic hormone secretion (SIADH) caused by tumours and by drugs Many tumours secrete ectopic vasopressin (AVP) or vasopressin-like peptide. Inappropriate AVP secretion causes excess renal water resorption; as volume expansion occurs aldosterone secretion is reduced as well, with a progressive salt loss in the urine. Thus, the pathogenesis of hyponatremia in SIADH involves both the retention of water (dilutional hyponatremia) and the loss of sodium in the urine. There is water intoxication due to hypo-osmolality and hyponatremia, but without oedema or signs of hypovolemia. Urine is concentrated with increased sodium levels. SIADH is typically seen in small cell lung carcinoma, but it has also been observed

S. Spinazz e, D. Schrijvers / Critical Reviews in Oncology/Hematology xxx (2005) xxxxxx

in pancreatic neoplasms, lymphomas, mesothelioma and primary and metastatic brain tumours. SIADH (caused by active metabolites) has been reported as a complication of treatment with a number of drugs, such as vinca alkaloids, vinorelbine, alkylating agents (high-dose cyclophosphamide and less commonly low-dose cyclophosphamide, melphalan and chlorambucil), opioids, anti-depressants and combination chemotherapy including cisplatin. Both chemotherapyinduced nausea (since nausea is an important stimulus to AVP release) and excessive prehydration play a role in SIADH observed after cisplatin administration. 5.1.3. Syndrome of inappropriate anti-diuretic hormone secretion associated with hypovolemia Decreased tissue perfusion is a potent stimulus to AVP release. Hyponatremia may be associated either with true volume depletion (in patient with severe vomiting or diarrhoea) or with oedematous states (peripheral oedema and/or ascite). Patients with true volume depletion are clinically hypovolemic (orthostatic hypotension, tachycardia and rapid weight loss), oliguric and the urine contains little sodium. Patients with peripheral oedema and/or ascites are oliguric and gaining weight and the urine is concentrated with low sodium levels. 5.1.4. Salt-wasting nephropathy Salt-wasting nephropathy may be secondary to cisplatin chemotherapy (hypomagnesemia may also be present), adrenal insufciency (reduced aldosterone secretion) and cerebral salt-wasting (associated with intracranial surgery and subarachnoid hemorrhage). Patients are clinically hypovolemic (orthostatic hypotension, tachycardia and rapid weight loss), non-oliguric and the urine contains high levels of sodium. 5.2. Signs, symptoms and diagnostic strategy Hyponatremia is dened as a serum sodium levels < 130 mEq/L. The signs and symptoms of hyponatremia are related both to the severity and the rapidity with which hyponatremia develops. There is water intoxication due to hypo-osmolality and hyponatremia; the symptoms are primarily neurological as a consequence of neurological dysfunction induced by cerebral oedema. If hyponatremia is mild, there may be fatigue, anorexia, nausea, diarrhoea and headache. Hyponatremia characterized by sodium <115 mEq/L or by acute (13 days) reduction in the plasma sodium concentration, may cause confusion, lethargy, seizures, coma and death. According to the aetiology, patients may be either hypovolemic or euvolemic. Plasma and urine osmolality values as well as urinary sodium concentration are recommended for the differential diagnosis [2,3,25]. In SIADH associated with hypovolemia, patients are clinically hypovolemic, oliguric and the urine contains little sodium. In SIADH associated with tumours or drugs, there is water

