Annals of Oncology 11: 1061-1065, 2000. 2000 Khmer Academic Publishers. Primed in the Netherlands.

Clinical case
Syndrome of inappropriate antidiuretic hormone associated with chemotherapy-induced tumour lysis in small-cell lung cancer: Case report and literature review
S. L.Vanhees,1 R. Paridaens2 & J. F.Vansteenkiste1
Departments of 'Pulmonology (Respiratory Oncology Unit), 2Oncology, University Hospital Gasthuisberg, Catholic University Leuven. Belgium

Summary

A patient with a small-cell lung cancer (SCLC) developed an asymptomatic hyponatremia, with all features of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), two days after the start of his first cycle of chemotherapy with vindesine, ifosfamide and cisplatin. Progression of the tumour with an increase in paraneoplastic SIADH, or drug-induced causes of hyponatremia, could be ruled out by his further clinical course. The event was interpreted as a consequence of ADH release during the initial tumour cell lysis after effective chemotherapy.

The occurrence of hyponatremia during the initial phase of chemotherapy for SCLC should be interpreted with caution. Although it is most commonly due to an increase in paraneoplastic ADH secretion reflecting ineffective therapy, it can also be due to release of ADH from malignant cells in the period of rapid tumour lysis, reflecting effective therapy. Based on this rare occurrence, a review of the aetiology, clinical findings, diagnosis, prognosis and treatment of SIADH in general is presented. Key words: hyponatremia, inappropriate ADH syndrome, review, small-cell-lung carcinoma, tumour lysis syndrome

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Introduction

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was first reported by Schwartz et al. in 1957 [1]. They described two patients with lung cancer, who developed unexplained hyponatremia due to renal sodium loss, and thought that production by the tumour of an ADH-like substance might be the responsible mechanism. The problem was reviewed by Bartter and Schwartz in 1967 [2]. Criteria for the definition of SIADH secretion are 1) hyponatremia with a serum sodium lower than 130 mEq/1; 2) plasma osmolality lower than 275 mOsm/kg; 3) urine osmolality higher than the plasma osmolality and above 500 mOsm/kg; 4) absence of clinical evidence of volume depletion; 5) normal renal and adrenal function; and 6) normal thyroid function [2]. SIADH has been reported in a variety of medical conditions including central nervous system and pulmonary disorders, and as a paraneoplastic phenomenon accompanying several malignancies. The tumour most frequently associated with SIADH is small-cell lung cancer (SCLC), but the syndrome may also occur in a variety of other carcinomas arising in the brain, prostate, bladder, pancreas, adrenal cortex, duodenum, head and neck, in mesothelioma, thymoma or sarcoma, and in Hodgkin's disease [3-6]. In tumour-associated SIADH, hyponatremia can most properly be alleviated by effective cancer treatment (tumour removal in operable cancer, radiotherapy and/

or chemotherapy in other cases). Otherwise it is difficult to treat, but water restriction can be of temporary help [7, 8]. Some drugs, especially thiazide diuretics, sulfonyl urea's and a number of cytotoxic drugs such as vincristine, vinblastine, cisplatin, cyclophosphamide and melphalan also have been shown to produce SIADH [3, 9, 10]. We report a case of hyponatremia following administration of the first course of chemotherapy in a previously untreated patient with SCLC. Case report A 62-year-old man with a history of a radical resection of a hypernephroma seven years ago, and a curative inferior lobectomy for a squamous-cell lung carcinoma one year ago, was admitted to the hospital with hemoptysis, anorexia and afivekg weight loss. Clinical examination was unremarkable. Initial electrolytes and renal function were entirely normal. Neuron specific enolase (NSE) was elevated (24.1 microgram/1, upper limit of normal: 12.5). Chest CT-scan showed a nodular opacity in the left hilum with mediastinal adenopathy. Fiberoptic bronchoscopy revealed a tumour in the left lower lobe and lingula. Pathologic examination of the biopsies showed SCLC (oat-cell carcinoma). Screening for distant metastases was negative (limited disease).