intoxication due to hypo-osmolality (<270 mmol/kg) and hyponatremia, but without oedema or signs of hypovolemia. Urine is concentrated (hyperosmolality >150 mmol/kg) with increased sodium levels (>20 mEq/L). 5.3. Treatment of hyponatremia and SIADH Prophylactic measures aiming at decreasing the risk of hyponatremia include the management of excessive diarrhoea, vomiting or hydration used before chemotherapy. Isotonic or slightly hypertonic saline perfusions is a standard option on a type C basis in patients with true extracellular uid volume depletion. Conversely, restriction of both water and salt is a standard option on a type C basis in patients with oedema and evidence of uid retention [3]. Fluid restriction to 500 mL/day or to the daily urinary output plus 500 mL/day is a standard option on a type C basis for patients with SIADH and asymptomatic hyponatremia [2,3]. Most patients improve on uid restriction alone, however, the compliance may be poor because ADH also stimulates thirst. Demeclocycline (300600 mg orally twice daily), a vasopressin V2 receptor antagonist, which interferes with the collecting tubules response to AVP, is suitable for individual clinical use on a type 3 level of evidence in patients with chronic SIADH who cannot be controlled with water restriction alone [3]. Other new anti-V2 drugs are experimental [26,27]. Correction of hyponatremia becomes an emergency when serum levels fall below 120115 mEq/L). Severe, symptomatic hyponatremia often requires the administration of hypertonic saline (with or without furosemide). In symptomatic patients with hyponatremia lasting for more than 48 h, the correction of serum sodium levels should be slow (1.52 mEq/(L h)) and should not exceed 1215 mEq in the rst 24 h, to avoid the hazards of osmotic demyelinating syndrome (central pontine myelinolysis, a complication whose denite incidence and pathogenesis is not known) (standard option on a type C basis). If the patient is asymptomatic, the correction should be slower (0.5 mEq/(L h)) and not exceed 1012 mEq in the rst 24 h (standard option on a type C basis). If the patient has neurological symptoms, the addition of intravenous furosemide every 4 h enhances the excretion of free water when saline solutions are administered. Furosemide is suitable for individual clinical use on a type 3 level of evidence for outpatients [2,3,28]. Hypomagnesemia may be combined with hyponatremia in salt-wasting nephropathy due to cisplatin. Hypomagnesemia is treated by oral or parenteral magnesium, depending on the severity of the disorder, on a type R basis.

6. Tumour lysis syndrome 6.1. Incidence, risk factors and pathophysiology Acute tumour lysis syndrome is caused by a rapid release of intracellular products originating from massive lysis of

S. Spinazz e, D. Schrijvers / Critical Reviews in Oncology/Hematology xxx (2005) xxxxxx

malignant cells into the blood, either spontaneously or during chemotherapy or radiation. It is characterized by acute hyperurcaemia, hyperkalaemia, hyperphosphatemia, hypocalcaemia, hyperazotemia or acute renal failure; these biochemical alterations may occur either individually or collectively. Hypocalcaemia is a result of the precipitation of calcium phosphate in soft tissues secondary to the acute development of hyperphosphatemia. Hyperphosphatemia is the usual precipitating factor of acute renal failure (secondary to the precipitation of calcium phosphate crystals in the renal tubules). In patients with hyperurcaemia and hyperuricosuria associated with a very high rate of cell turnover, a spontaneous acute renal failure due to the precipitation of uric acid crystals in the renal tubules (acute uric acid nephropathy) may be observed. Uric acid stones may develop in the renal pelvis or may lead to ureteral obstruction in patients with chronic hyperurcaemia. The tumour lysis syndrome occurs most often in patients with large tumour burdens that are very sensitive to chemotherapy and radiotherapy, such as acute or chronic leukaemias with high leukocyte counts and high-grade lymphomas. The syndrome has also been observed, although rarely, in patients with solid tumours or after treatment with agents that do not have a potent cytotoxic activity, such as interferon alfa, tamoxifen, intrathecal methotrexate. Prophylactic measures have considerably decreased the incidence of this syndrome. The severity of the syndrome is favoured by extensive disease (bulky retroperitoneal or intra-abdominal tumours, elevated LDH, high leukocyte count) and by preexisting renal insufciency since uric acid, potassium and phosphate are all excreted by the kidneys after tubular reabsorption and secretion [3,29]. 6.2. Signs, symptoms and diagnostic strategy This syndrome is characterized by acute hyperurcaemia, hyperkalaemia, hyperphosphatemia, hypocalcaemia and azotemia or acute renal failure. These abnormalities may occur either individually or simultaneously. Hyperkalaemia may result in lethal cardiac arrhythmia. Hyperphosphatemia and hyperurcaemia may result in acute renal failure, from the precipitation of uric acid crystals and/or calcium phosphate crystals in the renal tubules. Hypocalcaemia (as a result of acute hyperphosphatemia, with precipitation of calcium phosphate in soft tissues) can cause muscle cramps, cardiac arrhythmias and tetany. Measurement of serum electrolytes, uric acid, phosphorus, calcium and creatinine is recommended every few hours for 34 days after initiating cytotoxic therapy in high risk subjects on a type C basis. Other monitoring is optional and depends on the clinical condition of the patient [3,29]. 6.3. Treatment of tumour lysis syndrome 6.3.1. Prophylactic measures Patients at risk should be identied. At rst, it is essential to minimize or eliminate risk factors associated with acute