1062 Chemotherapy with vindesine, ifosfamide and cisplatin was started. Each infusion of cisplatin was accompanied by normal saline prehydration and a 5-HT3 antagonist. No other previous or concomitant medications were used. The day after the start of the chemotherapy, a hyponatremia (128 mEq/1) developed. The diagnosis of SIADH was confirmed by an elevated urine osmolality (590 mOsm/kg), a decreased serum osmolality (255 mOsm/kg) and an elevated urinary concentration of sodium. Fluid restriction (maximum 750 ml per day) was prescribed. Three weeks later, at the onset of the second chemotherapy cycle, the sodium was 118 mEq/1. The serum NSE fell to a normal value (4.6) (Figure 1). Response evaluation on chest X-ray showed clear tumour regression (Figure 2). A second course of vindesineifosfamide-cisplatin was administered. Radiological examination after two cycles confirmed the partial response. Electrolyte abnormalities were no longer present. Chemotherapy was continued up to six cycles. Serum sodium remained normal. A major partial remission was obtained. Therapy was completed by locoregional irradiation (39 Gy divided in 13 fractions of 3 Gy on the tumour, mediastinum and supraclavicular nodes). Comment to the case report A case of hyponatremia following the first course of chemotherapy in a previously untreated patient with SCLC is reported, with spontaneous resolution of hyponatremia during the second course. The occurrence of hyponatremia due to SIADH at initial diagnosis is a well known paraneoplastic feature of SCLC [3, 4, 11-13]. In our patient, however, electrolyte balance and renal function were perfectly normal at diagnosis. Hyponatremia due to SIADH can also occur after administration of cytotoxic drugs such as vincristine, vinblastine, cisplatin, cyclophosphamide and melphalan. In our patient, hyponatremia did not occur after repeated administration of the same chemotherapeutic agents in subsequent cycles. This strongly suggests that the cytotoxic medication per se was not responsible for the SIADH in our patient. We hypothesise that release of ADH from the malignant cells during the early tumour breakdown resulted in the transient hyponatremia. This event must be very rare. In a Medline search (using the terms 'inappropriate ADH syndrome', 'carcinoma, small-cell' and 'tumor lysis syndrome'), we retrieved a few individual reports of this phenomenon in other tumours such as one case after chemotherapy for acute myeloid leukaemia [14], one case after radiotherapy for bladder cancer [15], and two cases after chemotherapy for squamous-cell head-andneck-cancer [16]. The development of hyponatremia due to SIADH during the initial treatment of SCLC patients with a perfectly normal sodium balance at diagnosis is rare. In
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neuron specific enolase (ug/L)

start 1st

2nd

3rd

4th

5th

6th cycle

Figure 1. Evolution of the neuron specific enolase and serum sodium at diagnosis (start 1st cycle) and during subsequent treatment. Tablet Causes of SIADH.

Malignant tumours Small-cell lung cancer Other types Intrathoracic disorders Pulmonary infections Positive pressure ventilation Status asthmaticus Cystic fibrosis Pneumothorax Central nervous system disorders Brain tumours CNS infections Guillain-Barre syndrome Vascular disorders Drugs: cytotoxic agents Cisplatin Cyclophosphamide Melphalan Vinblastine Vincristine Drugs: others Carbamazepime Chlorpropamide Clofibrate Narcotics Sulfonyl urea's Thiazide diuretics Tricyclic antidepressants Exogenous vasopressin administration

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his review of 350 SCLC patients, List mentioned only one patient with a normal sodium at diagnosis, who subsequently developed a hyponatremia as low as 101 mEq/1 after one cycle of chemotherapy [4]. Although the phenomenon certainly must be very uncommon, it is important to be aware of this possibility. The occurrence of hyponatremia during SCLC treatment could be interpreted as an increase in paraneoplastic expression reflecting tumour progression, which could erroneously lead to discontinuation of effective chemotherapy. Etiology and clinical expression of SIADH SIADH is one of the most common causes of hyponatremia in hospitalised patients. It may occur in a variety