tumour lysis syndrome,s avoid administration of nephrotoxic drugs, correct volume depletion, control existing therapies, which may contribute to electrolyte abnormalities and avoid drugs that block tubular reabsorption of uric acid [30]. Then, patients at risk should be treated with prophylactic measures before administration of chemotherapy. The aim is to prevent hyperurcaemia (serum uric acid level should be maintained below 10 mg/dL) and to achieve a high urine ow, in order to increase the excretion of potassium and of phosphorus and to decrease the likelihood of uric acid and/or calcium phosphate precipitation in renal tissue. Vigorous hydration, starting 2448 h before chemotherapy and lasting throughout the duration of treatment and allopurinol are standard prophylactic options on a type C basis [30]. Intravenous hydration at a rate of 45 L/day is a standard option on a type C basis. If urine volume is less than 45 L/day, furosemide is suitable for individual clinical use on a type R basis. Allopurinol prevents the formation of uric acid through inhibition of xanthine oxidase; the standard daily dose, on a type C basis, is 300900 mg, administered orally once or twice per day. In patients with renal impairment, the dose must be reduced in relation to the creatinine clearance, up to a 50% reduction for patients receiving haemodialysis. Caution is required because allopurinol interferes with the degradation of 6-mercaptopurine and azathioprine and because it may enhance the marrow toxicity of cyclophosphamide. Intravenous allopurinol (200400 mg/(m2 day) in adult patients, 200 mg/(m2 day) in children) is suitable for individual clinical use on a type 3 level of evidence in patients for whom oral intake is restricted [31,32]. Recombinant urate oxidase (rasburicase) in a preventive or prophylactic setting is suitable for individual clinical use on a type 3 level of evidence in children with advanced stage lymphoma or high tumour burden leukaemia. It is a safe and effective alternative to allopurinol. A more rapid control and lower levels of plasma acid uric have been observed after rasburicase administration, compared with allopurinol [33]. 6.3.2. Management of specic metabolic disturbances Treatment of elevated uric acid levels is similar to prophylactic measures. Intensive intravenous hydration, urine alkalinization and allopurinol administration are standard options on a type C basis [30]. Allopurinol prevents the formation of uric acid through inhibition of xanthine oxidase; a standard daily dose, on a type C basis, is 300900 mg, administered orally once or twice per day. In patients with renal impairment, the dose must be reduced in relation to the creatinine clearance, up to a 50% reduction for patients receiving haemodialysis. Caution is required because allopurinol interferes with the degradation of 6-mercaptopurine and azathioprine and because it may enhance the marrow toxicity of cyclophosphamide. The decrease in uric acid level is observed 23 days after the initiation of allopurinol therapy, because allopurinol prevents the formation of additional acid uric but does not reduce the level of acid uric. Intravenous allopurinol (200400 mg/(m2 day) in adult