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Figure 2 (a) Chest X-ray at diagnosis shows a left hilar tumour and right paratracheal adenopathy (arrows); (b) after one cycle of chemotherapy, a normal mediastinal image and an important decrease of the left hilar mass is noted. The partial response was confirmed at the evaluation after two cycles.

of conditions (Table 1). The most frequent reports have been in patients with lung cancer, especially SCLC. In different studies, there is an occurrence of SIADH in SCLC of about 10% with a range of 1.3%-69% [3, 5, 8, 17-20], according to the different definitions of the syndrome. On the other hand, SCLC accounts for about 75% of the malignancies associated with SIADH. A broad spectrum of other malignant tumours have also been reported to cause this syndrome: primary brain tumours, haematological malignancies, intrathoracic non-pulmonary cancers, non-small-cell lung cancer, skin tumours, gastro-intestinal cancers, gynaecological cancers, breast cancer, prostate and bladder cancer, head and neck cancer, sarcomas, ... [3-6]. Several non-malignant intrathoracic disorders, such as pulmonary infections and conditions associated with changes in intrathoracic pressure can be accompanied by SIADH. Disorders of the central nervous system including mass lesions and vascular, infectious, or metabolic conditions can cause SIADH by increased secretion of vasopressin. A variety of drugs may enhance ADH-secretion or its action on the distant nephron [21]. Such effects have been described for cytotoxic agents (vincristine, vinblastine, cisplatin, melphalan, cyclophosphamide) and carbamazepine, chlorpropramide, clofibrate, narcotics, sulfonyl ureas, thiazide diuretics, oxytocine, and tricyclic antidepressants.

The signs and symptoms of SIADH depend on the degree of hyponatremia and the rate of development [3, 11,12]. In mild cases the complaints are usually fatigue, anorexia, nausea, diarrhoea and headache. When the serum sodium falls below 115 mEq/1, neurological symptoms occur: altered mental status, confusion, lethargy, psychosis, seizures, coma and occasionally death [11, 12]. In chronic disease the SIADH is mostly asymptomatic. In these patients, a largefluidintake can cause an acute symptomatic hyponatremia. Pathophysiology In SIADH there is an increased release of ADH which causes excessive water reabsorption in the collecting ducts and a resulting dilutional hyponatremia. There are 4 mechanisms for excessive ADH release: 1) ectopic ADH secretion (release by tumour tissue, infections, conditions with altered intrathoracic pressure such as pneumothorax or status asthmaticus...); 2) increased hypothalamic production of ADH-like substances in neurological disorders (infections, Guillain Barre syndrome, brain tumours); 3) administration of drugs (cytotoxic agents, carbamazepine, chlorpropramide, clofibrate, narcotics, sulfonyl ureas, thiazide diuretics, tri-