S. Spinazz e, D. Schrijvers / Critical Reviews in Oncology/Hematology xxx (2005) xxxxxx

patients, 200 mg/(m2 day) in children) is suitable for individual clinical use on a type 3 level of evidence in patients for whom oral intake is restricted [31,32]. Alkalinization of the urine, to maintain urine pH at least at 7.0, facilitates urinary urate solubility; it is suitable for individual clinical use on a type 3 level of evidence whenever hydration and allopurinol alone does not control hyperurcaemia. The addition of sodium bicarbonate to intravenous uids is a standard option on a type C basis. However, vigorous urinary alkalinization may increase the likelihood of calcium phosphate precipitation in the renal tubules and may worsen the neurological manifestations of hypocalcaemia. Recombinant urate oxidase (rasburicase) is suitable for individual clinical use on a type 3 level of evidence in patients with allopurinol hypersensitivity, in cases refractory to standard measures or in renal failure or in children with advanced stage lymphoma or high tumour burden leukaemia. The enzyme uricase, naturally present in all mammals, is able to catalyse the conversion of uric acid to allantoin, which is much more soluble in urine. A more rapid control and lower levels of plasma acid uric has been observed after rasburicase administration, compared to allopurinol [33]. Urate oxidase derived from natural sources may elicit allergic reactions [34]. The therapy of acidbase or electrolyte disorders is suitable for individual clinical use on a type 3 level of evidence [30]. Hyperkalaemia, which may be severe in renal insufciency, is treated by restricting potassium intake (in perfusions and food) and by enhancing renal excretion of potassium through diuretics (furosemide). Potassium levels above 7 mEq/L should be treated with an oral sodium-potassium exchange resin or with i.v. administration of hypertonic glucose with insulin. This solution is able to shift potassium from the extracellular to the intracellular space. It is useful for the management of hyperphosphatemia, as well. Alkalinization with sodium bicarbonate shifts potassium intracellularly, as well. Intravenous administration of calcium gluconate is appropriate for patients with symptomatic hypocalceamia. Phosphate binders, such as aluminum antacids are able to decrease the gut absorbtion of phosphate. In cases of severe renal failure, oliguria and/or biochemical abnormalities (hyperkalaemia, hyperurcaemia, hyperphosphatemia), which are not corrected by conservative measures, early haemodialysis is a standard option on a type C basis [3,30].

(b) Production of insulin-like products by large nonislet-cell tumours, such as mesenchymal tumours (hemangiopericytomas, brosarcomas, leiomyomas, mesotheliomas, neurobromas) as well as other tumour types (hepatomas, neuroblastomas). (c) Excessive glucose consumption by large tumours that exceeds hepatic production. (d) In addition hypoglycaemia may occur in the end-stages of hepatic failure (as a consequence of decreased glycogenolysis and gluconeogenesis) or in pituitary failure (as a consequence of depressed secretion of counterregulatory hormones, such as ACTH and growth hormone). However, only a few patients develop hypoglycaemia as a result of these mechanisms [35]. 7.2. Signs, symptoms and diagnostic strategy Classic symptoms of hypoglycaemia include neurogenic symptoms (tremulousness, palpitations, anxiety, sweating, hunger and paresthesias) as the result of the perception of physiological changes caused by the autonomic response to hypoglycaemia followed by neuroglycopenic symptoms (confusion, sensation of warmth, weakness or fatigue, severe cognitive failure, seizure, coma). They may develop slowly and be worse early in the morning (after overnight fasting) and improve after a meal. However, some patients may present acute and severe symptoms. Biochemical evaluation reveals hypoglycaemia. Glycemic thresholds for symptoms of hypoglycaemia varies; patients with recurrent hypoglycaemia often tolerate abnormally low plasma glucose concentrations without presenting warning symptoms of hypoglycaemia [36]. The glucagon stimulation test (serial glucose measurements after a 1 mg infusion of glucagon) is optional. Patients with an insulinoma or with secretion of insulin-like products by non-islet-cell tumours respond to glucagon with a rise in serum glucose levels, indicating adequate glycogen stores. Glucose levels do not rise when hypoglycaemia is due to poor hepatic glycogen reserve/liver failure. A glycemic response > 30 mg/dL to glucagon is predictive of a good response to long-term treatment with glucagon [35]. 7.3. Treatment Specic anti-tumour therapy (surgery or radiotherapy or chemotherapy) is standard option on a type C basis. Prophylaxis of hypoglycaemia, especially, in patients with insulinoma, and treatment of mild hypoglycaemia includes frequent light meals and carbohydrate snacks on a type C basis. In patients with severe or unpredictable symptoms, either rapid hypertonic glucose intravenous infusions or the administration of corticosteroids and glucagon are suitable for individual clinical use on a type R basis. Continuous infusion of glucagon (0.060.3 mg/h, delivered by a portable pump) is suitable for individual clinical use on a type 3 level of evidence for patients who showed a glycemic response to glucagon [35].

7. Hypoglycaemia 7.1. Incidence, risk factors and pathophysiology Hypoglycaemia specically related to cancer is rare and is caused by several mechanisms. (a) Production of insulin by islet-cell tumours (malignant insulinomas, which represent about 10% of all insulinomas).

S. Spinazz e, D. Schrijvers / Critical Reviews in Oncology/Hematology xxx (2005) xxxxxx

8. Hyperammoniemia 8.1. Incidence, risk factors and pathophysiology Liver is one of the most common site for metastases originating from a variety of primaries mainly the digestive tract, lung or breast. Its functional failure, however, which requires the destruction of more than 70% of the hepatic parenchyma, is usually seen in the late stages of neoplastic disease. However, in some cases, acute liver failure may lead to the identication of a primary or metastatic cancer. Changes in liver function tests are often seen in patients receiving chemotherapy. However, except for patients treated with asparaginase, severe hepatic failure and hyperammoniemia due to chemotherapy are rare. In the last 15 years, however, idiopathic hyperammoniemia has been described after intensive chemotherapy for leukaemia (2.5% of patients) and following bone marrow transplantation (0.51% of patients). This syndrome occurs 24 weeks after chemotherapy or bone marrow transplantation; mortality is very high (7080%). The aetiology is unknown. Hepatic failure secondary to sclerotising cholangitis has been reported after infusion of the hepatic artery with uorouridine. Due to increased central venous pressure, hepatic dysfunction may be seen in superior vena cava syndrome. However, clinically signicant liver necrosis, which may occur, is probably rare. 8.2. Diagnosis 8.2.1. Signs, symptoms and diagnostic strategy Severe hyperammoniemia is associated with a metabolic encephalopathy with lethargy, confusion, disorientation, agitation. Evolution to coma and seizures is rapid. These patients have respiratory alkalosis; liver function tests are abnormal with advanced liver disease, while they are normal after bone marrow transplantation. 8.3. Treatment

ondary to accumulation of blood lactate (more than 2 mEq/L). It often occurs as a consequence of hypoperfusion and severe tissue hipoxia as seen in patients with shock and septicemia (type A lactic acidosis). Type B lactic acidosis is associated with a number of predisposing diseases (diabetes mellitus, renal disease, alcoholism, liver disease) and has been described occasionally in cancer patients, as well. The majority of cancer patients are adults with rapidly progressive leukaemia or lymphoma (and possible tumour overproduction of lactate under anaerobic circumstances or for a high rate of glycolysis), whereas patients with solid tumours have extensive liver metastases (and reduced hepatic clearance of lactate). However, the pathogenesis is poorly understood [3,37]. 9.2. Signs, symptoms and diagnostic strategy The patient presents with hyperventilation, hypotension, tachycardia, nausea, confusion and rapidly progressive shock as the acidosis worsens. Biochemical evaluation reveals a decreased arterial pH (<7.37), low serum bicarbonate, increased anion gap and elevated lactate level (>2 mEq/L). Since lactic acidosis secondary to cancer is rare, a diagnostic work-up to seek other potentially treatable causes is recommended. 9.3. Treatment Chemotherapy of the underlying haematological cancer is a standard option on a type C basis, and it may lead to a resolution of the lactic acidosis in chemotherapy sensitive tumours. Remission of acidosis has been reported in less than 10% of cases; however, prognosis is extremely poor even in these patients [3,37].