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cyclic antidepressants); and finally 4) administration of exogenous ADH or oxytocine [3, 22]. Diagnosis The medical history and physical examination can provide important clues to a correct diagnosis. The hallmarks of SIADH are hyponatremia, low plasma osmolality and a less than maximally diluted urine in the absence of volume depletion (Criteria of Bartter and Schwartz) [2]. Plasma ADH levels are usually elevated. Renal, adrenal and thyroid function are normal. A low serum uric acid is a common finding [23, 24]. Prognosis The prognosis of SIADH depends on the underlying cause. Drug-induced SIADH is rapidly and completely reversed by withdrawal of the causative agent. Effective treatment of infections (pulmonary or central nervous system infections) usually restores a normal sodium homeostasis [3, 11]. In SIADH due to malignancies, the correlation with the prognosis of the disease is not always clear and the results are controversial. Lokich et al. described a strong correlation with development of cerebral metastases [25], but this was not confirmed by others [4]. In a large series of SCLC patients, List found no correlation with histologic subtype, stage or other metastatic sites [4]. Harper et al. showed that the prognosis was better for patients without SIADH than those with the syndrome, especially in limited disease SCLC [8]. They hypothesised that SIADH is associated with tumours where drug resistance emerges quickly. In the Vanderbilt experience, however, no relationship was found between the presence of SIADH and the response to chemotherapy or overall survival [4]. less than 500 ml/day is usually sufficient to cause a gradual increase in serum sodium and decrease in symptoms. Patients with life-threatening symptoms such as coma or seizures may also be treated by infusion of hypertonic saline (200-300 ml of 5% saline) together with intravenous loop diuretics (furosemide) at a dose of 1 mg/kg. This treatment requires careful monitoring of urinary sodium and potassium with intravenous replacement of the appropriate amounts of sodium- and potassium chloride. Oral potassium chloride or potassium sparing diuretics like triamterene or amiloride are sometimes necessary to correct the potassium levels. Thiazide diuretics are contraindicated because they aggravate the hyponatremia [27]. Patients whose SIADH is refractory or unresponsive to fluid restriction or who are unable to comply, may be treated with drugs that interfere with ADH at the level of the renal collecting tubules by blocking ADH-induced cyclic adenosine monophosphate (cAMP). This action blocks ADH-dependent water retention and facilitates free water excretion. The result of this action is the development of a nephrogenic diabetes insipidus. Three drugs have this effect: diphenylhydantoin, dimethylchlortetracycline (demeclocycline) and lithium, of which demeclocycline is the most widely applied for this purpose. The recommended initial dose of demeclocycline is 600 mg daily [27-29]. The total dose is divided and given BID or TID. Demeclocycline is not useful for acute therapy: the onset of its effect starts after four to seven days. Significant side effects are gastrointestinal intolerance, phosphate diabetes, photosensivity, and most importantly renal toxicity. Urea has also been reported to be effective [27, 30]. The recommended dose is 30-60 grams daily, divided in three to four gifts a day, after the meals, and together with antacids. Ureum is contraindicated in patients with renal failure (serum creatinine more than 2 mg/dl and/ or urea more than 80 mg/dl), gastric ulcer and advanced liver disease (risk of hyperammonemia and hepatic encephalopathy). There must be an adequate intake of water to prevent a deficit of water. Ureum is cheap and can be given orally or intravenously. The most important side effects are headache and gastrointestinal irritation.

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Management of SIADH in cancer patients It is important to identify and correct the cause of the SIADH as quickly as possible [3]. Treatment depends on the rate by which the hyponatremia has developed (acute versus chronic), the serum sodium concentration, and the patients clinical condition (symptomatic versus asymptomatic). An acute symptomatic hyponatremia is a medical emergency that needs immediate attention. The correction however must be slow, since a rapid correction may cause brain damage, sometimes even development of brain demyelinating lesions (central pontine or extrapontine myelinolysis). The rate of correction should be no more than 0.5 mEq per litre per hour and the initial treatment should be halted when the serum sodium concentration is 125-130 mEq/1 [26, 27]. In individuals with symptomatic hyponatremia and serum sodium less than 130 mEq/1, fluid restriction to

Conclusion

SIADH is the most common cause of hyponatremia in hospitalised cancer patients. Attempts should be made to identify and correct the cause of SIADH as soon as possible. The criteria for diagnosis of SIADH should be used and the correct cause identified from the numerous possible differential diagnoses. The occurrence of hyponatremia during the initial phase of chemotherapy for SCLC, and other tumours, should be interpreted with caution. Most commonly, this is due to an increase in paraneoplastic ADH secretion, pointing to ineffective chemotherapy and tumour progression. In the early treatment phase, one should also include in the differential

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diagnosis the release of ADH from malignant cells in the period of rapid cell necrosis. Although the last event is far more rare, it is important to be aware of its possibility, since it points to effective chemotherapy.
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Received 26 October 1998; accepted 21 September 1999.

Correspondence to: J.Vansteenkiste, MD, PhD Department of Pulmonology (Respiratory Oncology Unit) University Hospital Gasthuisberg Herestraat 49 B-3000 Leuven Belgium E-mail: johan.vansteenkiste@uz.kuleuven.ac.be

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