10. Adrenal failure 10.1. Incidence, risk factors and pathophysiology Liver failure observed in cancer patients is primarily related to the neoplastic spread. The prognosis of patients with extensive liver metastases of solid tumours is poor. Haemodialysis and ammonium-trapping therapy are suitable for individual clinical use on a type R basis in patients with idiopathic hyperammoniemia following highdose chemotherapy; however, reported mortality is very high (7080%). Hepatic toxicity due to l-asparaginase requires a decrease of the administered doses on a type R basis. Symptomatic adrenocortical insufciency (Addisons disease) occurs after destruction of more than 90% of adrenal tissue by metastatic carcinoma (lung and breast cancer); iatrogenic adrenal insufciency (secondary to surgical adrenalectomy, treatment with mitotane, inhibition of steroid synthesis by aminoglutethimide, megestrol acetate therapy, chronic corticosteroid therapy) is more common. Symptoms of adrenal insufciency may develop insidiously in 2030% of patients with metastatic cancer and adrenal enlargement on CT. Chronic corticosteroid therapy can partially mask adrenal failure or can precipitate it after withdrawal [2,38]. 10.2. Signs, symptoms and diagnostic strategy Classic signs and symptoms of chronic adrenal insufciency are secondary to reduced production of

9. Lactic acidosis 9.1. Incidence, risk factors and pathophysiology Lactic acidosis is a life-threatening metabolic acidosis, characterized by decreased arterial pH (less than 7.37) sec-

S. Spinazz e, D. Schrijvers / Critical Reviews in Oncology/Hematology xxx (2005) xxxxxx

mineralcorticosteroids and glucocorticosteroids by the adrenal glands. They include weakness, weight loss, anorexia, nausea and vomiting (90%), hyperpigmentation of skin and mucous membranes or postural hypotension (80%). The insidious onset and the non-specicity of symptoms make diagnosis difcult in cancer patients. Recent corticosteroid use should be recorded, since it can partially mask adrenal failure or precipitate it after withdrawal. Circulatory collapse and shock are uncommon but they may develop with corticosteroid withdrawal or with the onset of infection or after adrenal haemorrhage. Biochemical evaluation frequently reveals hyponatremia, hyperkalaemia, hypercalcaemia, hypoglycaemia and mild metabolic acidosis. If adrenal failure is sudden, serum electrolytes may be normal. Electrocardiographic abnormalities are observed in 50% of patients. Abdominal computed tomography is recommended in metastatic patients in order to detect adrenal metastases. High-resolution endosonography can offer additional information and is optional [39,40]. After ACTHstimulation test (Cosyntropin 250 g i.v.), serum cortisol values (measured 30 and 60 min later) do not rise to the levels seen in healthy individuals. This test is recommended on a type R basis, unless the patient is in shock [2]. However, recent data suggest that this usual dose could be a pharmacological rather than a physiological stimulus, losing sensitivity for detecting adrenocortical failure. A low-dose test (Cosyntropin 10 g i.v.) showed better sensitivity [41]. 10.3. Treatment If acute adrenal failure is suspected clinically and if there is haemodynamic instability, steroid replacement should be started promptly, before laboratory results are obtained. Hydrocortisone 100200 mg i.v. every 8 h and rehydratation are a standard option on a type C basis. Physiological glucocorticoid replacement with cortisone acetate orally 25 mg in the morning and 12.5 mg in the afternoon is a standard option on a type C basis in patients with chronic adrenal insufciency. During periods of stress (infection or operative procedures), these doses may be doubled or tripled or stress doses of parenteral glucocorticoids may be required. Mineralcorticoid replacement (udrocortisone 0.10.3 mg orally) is suitable for individual clinical use on a type R basis, according to the symptoms, serum electrolytes levels and blood pressure [2].

References
[1] Seymour JF, Gagel RF. Calcitriol: the major humoral mediator of hypercalcemia in Hodgkins disease and non-Hodgkins lymphomas. Blood 1993;82:138394. [2] Nelson KA, Walsh D, Abdullah O, et al. Common complications of advanced cancer. Semin Oncol 2000;27:3444. [3] Flombaum CD. Metabolic emergencies in the cancer patient. Semin Oncol 2000;27:32234.

[4] Body JJ. Current and future directions in medical therapy: hypercalcemia. Cancer 2000;88:30548. [5] Hortobagyi GN, Theriault RL, Lipton A, et al., Protocol 19 Aredia Breast Cancer Study Group. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol 1998;16:203844. [6] Berenson JR, Lichtenstein A, Porter L, et al., Myeloma Aredia Study Group. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol 1998;16:593602. [7] Kanis JA, McCloskey EV. Clodronate Cancer 1997;80:16915. [8] Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001;7:37787. [9] Body JJ, Bartl R, Burckhardt P, et al., International Bone and Cancer Study Group. Current use of bisphosphonates in oncology. J Clin Oncol 1998;16:38909. [10] Nussbaum SR, Younger J, Vandepol CJ, et al. Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-, 60-, and 90-mg dosages. Am J Med 1993;95:297304. [11] Purohit OP, Radstone CR, Anthony C, Kanis JA, Coleman RE. A randomised double-blind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy. Br J Cancer 1995;72:128993. [12] Gucalp R, Ritch P, Wiernik PH, et al. Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol 1992;10:13442. [13] Vinholes J, Guo CY, Purohit OP, Eastell R, Coleman RE. Evaluation of new bone resorption markers in a randomized comparison of pamidronate or clodronate for hypercalcemia of malignancy. J Clin Oncol 1997;15:1318. [14] ORourke NP, McCloskey EV, Vasikaran S, Eyres K, Fern D, Kanis JA. Effective treatment of malignant hypercalcaemia with a single intravenous infusion of clodronate. Br J Cancer 1993;67:5603. [15] Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001;19:55867. [16] UKMF. The UK Myeloma Forum. Diagnosis and management of multiple myeloma. Br J Haematol 2001;115:52240. [17] Pecherstorfer M, Herrmann Z, Body JJ, et al. Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy. J Clin Oncol 1996;14:26876. [18] Ralston SH, Thiebaud D, Herrmann Z, et al. Doseresponse study of ibandronate in the treatment of cancer-associated hypercalcaemia. Br J Cancer 1997;75:295300. [19] Zojer N, Keck AV, Pecherstorfer M. Comparative tolerability of drug therapies for hypercalcaemia of malignancy. Drug Saf 1999;21:389406. [20] Warrell RPJ, Israel R, Frisone M, Snyder T, Gaynor JJ, Bockman RS. Gallium nitrate for acute treatment of cancer-related hypercalcemia: a randomized, double-blind comparison to calcitonin. Ann Intern Med 1988;108:66974. [21] Warrell RPJ, Murphy WK, Schulman P, ODwyer PJ, Heller G. A randomized double-blind study of gallium nitrate compared with etidronate for acute control of cancer-related hypercalcemia. J Clin Oncol 1991;9:146775. [22] Warrell RPJ. Gallium nitrate for the treatment of bone metastases. Cancer 1997;80:16805. [23] Sekine M, Takami H. Combination of calcitonin and pamidronate for emergency treatment of malignant hypercalcemia. Oncol Rep 1998;5:1979. [24] Greipp P, Williams CD, Lipton A, et al. A single subcutaneous dose of an osteoprotegerin (OPG) construct (AMGN-0007) causes

10

S. Spinazz e, D. Schrijvers / Critical Reviews in Oncology/Hematology xxx (2005) xxxxxx a profound and sustained decrease of bone resorption comparable to standard intravenous bisphosphonate in patients with multiple myeloma. Blood 2001;98:775a. Berghmans T, Paesmans M, Body JJ. A prospective study on hyponatraemia in medical cancer patients: epidemiology, aetiology and differential diagnosis. Support Care Cancer 2000;8: 1927. Decaux G. Long-term treatment of patients with inappropriate secretion of antidiuretic hormone by the vasopressin receptor antagonist conivaptan, urea, or furosemide. Am J Med 2001;2001(110):5824. Decaux G. Difference in solute excretion during correction of hyponatremic patients with cirrhosis or syndrome of inappropriate secretion of antidiuretic hormone by oral vasopressin V2 receptor antagonist VPA-985. J Lab Clin Med 2001;138:1821. Decaux G, Waterlot Y, Genette F, Mockel J. Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with furosemide. N Engl J Med 1981;304:32930. Altman A. Acute tumor lysis syndrome. Semin Oncol 2001;28:38. Sallan S. Management of acute tumor lysis syndrome. Semin Oncol 2001;28:912. Smalley RV, Guaspari A, Haase-Statz S, Anderson SA, Cederberg D, Hohneker JA. Allopurinol: intravenous use for prevention and treatment of hyperuricemia. J Clin Oncol 2000;18:175863. Feusner J, Farber MS. Role of intravenous allopurinol in the management of acute tumor lysis syndrome. Semin Oncol 2001;28: 138. Goldman SC, Holcenberg JS, Finklestein JZ, et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 2001;97:29983003. Leach M, Parsons RM, Reilly JT, Wineld DA. Efcacy of urate oxidase (uricozyme) in tumour lysis induced urate nephropathy. Clin Lab Haematol 1998;20:16972. Hoff AO, Vassilopoulou-Sellin R. The role of glucagon administration in the diagnosis and treatment of patients with tumor hypoglycemia. Cancer 1998;82:158592. Cryer PE. Symptoms of hypoglycemia, thresholds for their occurrence, and hypoglycemia unawareness. Endocrinol Metab Clin North Am 1999;28, 495-500. [37] Sillos EM, Shenep JL, Burghen GA, Pui CH, Behm FG, Sandlund JT. Lactic acidosis: a metabolic complication of hematologic malignancies. Case report and review of the literature. Cancer 2001;2001(92):223746. [38] Naing KK, Dewar JA, Leese GP. Megestrol acetate therapy and secondary adrenal suppression. Cancer 1999;86:10449. [39] Kann P, Hengstermann C, Heussel CP, Bittinger F, Engelbach M, Beyer J. Endosonography of the adrenal glands: normal size pathological ndings. Exp Clin Endocrinol Diabetes 1998;106: 1239. [40] Kawashima A, Sandler CM, Fishman EK, et al. Spectrum of CT ndings in nonmalignant disease of the adrenal gland. Radiographics 1998;18:393412. [41] Gonzalez-Gonzalez JG, De la Garza-Hernandez NE, MancillasAdame LG, Montes-Villarreal J, Villarreal-Perez JZ. A highsensitivity test in the assessment of adrenocortical insufciency: 10 microg vs 250 microg cosyntropin dose assessment of adrenocortical insufciency. J Endocrinol 1998;159:27580.

[25]

[26]

[27]

[28]

[29] [30] [31]

Biographies Silvia Spinazz e is Board certied in Medical Oncology, currently employed as medical oncologist at Ospedale Regionale in Aosta, Italy. Dirk Schrijvers is employed as a medical oncologist at the Antwerp Oncological Centre, ZNA Middelheim, Antwerp, Belgium and is responsible for new drug development, head and neck cancer, urological cancer and supportive and palliative care. He is certied member of European Society of Medical Oncology (ESMO) and Belgian Society of Medical Oncology (BSMO). He is chairman of the Education and Training Committee of Federation of European Cancer Societies (FECS) and involved in the Educational Programme of ECCO 2005.

[32]

[33]

[34]

[35]

[36]

S. Spinazz e, D. Schrijvers / Critical Reviews in Oncology/Hematology xxx (2005) xxxxxx

11